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Kosheleva L, Koshelev D, Lagunas-Rangel FA, Levit S, Rabinovitch A, Schiöth HB. Disease-modifying pharmacological treatments of type 1 diabetes: Molecular mechanisms, target checkpoints, and possible combinatorial treatments. Pharmacol Rev 2025; 77:100044. [PMID: 40014914 PMCID: PMC11964952 DOI: 10.1016/j.pharmr.2025.100044] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2024] [Accepted: 01/10/2025] [Indexed: 03/01/2025] Open
Abstract
After a century of extensive scientific investigations, there is still no curative or disease-modifying treatment available that can provide long-lasting remission for patients diagnosed with type 1 diabetes (T1D). Although T1D has historically been regarded as a classic autoimmune disorder targeting and destroying pancreatic islet β-cells, significant research has recently demonstrated that β-cells themselves also play a substantial role in the disease's progression, which could explain some of the unfavorable clinical outcomes. We offer a thorough review of scientific and clinical insights pertaining to molecular mechanisms behind pathogenesis and the different therapeutic interventions in T1D covering over 20 possible pharmaceutical intervention treatments. The interventions are categorized as immune therapies, treatments targeting islet endocrine dysfunctions, medications with dual modes of action in immune and islet endocrine cells, and combination treatments with a broader spectrum of activity. We suggest that these collective findings can provide a valuable platform to discover new combinatorial synergies in search of the curative disease-modifying intervention for T1D. SIGNIFICANCE STATEMENT: This research delves into the underlying causes of T1D and identifies critical mechanisms governing β-cell function in both healthy and diseased states. Thus, we identify specific pathways that could be manipulated by existing or new pharmacological interventions. These interventions fall into several categories: (1) immunomodifying therapies individually targeting immune cell processes, (2) interventions targeting β-cells, (3) compounds that act simultaneously on both immune cell and β-cell pathways, and (4) combinations of compounds simultaneously targeting immune and β-cell pathways.
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Affiliation(s)
- Liudmila Kosheleva
- Department of Surgical Sciences, Functional Pharmacology and Neuroscience, Uppsala University, Uppsala, Sweden
| | - Daniil Koshelev
- Department of Surgical Sciences, Functional Pharmacology and Neuroscience, Uppsala University, Uppsala, Sweden
| | - Francisco Alejandro Lagunas-Rangel
- Department of Surgical Sciences, Functional Pharmacology and Neuroscience, Uppsala University, Uppsala, Sweden; Laboratory of Pharmaceutical Pharmacology, Latvian Institute of Organic Synthesis, Riga, Latvia
| | - Shmuel Levit
- Diabetes and Metabolism Institute, Assuta Medical Centers, Tel Aviv, Israel
| | | | - Helgi B Schiöth
- Department of Surgical Sciences, Functional Pharmacology and Neuroscience, Uppsala University, Uppsala, Sweden; Laboratory of Pharmaceutical Pharmacology, Latvian Institute of Organic Synthesis, Riga, Latvia.
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Ray S, Palui R. Immunotherapy in type 1 diabetes: Novel pathway to the future ahead. World J Diabetes 2024; 15:2022-2035. [PMID: 39493558 PMCID: PMC11525730 DOI: 10.4239/wjd.v15.i10.2022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2024] [Revised: 07/23/2024] [Accepted: 07/26/2024] [Indexed: 09/26/2024] Open
Abstract
Since the discovery of insulin over 100 years ago, the focus of research in the management of type 1 diabetes (T1D) has centered around glycemic control and management of complications rather than the prevention of autoimmune destruction of pancreatic β cells. Fortunately, in recent years, there has been significant advancement in immune-targeted pharmacotherapy to halt the natural progression of T1D. The immune-targeted intervention aims to alter the underlying pathogenesis of T1D by targeting different aspects of the immune system. The immunotherapy can either antagonize the immune mediators like T cells, B cells or cytokines (antibody-based therapy), or reinduce self-tolerance to pancreatic β cells (antigen-based therapy) or stem-cell treatment. Recently, the US Food and Drug Administration approved the first immunotherapy teplizumab to be used only in stage 2 of T1D. However, the window of opportunity to practically implement this approved molecule in the selected target population is limited. In this Editorial, we briefly discuss the various promising recent developments in the field of immunotherapy research in T1D. However, further studies of these newer therapeutic agents are needed to explore their true potential for prevention or cure of T1D.
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Affiliation(s)
- Sayantan Ray
- Department of Endocrinology, All India Institute of Medical Sciences, Bhubaneswar 751019, India
| | - Rajan Palui
- Department of Endocrinology, The Mission Hospital, Durgapur 713212, India
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Becker N, Pereyra D, Dingfelder J, Tortopis C, Saffarian Zadeh T, Riha M, Kacar S, Soliman T, Berlakovich GA, Györi G. Immunosuppressive Induction Therapy Using the Antithymocyteglobulin Grafalon: A Single-Center Non-Interventional Study. J Clin Med 2024; 13:4051. [PMID: 39064090 PMCID: PMC11277975 DOI: 10.3390/jcm13144051] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2024] [Revised: 07/07/2024] [Accepted: 07/08/2024] [Indexed: 07/28/2024] Open
Abstract
Background: Induction therapy with depleting antibodies in the setting of liver transplantation (LT) is discussed controversially to this day. The rabbit antithymocyteglobulin (ATG) Thymoglobulin (rATG) was introduced as early as 1984 and was frequently used as a standard regime for induction therapy after LT. There are no public reports characterizing Grafalon (ATG-F), a novel ATG, as an induction agent after LT. Objectives: The aim of this observational non-interventional study was to investigate the safety and efficacy of Grafalon induction therapy and characterize its clinical effects in the setting of LT. Methods: A cohort of 80 patients undergoing deceased donor LT at the Medical University of Vienna and receiving Grafalon as part of the clinical standard immunosuppressive regimen was prospectively included between March 2021 and November 2022. Patients were monitored closely for leukocytopenia and thrombocytopenia during the first postoperative week and followed up for incidence and severity of biopsy-proven acute rejection (BPAR), overall survival, and bacterial infections in the first year after LT. Results: The incidences of thrombocytopenia and leukocytopenia following Grafalon treatment peaked on postoperative day four, with 64% and 31%, respectively. However, there were no cases of severe leukocytopenia after the first postoperative week. Induction therapy with Grafalon resulted in a rate of localized bacterial infections and bacteremia of 28% and 21%, respectively. The rate of BPAR was 12.5% in the first year after LT; the one-year survival rate in this cohort was 90%. Conclusions: Overall, this study provides evidence of the safety and efficacy of Grafalon as an induction agent. Further studies investigating the potential long-term effects of Grafalon, as well as comparison studies with different immunosuppressive regimens, are needed in order to draw further conclusions.
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Affiliation(s)
- Nikolaus Becker
- Department of General Surgery, Division of Transplantation, Medical University of Vienna, 1090 Wien, Austria (T.S.); (G.A.B.); (G.G.)
| | - David Pereyra
- Department of General Surgery, Division of Transplantation, Medical University of Vienna, 1090 Wien, Austria (T.S.); (G.A.B.); (G.G.)
- Department of General Surgery, Division of Visceral Surgery, Medical University of Vienna, 1090 Wien, Austria
| | - Jule Dingfelder
- Department of General Surgery, Division of Transplantation, Medical University of Vienna, 1090 Wien, Austria (T.S.); (G.A.B.); (G.G.)
- Department of General Surgery, Division of Visceral Surgery, Medical University of Vienna, 1090 Wien, Austria
| | - Chiara Tortopis
- Department of General Surgery, Division of Transplantation, Medical University of Vienna, 1090 Wien, Austria (T.S.); (G.A.B.); (G.G.)
| | - Tina Saffarian Zadeh
- Department of General Surgery, Division of Transplantation, Medical University of Vienna, 1090 Wien, Austria (T.S.); (G.A.B.); (G.G.)
| | - Moriz Riha
- Department of General Surgery, Division of Transplantation, Medical University of Vienna, 1090 Wien, Austria (T.S.); (G.A.B.); (G.G.)
| | - Sertac Kacar
- Department of General Surgery, Division of Transplantation, Medical University of Vienna, 1090 Wien, Austria (T.S.); (G.A.B.); (G.G.)
| | - Thomas Soliman
- Department of General Surgery, Division of Transplantation, Medical University of Vienna, 1090 Wien, Austria (T.S.); (G.A.B.); (G.G.)
| | - Gabriela A. Berlakovich
- Department of General Surgery, Division of Transplantation, Medical University of Vienna, 1090 Wien, Austria (T.S.); (G.A.B.); (G.G.)
| | - Georg Györi
- Department of General Surgery, Division of Transplantation, Medical University of Vienna, 1090 Wien, Austria (T.S.); (G.A.B.); (G.G.)
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Giordano U, Mordak-Domagała M, Sobczyk-Kruszelnicka M, Giebel S, Gil L, Dudek KD, Dybko J. Comparing the Outcomes of Matched and Mismatched Unrelated Allogeneic Hematopoietic Stem Cell Transplantation with Different Anti-Thymocyte Globulin Formulations: A Retrospective, Double-Centre Experience on Behalf of the Polish Adult Leukemia Group. Cancers (Basel) 2024; 16:1891. [PMID: 38791969 PMCID: PMC11119435 DOI: 10.3390/cancers16101891] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2024] [Revised: 05/08/2024] [Accepted: 05/13/2024] [Indexed: 05/26/2024] Open
Abstract
Despite notable advancements in immunotherapy in the past decades, allogeneic hematopoietic stem cell transplantation (allo-HCT) remains a promising, potentially curative treatment modality. Only a limited number of studies have performed a direct comparison of two prevalent rabbit anti-thymocyte globulin (r-ATG) formulations-specifically, Thymoglobuline (ATG-T, formerly Genzyme) and Grafalon (ATG-G, formerly Fresenius). The primary objective of our retrospective analysis was to compare the outcomes of adult patients undergoing matched or mismatched unrelated donor (MUD/MMUD) allo-HCT, with a graft-versus-host disease (GvHD) prophylaxis based on either ATG-T or ATG-G. A total of 87 patients who had undergone allo-HCT between 2012 and 2022 were included. We observed no significant differences between ATG-T and ATG-G concerning the occurrence of acute graft-versus-host disease (aGvHD), regardless of its severity. Conversely, chronic graft-versus-host disease (cGvHD) occurred less frequently in the ATG-T group compared to the ATG-G group (7.5% vs. 38.3%, p = 0.001). The negative impact of ATG-G on cGvHD was confirmed by multivariate analysis (HR 8.12, 95% CI 2.06-32.0, p = 0.003). Patients treated with ATG-T manifested a higher incidence of cytomegalovirus (CMV) reactivations (70% vs. 31.9%, p < 0.001), with a shorter time between transplant and CMV (<61 days, 77.8% vs. 33.3%, p = 0.008) and a higher median CMV copy number (1000 vs. 0, p = 0.004). Notably, despite a higher occurrence of CMV reactivations in the ATG-T cohort, most patients were asymptomatic compared to ATG-G (85.7% vs. 43.8%, p = 0.005). By multivariate analysis, only aGvHD had an influence on CMV reactivations (HR 0.18, 95% CI 0.04-0.75, p = 0.019). Finally, we observed no significant differences in terms of 5-year overall survival (OS) and 3-year relapse-free survival (RFS) while comparing ATG-T and ATG-G (32.0% vs. 40.3%, p = 0.423; 66.7% vs. 60.4%, p = 0.544, respectively).
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Affiliation(s)
- Ugo Giordano
- Department and Clinic of Endocrinology, Diabetes and Isotope Therapy, 50-367 Wroclaw, Poland
| | - Monika Mordak-Domagała
- Lower Silesian Center of Oncology, Pulmonology and Hematology, 53-439 Wroclaw, Poland; (M.M.-D.); (J.D.)
| | | | - Sebastian Giebel
- Maria Sklodowska-Curie National Research Institute of Oncology, 44-102 Gliwice, Poland; (M.S.-K.); (S.G.)
| | - Lidia Gil
- Department of Hematology and Bone Marrow Transplantation, Poznan University of Medical Sciences, 61-701 Poznań, Poland;
| | - Krzysztof D. Dudek
- Faculty of Mechanical Engineering, Wroclaw University of Science and Technology, 50-370 Wroclaw, Poland;
| | - Jarosław Dybko
- Lower Silesian Center of Oncology, Pulmonology and Hematology, 53-439 Wroclaw, Poland; (M.M.-D.); (J.D.)
- Department of Oncology and Hematology, Faculty of Medicine, Wroclaw University of Science and Technology, 50-370 Wroclaw, Poland
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Acharya S, Lama S, Kanigicherla DA. Anti-thymocyte globulin for treatment of T-cell-mediated allograft rejection. World J Transplant 2023; 13:299-308. [PMID: 38174145 PMCID: PMC10758678 DOI: 10.5500/wjt.v13.i6.299] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2023] [Revised: 11/01/2023] [Accepted: 11/17/2023] [Indexed: 12/15/2023] Open
Abstract
Anti-thymocyte globulin (ATG) is a pivotal immunosuppressive therapy utilized in the management of T-cell-mediated rejection and steroid-resistant rejection among renal transplant recipients. Commercially available as Thymoglobulin (rabbit-derived, Sanofi, United States), ATG-Fresenius S (rabbit-derived), and ATGAM (equine-derived, Pfizer, United States), these formulations share a common mechanism of action centered on their interaction with cell surface markers of immune cells, imparting immunosuppressive effects. Although the prevailing mechanism predominantly involves T-cell depletion via the com plement-mediated pathway, alternate mechanisms have been elucidated. Optimal dosing and treatment duration of ATG have exhibited variance across ran domised trials and clinical reports, rendering the establishment of standardized guidelines a challenge. The spectrum of risks associated with ATG administration spans from transient adverse effects such as fever, chills, and skin rash in the acute phase to long-term concerns related to immunosuppression, including susceptibility to infections and malignancies. This comprehensive review aims to provide a thorough exploration of the current understanding of ATG, encom passing its mechanism of action, clinical utility in the treatment of acute renal graft rejections, specifically steroid-resistant cases, efficacy in rejection episode reversal, and a synthesis of findings from different eras of maintenance immunosuppression. Additionally, it delves into the adverse effects associated with ATG therapy and its impact on long-term graft function. Furthermore, the review underscores the existing gaps in evidence, particularly in the context of the Banff classification of rejections, and highlights the challenges faced by clinicians when navigating the available literature to strike the optimal balance between the risks and benefits of ATG utilization in renal transplantation.
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Affiliation(s)
- Sumit Acharya
- Department of Nephrology, Shahid Dharmabhakta National Transplant Center, Bhaktapur 44800, Nepal
| | - Suraj Lama
- Department of Nephrology, Shahid Dharmabhakta National Transplant Center, Bhaktapur 44800, Nepal
| | - Durga Anil Kanigicherla
- Department of Renal Medicine, Manchester University NHS Foundation Trust, Manchester M13 9WL, United Kingdom
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Wang L, Kong P, Zhang C, Gao L, Zhu L, Liu J, Gao S, Chen T, Liu H, Yao H, Liu Y, Feng Y, Zhao L, Li Y, Gao L, Zhang X. Outcomes of patients with hematological malignancies who undergo unrelated donor hematopoietic stem cell transplantation with ATG-Fresenius versus ATG-Genzyme. Ann Hematol 2023; 102:1569-1579. [PMID: 37097455 PMCID: PMC10182153 DOI: 10.1007/s00277-023-05220-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2022] [Accepted: 04/07/2023] [Indexed: 04/26/2023]
Abstract
To compare the outcomes of patients with hematological malignancies who received ATG-Fresenius (ATG-F) 20 mg/kg versus those who received ATG-Genzyme (ATG-G) 10 mg/kg in an unrelated donor hematopoietic stem cell transplantation (HSCT) procedure, a total of 186 patients who underwent their first allogeneic HSCT with an unrelated donor were retrospectively analyzed. One hundred and seven patients received ATG-F, and seventy-nine patients received ATG-G. Multivariate analysis showed that the type of ATG preparation had no effect on neutrophil engraftment (P = 0.61), cumulative incidence of relapse (P = 0.092), nonrelapse mortality (P = 0.44), grade II-IV acute graft-versus-host disease (GVHD) (P = 0.47), chronic GVHD (P = 0.29), overall survival (P = 0.795), recurrence-free survival (P = 0.945) or GVHD-free relapse-free survival (P = 0.082). ATG-G was associated with a lower risk of extensive chronic GVHD and a higher risk of cytomegaloviremia (P = 0.01 and HR = 0.41, P < 0.001 and HR = 4.244, respectively). The results of this study suggest that the preparation of rabbit ATG used for unrelated HSCT should be selected based on the incidence of extensive chronic GVHD of each center, and the posttransplant management strategy should be adjusted according to the ATG preparation.
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Affiliation(s)
- Lu Wang
- Medical Center of Hematology, Xinqiao Hospital, Army Medical University, Chongqing, China
| | - Peiyan Kong
- Medical Center of Hematology, Xinqiao Hospital, Army Medical University, Chongqing, China
| | - Cheng Zhang
- Medical Center of Hematology, Xinqiao Hospital, Army Medical University, Chongqing, China
| | - Li Gao
- Medical Center of Hematology, Xinqiao Hospital, Army Medical University, Chongqing, China
| | - Lidan Zhu
- Medical Center of Hematology, Xinqiao Hospital, Army Medical University, Chongqing, China
| | - Jia Liu
- Medical Center of Hematology, Xinqiao Hospital, Army Medical University, Chongqing, China
| | - Shichun Gao
- Medical Center of Hematology, Xinqiao Hospital, Army Medical University, Chongqing, China
| | - Ting Chen
- Medical Center of Hematology, Xinqiao Hospital, Army Medical University, Chongqing, China
| | - Huanfeng Liu
- Medical Center of Hematology, Xinqiao Hospital, Army Medical University, Chongqing, China
| | - Han Yao
- Medical Center of Hematology, Xinqiao Hospital, Army Medical University, Chongqing, China
| | - Yuqing Liu
- Medical Center of Hematology, Xinqiao Hospital, Army Medical University, Chongqing, China
| | - Yimei Feng
- Medical Center of Hematology, Xinqiao Hospital, Army Medical University, Chongqing, China
| | - Lu Zhao
- Medical Center of Hematology, Xinqiao Hospital, Army Medical University, Chongqing, China
| | - Yuxia Li
- Medical Center of Hematology, Xinqiao Hospital, Army Medical University, Chongqing, China
| | - Lei Gao
- Medical Center of Hematology, Xinqiao Hospital, Army Medical University, Chongqing, China.
| | - Xi Zhang
- Medical Center of Hematology, Xinqiao Hospital, Army Medical University, Chongqing, China
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Habib JG, Liu D, Crepeau RM, Wagener ME, Ford ML. Selective CD28 blockade impacts T cell differentiation during homeostatic reconstitution following lymphodepletion. Front Immunol 2023; 13:1081163. [PMID: 36761170 PMCID: PMC9904166 DOI: 10.3389/fimmu.2022.1081163] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Accepted: 12/28/2022] [Indexed: 01/26/2023] Open
Abstract
Introduction Costimulation blockade targeting the CD28 pathway provides improved long-term renal allograft survival compared to calcineurin inhibitors but may be limited as CTLA-4-Ig (abatacept, belatacept) blocks both CD28 costimulation and CTLA-4 coinhibition. Directly targeting CD28 while leaving CTLA-4 intact may provide a mechanistic advantage. Fc-silent non-crosslinking CD28 antagonizing domain antibodies (dAb) are currently in clinical trials for renal transplantation. Given the current standard of care in renal transplantation at most US centers, it is likely that lymphodepletion via thymoglobulin induction therapy could be used in patients treated with CD28 antagonists. Thus, we investigated the impact of T cell depletion (TCD) on T cell phenotype following homeostatic reconstitution in a murine model of skin transplantation treated with anti-CD28dAb. Methods Skin from BALB/cJ donors was grafted onto C56BL/6 recipients which were treated with or without 0.2mg anti-CD4 and 10μg anti-CD8 one day prior to transplant and with or without 100μg anti-CD28dAb on days 0, 2, 4, 6, and weekly thereafter. Mice were euthanized six weeks post-transplant and lymphoid cells were analyzed by flow cytometry. Results Anti-CD28dAb reversed lymphopenia-induced differentiation of memory CD4+ T cells in the spleen and lymph node compared to TCD alone. Mice treated with TCD+anti-CD28dAb exhibited significantly improved skin graft survival compared to anti-CD28dAb alone, which was also improved compared to no treatment. In addition, the expression of CD69 was reduced on CD4+ and CD8+ T cells in the spleen and lymph node from mice that received TCD+anti-CD28dAb compared to TCD alone. While a reduced frequency of CD4+FoxP3+ T cells was observed in anti-CD28dAb treated mice relative to untreated controls, this was balanced by an increased frequency of CD8+Foxp3+ T cells that was observed in the blood and kidney of mice given TCD+anti-CD28dAb compared to TCD alone. Discussion These data demonstrate that CD28 signaling impacts the differentiation of both CD4+ and CD8+ T cells during homeostatic reconstitution following lymphodepletion, resulting in a shift towards fewer activated memory T cells and more CD8+FoxP3+ T cells, a profile that may underpin the observed prolongation in allograft survival.
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Wu Y, Ni L, Liu Y, Yang L, Zhu P, Shi J, Wu Z, Zhao Y, Yu J, Lai X, Liu L, Fu H, Xie J, Huang H, Luo Y. Impact of Donor-to-Recipient ABO Mismatch on Outcomes of Antithymocyte Globulin-Based Peripheral Blood Stem Cell-Derived Myeloablative Conditioning Haploidentical Stem Cell Transplantation. Transplant Cell Ther 2022; 28:331.e1-331.e10. [PMID: 35231641 DOI: 10.1016/j.jtct.2022.02.020] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Revised: 02/18/2022] [Accepted: 02/21/2022] [Indexed: 01/05/2023]
Abstract
ABO incompatibility is common in hematopoietic stem cell transplantation (HSCT); however, the impact of donor-recipient ABO compatibility on transplantation outcomes in different HSCT settings is controversial. Moreover, haploidentical stem cell transplantation (haplo-SCT) with peripheral blood stem cell (PBSC)-derived grafts has not been well investigated. The present study aimed to investigate the impact of ABO incompatibility on post-transplantation outcomes, engraftment kinetics, blood product requirements, transfusion independence, and the incidence of poor graft function (PGF) in antithymocyte globulin (ATG)-based haplo-SCT with PBSC grafts during long-term follow-up. We prospectively evaluated 510 patients with hematologic malignancies who underwent haplo-SCT after myeloablative conditioning (MAC). The primary endpoint was overall survival (OS), and secondary endpoints were nonrelapse mortality (NRM), graft-versus-host disease (GVHD), relapse, neutrophil and platelet engraftment, blood transfusion requirements, transfusion independence, and the incidence of PGF. There was no significant association between ABO matching and OS, disease-free survival (DFS), relapse, NRM, grade II-IV acute GVHD, grade III-IV acute GVHD, and moderate and severe chronic GVHD. There were also no significant differences in neutrophil and platelet engraftment, blood transfusion independence, and transfusion requirements at 30, 60, 90, 180, and 365 days post-transplantation among patients with ABO matching and those with minor, major, or bidirectional ABO incompatibility. Donor-recipient ABO matching did not differ significantly according to graft function (good versus poor). ABO incompatibility status has no major impact on patient outcomes in patients with hematologic malignancies undergoing ATG-based MAC haplo-SCT with PBSC-derived grafts.
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Affiliation(s)
- Yibo Wu
- Bone Marrow Transplantation Center, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, China; Institute of Hematology, Zhejiang University, Hangzhou, China; Zhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy, Hangzhou, China
| | - Lihong Ni
- Department of Hematology, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yan Liu
- Department of Blood Transfusion, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Luxin Yang
- Bone Marrow Transplantation Center, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, China; Institute of Hematology, Zhejiang University, Hangzhou, China; Zhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy, Hangzhou, China
| | - Panpan Zhu
- Bone Marrow Transplantation Center, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, China; Institute of Hematology, Zhejiang University, Hangzhou, China; Zhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy, Hangzhou, China
| | - Jimin Shi
- Bone Marrow Transplantation Center, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, China; Institute of Hematology, Zhejiang University, Hangzhou, China; Zhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy, Hangzhou, China
| | - Zhuoping Wu
- Zhejiang University School of Medicine, Hangzhou, China
| | - Yanmin Zhao
- Bone Marrow Transplantation Center, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, China; Institute of Hematology, Zhejiang University, Hangzhou, China; Zhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy, Hangzhou, China
| | - Jian Yu
- Bone Marrow Transplantation Center, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, China; Institute of Hematology, Zhejiang University, Hangzhou, China; Zhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy, Hangzhou, China
| | - Xiaoyu Lai
- Bone Marrow Transplantation Center, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, China; Institute of Hematology, Zhejiang University, Hangzhou, China; Zhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy, Hangzhou, China
| | - Lizhen Liu
- Bone Marrow Transplantation Center, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, China; Institute of Hematology, Zhejiang University, Hangzhou, China; Zhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy, Hangzhou, China
| | - Huarui Fu
- Bone Marrow Transplantation Center, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, China; Institute of Hematology, Zhejiang University, Hangzhou, China; Zhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy, Hangzhou, China
| | - Jue Xie
- Department of Blood Transfusion, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - He Huang
- Bone Marrow Transplantation Center, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, China; Institute of Hematology, Zhejiang University, Hangzhou, China; Zhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy, Hangzhou, China
| | - Yi Luo
- Bone Marrow Transplantation Center, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, China; Institute of Hematology, Zhejiang University, Hangzhou, China; Zhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy, Hangzhou, China
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Martin F, Tullius SG. Immunosuppression after uterus transplantation. Curr Opin Organ Transplant 2021; 26:627-633. [PMID: 34581290 DOI: 10.1097/mot.0000000000000925] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
PURPOSE OF REVIEW Clinical uterus transplantation (UTx) is growing rapidly. The procedure represents the only therapy for women with absolute uterine factor infertility to give birth to a biological baby. Immunosuppression after UTx needs to carefully balance effects with the healthy mother and baby. Unique for UTx is the 'temporary' character of the procedure with a transplant hysterectomy being performed after delivery. Most of the practice on immunosuppression in UTx is currently based on the experience in solid organ transplantation (SOT). RECENT FINDINGS Clinical UTx-trials have been performed in centers worldwide during the recent years and experience on immunosuppression has accumulated. SUMMARY Immunosuppression in UTx has been successfully applied as maintenance treatment in addition to effectively treating acute T- and B-cell mediated rejections. Understanding the biology of UTx in more detail is expected to refine future approaches.
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Affiliation(s)
- Friederike Martin
- Department of General, Visceral and Transplant Surgery, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Stefan G Tullius
- Division of Transplant Surgery and Transplant Surgery Research Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
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10
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Bubik RJ, Dierkhising RA, Mara KC, Daly RC, Kushwaha SS, Clavell AL, Bernard SA. Malignancy among adult heart transplant recipients following patient-tailored dosing of anti-thymocyte globulin: a retrospective, nested case-control study of individualized dosing. Transpl Int 2021; 34:2175-2183. [PMID: 34411345 DOI: 10.1111/tri.14012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Revised: 07/22/2021] [Accepted: 08/13/2021] [Indexed: 11/29/2022]
Abstract
Post-transplant malignancy is diagnosed in approximately 18% of heart transplant patients and is a leading cause of death post-transplant. One modifiable risk factor is the type and amount of immunosuppression received. Contemporary rabbit anti-thymocyte globulin (rATG) dosing strategy using T-cell-guided dosing, and its effect on malignancy in heart transplant patients is unclear. This was a single-center, retrospective chart review of heart transplant recipients receiving rATG for induction. Patients diagnosed with malignancy post-transplant were matched 1:2 to controls using a nested case-control design. The primary endpoint was to determine the relative risk of rATG exposure with the actual incidence of malignancy post-transplant. The secondary endpoint was the impact of maintenance immunosuppression on malignancy risk. Of the 126 patients included in the study, 25 developed malignancy and were matched to 50 control patients. The median cumulative rATG dose in milligrams (mg) between groups was 365 mg in malignancy cases and 480 mg in controls (OR 0.90, 95% CI 0.75-1.08, P = 0.28). In both the univariate and multivariable analysis, there was no statistically significant difference in malignancy risk found with any maintenance immunosuppressant. The results of this study showed that patient-tailored rATG dosing strategies may not be associated with malignancy development as previously thought.
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Affiliation(s)
| | - Ross A Dierkhising
- Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, USA
| | - Kristin C Mara
- Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, USA
| | - Richard C Daly
- Division of Cardiovascular Surgery, Mayo Clinic, Rochester, MN, USA.,Divison of Transplantation Surgery, Mayo Clinic, Rochester, MN, USA
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11
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Azzopardi N, Longuet H, Ternant D, Thibault G, Gouilleux-Gruart V, Lebranchu Y, Büchler M, Gatault P, Paintaud G. Relationship Between Antithymocyte Globulin Concentrations and Lymphocyte Sub-Populations in Kidney Transplant Patients. Clin Pharmacokinet 2021; 61:111-122. [PMID: 34292526 DOI: 10.1007/s40262-021-01053-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/20/2021] [Indexed: 10/20/2022]
Abstract
BACKGROUND Rabbit antithymocyte globulins (rATGs) are polyclonal antibodies used to prevent acute cellular rejection in kidney transplantation. Their dosing remains largely empirical and the question of an individualized dose is still unresolved. METHODS Data from a prospective study in 17 kidney transplant patients were used to develop a model describing the dose-concentration-response relationship of rATG with T-lymphocyte subpopulation counts over time. The model was validated using an independent cohort of kidney transplant patients treated by rATG in the same center. RESULTS Pharmacokinetics of rATG was described using a two-compartment model integrating a third compartment and a target-mediated elimination for active rATG. The kinetics of CD3+, CD4+, CD8+, and CD3-CD56+ cell counts over time were described by a pharmacokinetic-pharmacodynamic model with transit compartments, integrating both CD3-CD56+-independent and CD3-CD56+-dependent rATG-mediated lymphocyte depletion, and a positive feedback. Elimination of rATG was influenced by age and body surface area, while its distribution was also influenced by body surface area. CD3+ proliferation rate decreased with age and CD3-CD56+-mediated elimination was influenced by the V158F-FCGR3A polymorphism. Binary efficacy and tolerance endpoints were defined as a CD3+ count < 20 mm-3 for at least 7 days and a CD4+ count > 200 mm-3 at 1 year, respectively. Simulations showed that increasing or decreasing the standard 6-mg/kg dose will impact both tolerance and efficacy, while a dose decrease may be beneficial in elderly patients. CONCLUSIONS Our results can be used to design prospective clinical trials testing dose individualization based on patients' characteristics. CLINICAL TRIAL REGISTRATION Eudract No. 2009-012673-35.
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Affiliation(s)
| | - Hélène Longuet
- Department of Nephrology and Clinical Immunology, CHRU de Tours, Tours, France
| | - David Ternant
- University of Tours, EA4245 T2I, Tours, France. .,Department of Medical Pharmacology, CHRU de Tours, 37044, Tours, France.
| | - Gilles Thibault
- University of Tours, EA7501 GICC, Tours, France.,Laboratory of Immunology, CHRU de Tours, Tours, France
| | - Valérie Gouilleux-Gruart
- University of Tours, EA7501 GICC, Tours, France.,Laboratory of Immunology, CHRU de Tours, Tours, France
| | | | - Matthias Büchler
- Department of Nephrology and Clinical Immunology, CHRU de Tours, Tours, France.,University of Tours, EA4245 T2I, Tours, France
| | - Philippe Gatault
- Department of Nephrology and Clinical Immunology, CHRU de Tours, Tours, France.,University of Tours, EA4245 T2I, Tours, France
| | - Gilles Paintaud
- University of Tours, EA4245 T2I, Tours, France.,Department of Medical Pharmacology, CHRU de Tours, 37044, Tours, France
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12
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Ruggenenti P, Cravedi P, Gotti E, Plati A, Marasà M, Sandrini S, Bossini N, Citterio F, Minetti E, Montanaro D, Sabadini E, Tardanico R, Martinetti D, Gaspari F, Villa A, Perna A, Peraro F, Remuzzi G. Mycophenolate mofetil versus azathioprine in kidney transplant recipients on steroid-free, low-dose cyclosporine immunosuppression (ATHENA): A pragmatic randomized trial. PLoS Med 2021; 18:e1003668. [PMID: 34166370 PMCID: PMC8224852 DOI: 10.1371/journal.pmed.1003668] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2020] [Accepted: 05/23/2021] [Indexed: 01/09/2023] Open
Abstract
BACKGROUND We compared protection of mycophenolate mofetil (MMF) and azathioprine (AZA) against acute cellular rejection (ACR) and chronic allograft nephropathy (CAN) in kidney transplant recipients on steroid-free, low-dose cyclosporine (CsA) microemulsion maintenance immunosuppression. METHODS AND FINDINGS ATHENA, a pragmatic, prospective, multicenter trial conducted by 6 Italian transplant centers, compared the outcomes of 233 consenting recipients of a first deceased donor kidney transplant induced with low-dose thymoglobulin and basiliximab and randomized to MMF (750 mg twice/day, n = 119) or AZA (75 to 125 mg/day, n = 114) added-on maintenance low-dose CsA microemulsion and 1-week steroid. In patients without acute clinical or subclinical rejections, CsA dose was progressively halved. Primary endpoint was biopsy-proven CAN. Analysis was by intention to treat. Participants were included between June 2007 and July 2012 and followed up to August 2016. Between-group donor and recipient characteristics, donor/recipient mismatches, and follow-up CsA blood levels were similar. During a median (interquartile range (IQR)) follow-up of 47.7 (44.2 to 48.9) months, 29 of 87 biopsied patients on MMF (33.3%) versus 31 of 88 on AZA (35.2%) developed CAN (hazard ratio (HR) [95% confidence interval (CI)]: 1.147 (0.691 to 1.904, p = 0.595). Twenty and 21 patients on MMF versus 34 and 14 on AZA had clinical [HR (95% CI): 0.58 (0.34 to 1.02); p = 0.057) or biopsy-proven subclinical [HR (95% CI): 1.49 (0.76 to 2.92); p = 0.249] ACR, respectively. Combined events [HR (95% CI): 0.85 (0.56 to 1.29); p = 0.438], patient and graft survival, delayed graft function (DGF), 3-year glomerular filtration rate (GFR) [53.8 (40.6;65.7) versus 49.8 (36.8;62.5) mL/min/1.73 m2, p = 0.50], and adverse events (AEs) were not significantly different between groups. Chronicity scores other than CAN predict long-term graft outcome. Study limitations include small sample size and unblinded design. CONCLUSIONS In this study, we found that in deceased donor kidney transplant recipients on low-dose CsA and no steroids, MMF had no significant benefits over AZA. This finding suggests that AZA, due to its lower costs, could safely replace MMF in combination with minimized immunosuppression. TRIAL REGISTRATION ClinicalTrials.gov NCT00494741; EUDRACT 2006-005604-14.
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Affiliation(s)
- Piero Ruggenenti
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
- Unit of Nephrology and Dialysis, ASST Papa Giovanni XXIII, Bergamo, Italy
| | - Paolo Cravedi
- Division of Nephrology, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America
| | - Eliana Gotti
- Unit of Nephrology and Dialysis, ASST Papa Giovanni XXIII, Bergamo, Italy
| | - Annarita Plati
- Unit of Nephrology and Dialysis, ASST Papa Giovanni XXIII, Bergamo, Italy
| | - Maddalena Marasà
- Unit of Nephrology and Dialysis, ASST Papa Giovanni XXIII, Bergamo, Italy
| | - Silvio Sandrini
- Unit of Nephrology, ASST degli Spedali Civili di Brescia, Brescia, Italy
| | - Nicola Bossini
- Unit of Nephrology, ASST degli Spedali Civili di Brescia, Brescia, Italy
| | - Franco Citterio
- Unit of Kidney Transplantation, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Roma, Italy
| | - Enrico Minetti
- Unit of Nephrology, ASST Grande Ospedale Metropolitano Niguarda, Milano, Italy
| | - Domenico Montanaro
- SOC di Nefrologia, Dialisi e Trapianto Renale della Azienda Ospedaliero Universitaria “S. Maria della Misericordia,” Udine, Italy
| | - Ettore Sabadini
- Unit of Nephrology and Dialysis, ASST Papa Giovanni XXIII, Bergamo, Italy
| | - Regina Tardanico
- Unit of Nephrology, ASST degli Spedali Civili di Brescia, Brescia, Italy
| | - Davide Martinetti
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
| | - Flavio Gaspari
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
| | - Alessandro Villa
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
| | - Annalisa Perna
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
| | - Francesco Peraro
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
| | - Giuseppe Remuzzi
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
- * E-mail:
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13
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Liu L, Xu G, Zhang Y, Jiao W, Lei M, Zhou H, Wang Q, Qiu H, Tang X, Han Y, Fu C, Jin Z, Chen S, Sun A, Miao M, Wu D. Comparison of 2 Different Rabbit Anti-Thymocyte Globulin (r-ATG) Preparations: Thymocyte r-ATG versus T Lymphoblast Cell Line r-ATG in Allogeneic Hematopoietic Stem Cell Transplantation for Acquired Severe Aplastic Anemia: Propensity Score-Matched Analysis. Transplant Cell Ther 2020; 27:186.e1-186.e3. [PMID: 32829081 DOI: 10.1016/j.bbmt.2020.08.020] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2020] [Revised: 07/21/2020] [Accepted: 08/14/2020] [Indexed: 11/27/2022]
Abstract
We retrospectively analyzed the outcomes of 214 patients with severe aplastic anemia (SAA) who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) with rabbit anti-thymocyte globulin (r-ATG) or ATG-Fresenius (ATG-F). Using propensity score matching, we performed a case-control study comparing 44 and 23 patients in the r-ATG and ATG-F groups, respectively. The median time was 11 versus 11 days (P = .368) for myeloid engraftment and 11 versus 13 days (P = .030) for platelet engraftment in the r-ATG and ATG-F groups, respectively. The r-ATG group showed a lower incidence of grade III to IV acute graft-versus-host disease (GVHD) than the ATG-F group (2.27% versus 17.39%, P = .026). Similar outcomes were observed between the r-ATG and ATG-F groups for infection rate (59.09% versus 56.52%, P = .840), grade II to IV acute GVHD (20.45% versus 21.74%, P = .948), overall incidence of chronic GVHD (26.83% versus 22.73%, P = .704), moderate to severe chronic GVHD (9.76% versus 13.64%, P = .648), and transplantation-related mortality (11.36% versus 4.35%, P = .614). There was no statistical difference in 5-year overall survival (86.40% versus 95.7%, P = .245); GVHD-free, failure-free survival (77.30% versus 78.30%, P = .986); or health-related quality of life (P > .05) between r-ATG and ATG-F.
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Affiliation(s)
- Limin Liu
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematolog, The First Affiliated Hospital of Soochow University, Institute of Blood and Marrow Transplantation of Soochow University, Suzhou, China
| | - Guofa Xu
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematolog, The First Affiliated Hospital of Soochow University, Institute of Blood and Marrow Transplantation of Soochow University, Suzhou, China; Department of Hematology, Fuling Central Hospital, Chongqing, China
| | - Yanming Zhang
- Department of Hematology, The Affiliated Huai'an Hospital of Xuzhou Medical University and The Second People's Hospital of Huai'an, Huai'an, Jiangsu Province, China
| | - Wenjing Jiao
- Department of Hematology, Xian Yang Central Hospital, Xianyang, Shanxi Province, China
| | - Meiqing Lei
- Department of Hematology in Haikou Municipal People's Hospital, Affiliated Haikou Hospital Xiangya School of Medicine Central South University, Haikou, Hainan Province, China
| | - Huifen Zhou
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematolog, The First Affiliated Hospital of Soochow University, Institute of Blood and Marrow Transplantation of Soochow University, Suzhou, China
| | - Qingyuan Wang
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematolog, The First Affiliated Hospital of Soochow University, Institute of Blood and Marrow Transplantation of Soochow University, Suzhou, China
| | - Huiying Qiu
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematolog, The First Affiliated Hospital of Soochow University, Institute of Blood and Marrow Transplantation of Soochow University, Suzhou, China
| | - Xiaowen Tang
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematolog, The First Affiliated Hospital of Soochow University, Institute of Blood and Marrow Transplantation of Soochow University, Suzhou, China
| | - Yue Han
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematolog, The First Affiliated Hospital of Soochow University, Institute of Blood and Marrow Transplantation of Soochow University, Suzhou, China
| | - Chengcheng Fu
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematolog, The First Affiliated Hospital of Soochow University, Institute of Blood and Marrow Transplantation of Soochow University, Suzhou, China
| | - Zhengming Jin
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematolog, The First Affiliated Hospital of Soochow University, Institute of Blood and Marrow Transplantation of Soochow University, Suzhou, China
| | - Suning Chen
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematolog, The First Affiliated Hospital of Soochow University, Institute of Blood and Marrow Transplantation of Soochow University, Suzhou, China
| | - Aining Sun
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematolog, The First Affiliated Hospital of Soochow University, Institute of Blood and Marrow Transplantation of Soochow University, Suzhou, China
| | - Miao Miao
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematolog, The First Affiliated Hospital of Soochow University, Institute of Blood and Marrow Transplantation of Soochow University, Suzhou, China
| | - Depei Wu
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematolog, The First Affiliated Hospital of Soochow University, Institute of Blood and Marrow Transplantation of Soochow University, Suzhou, China.
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14
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Khan T, Mirza I, Anwar N. Antithymocyte Globulin: Indiscriminate Use and Complications. Ann Transplant 2019; 24:605-607. [PMID: 31754089 PMCID: PMC6886324 DOI: 10.12659/aot.919655] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
Abstract
The safety profile of rATG is impressive, with its use in 40% of inductions in living donor transplants in the US, with a reduced incidence of acute rejection, a low incidence of CMV infections with universal prophylaxis and enabling steroid sparing regimes.
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Affiliation(s)
- Taqi Khan
- Kidney Transplant Surgery, Rehman Medical Institute, Peshawar, Pakistan
| | - Irfan Mirza
- Department of Nephrology and Transplantation, Rehman Medical Institute, Peshawar, Pakistan
| | - Nisar Anwar
- Department of Nephrology and Transplantation, Rehman Medical Institute, Peshawar, Pakistan
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15
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Lee CH, Gwon JG, Jung CW. Effectiveness of Thymoglobulin Induction Therapy in Kidney Transplant From Deceased Donor With Mild to Moderate Acute Kidney Injury. Transplant Proc 2019; 51:2611-2614. [PMID: 31474447 DOI: 10.1016/j.transproceed.2019.02.061] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2018] [Accepted: 02/06/2019] [Indexed: 10/26/2022]
Abstract
BACKGROUND The clinical benefit of rabbit antithymocyte globulin (Thymoglobulin) compared with basiliximab for induction therapy in kidney transplant (KT) resulting from acute kidney injury (AKI) donors remains controversial. In cases of severe AKI, the degree of kidney injury is too great to reveal influence of different induction therapies on clinical outcomes. We aimed to compare clinical outcomes of Thymoglobulin and basiliximab induction therapy in KTs from deceased donors (DDs) with mild to moderate AKI. METHODS We retrospectively studied 147 patients who received KTs from DDs between 2009 and 2017 in our center; 91 patients received kidneys from AKI donors. The AKI severity was classified based on the Acute Kidney Injury Network (AKIN) staging, and patients with AKIN stage 3 (43 patients) were excluded. Clinical outcomes were compared according to the type of induction therapy. RESULTS Thymoglobulin and basiliximab induction groups showed no significant differences in demographic and baseline characteristics except donor age and follow-up period. The Thymoglobulin group had lower incidences of acute rejection and a trend toward a lower incidence of delayed graft function and better graft survival than the basiliximab group. There was no significant difference in BK infection rate; however, cytomegalovirus infection rate showed a trend toward a lower incidence in the basiliximab group. CONCLUSIONS In cases of KT from AKIN stage 1 and 2 donors, Thymoglobulin showed better clinical outcomes than basiliximab, although it had a somewhat high rate of cytomegalovirus infection. It seems beneficial to use Thymoglobulin induction therapy in KTs from DDs with mild to moderate AKI.
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Affiliation(s)
- Chang Hun Lee
- Department of Transplantation and Vascular Surgery, Korea University College of Medicine, Seoul, Korea
| | - Jun Gyo Gwon
- Department of Transplantation and Vascular Surgery, Korea University College of Medicine, Seoul, Korea
| | - Cheol Woong Jung
- Department of Transplantation and Vascular Surgery, Korea University College of Medicine, Seoul, Korea.
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16
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Nanmoku K, Shinzato T, Kubo T, Shimizu T, Yagisawa T. Effect of Rabbit Antithymocyte Globulin on Acute and Chronic Active Antibody-Mediated Rejection After Kidney Transplantation. Transplant Proc 2019; 51:2602-2605. [PMID: 31324482 DOI: 10.1016/j.transproceed.2019.02.051] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2018] [Revised: 02/06/2019] [Accepted: 02/17/2019] [Indexed: 12/26/2022]
Abstract
BACKGROUND Rabbit antithymocyte globulin (rATG) induction is associated with reduction in the occurrence of de novo donor-specific antibody (DSA) and antibody-mediated rejection (AMR). Therefore, rATG administration is considered as a treatment for AMR. However, only a few studies have investigated the treatment of AMR with rATG after kidney transplantation. METHODS Between April 2013 and March 2018, 162 consecutive de novo kidney transplantations were performed with induction immunosuppressive therapy comprising tacrolimus, mycophenolate mofetil, methylprednisolone, and basiliximab. AMR was diagnosed on the basis of the presence of DSA and episode biopsy findings. For DSA-positive recipients, plasmapheresis was performed to remove DSA before rATG administration (1.5 mg/kg for 5 days). Patients treated with rATG against active AMR were retrospectively analyzed for graft function. RESULTS A total of 13 kidney transplant recipients developed active AMR within 302 days after transplantation. After rATG administration, the mean serum creatinine and urine protein levels significantly declined from 3.03 mg/dL to 1.68 mg/dL (P = .002) within 46 days and from 3.01 g/gCr to 0.54 g/gCr (P = .006) within 106 days, respectively. The peripheral blood lymphocyte count rapidly decreased after rATG administration and remained low for 12 months. With regard to adverse events, fever (84.6%), cytomegaloviremia (84.6%), thrombocytopenia (61.5%), anemia (30.8%), and neutropenia (15.4%) occurred within 3 months after rATG administration. CONCLUSIONS rATG improved graft function by suppressing peripheral blood lymphocytes in kidney transplant recipients with active AMR. The rATG administration as a treatment for active AMR may contribute to positive graft outcomes after kidney transplantation.
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Affiliation(s)
- Koji Nanmoku
- Surgical Branch, Institute of Kidney Diseases, Jichi Medical University Hospital, Shimotsuke, Japan.
| | - Takahiro Shinzato
- Surgical Branch, Institute of Kidney Diseases, Jichi Medical University Hospital, Shimotsuke, Japan
| | - Taro Kubo
- Surgical Branch, Institute of Kidney Diseases, Jichi Medical University Hospital, Shimotsuke, Japan
| | - Toshihiro Shimizu
- Surgical Branch, Institute of Kidney Diseases, Jichi Medical University Hospital, Shimotsuke, Japan
| | - Takashi Yagisawa
- Surgical Branch, Institute of Kidney Diseases, Jichi Medical University Hospital, Shimotsuke, Japan
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17
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Sun Y, Wei C, Cao C, Tan X, Zeng H, Luo Y, Chen L. New Strategy of Acute Graft-vs-Host Disease: Investigation of a Reduced Dose of Antithymocyte Globulin in Haploidentical Hematopoietic Stem Cell Transplantation. Transplant Proc 2019; 51:890-895. [PMID: 30979481 DOI: 10.1016/j.transproceed.2018.10.028] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2018] [Revised: 09/05/2018] [Accepted: 10/09/2018] [Indexed: 12/11/2022]
Abstract
Graft-vs-host disease (GVHD) is one of the biggest challenges in haploidentical hematopoietic stem cell transplantation. Antithymocyte globulins (ATGs) are widely used to overcome GVHD, but excessive immunosuppression increases the chances of relapse and infection following transplantation. No defined standard of the appropriate dose of ATG usage is recognized. The study included 11 patients who were treated with a reduced dose of ATG to prevent GVHD in haploidentical hematopoietic stem cell transplantation. A reduced dose of ATG-Thymoglobulin (total dose of 5 mg/kg) was used in the pretreatment protocol for 2 consecutive days. All patients had successful transplantation. The median time of neutrophil engraftment was 12 days. All chimerism tests passed on day 30, 60, and 90 post transplantation. None of the patients had acute GVHD, while only 2 patients had I to II degree chronic GVHD (18.2%). No transplantation-related deaths were observed. The current findings suggest that the reduced dose of ATG can effectively prevent the incidence of acute GVHD in haploidentical hematopoietic stem cell transplantation.
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Affiliation(s)
- Y Sun
- Department of Hematology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, P.R. China
| | - C Wei
- Department of Hematology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, P.R. China
| | - C Cao
- Department of Hematology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, P.R. China
| | - X Tan
- Department of Hematology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, P.R. China
| | - H Zeng
- Department of Hematology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, P.R. China
| | - Y Luo
- Department of Hematology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, P.R. China
| | - L Chen
- Department of Hematology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, P.R. China.
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18
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Soltermann Y, Heim D, Medinger M, Baldomero H, Halter JP, Gerull S, Arranto C, Passweg JR, Kleber M. Reduced dose of post-transplantation cyclophosphamide compared to ATG for graft-versus-host disease prophylaxis in recipients of mismatched unrelated donor hematopoietic cell transplantation: a single-center study. Ann Hematol 2019; 98:1485-1493. [DOI: 10.1007/s00277-019-03673-3] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2018] [Accepted: 03/17/2019] [Indexed: 01/08/2023]
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19
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Ritschl PV, Günther J, Hofhansel L, Kühl AA, Sattler A, Ernst S, Friedersdorff F, Ebner S, Weiss S, Bösmüller C, Weissenbacher A, Oberhuber R, Cardini B, Öllinger R, Schneeberger S, Biebl M, Denecke C, Margreiter C, Resch T, Aigner F, Maglione M, Pratschke J, Kotsch K. Graft Pre-conditioning by Peri-Operative Perfusion of Kidney Allografts With Rabbit Anti-human T-lymphocyte Globulin Results in Improved Kidney Graft Function in the Early Post-transplantation Period-a Prospective, Randomized Placebo-Controlled Trial. Front Immunol 2018; 9:1911. [PMID: 30197644 PMCID: PMC6117415 DOI: 10.3389/fimmu.2018.01911] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2018] [Accepted: 08/02/2018] [Indexed: 12/21/2022] Open
Abstract
Introduction: Although prone to a higher degree of ischemia reperfusion injury (IRI), the use of extended criteria donor (ECD) organs has become reality in transplantation. We therefore postulated that peri-operative perfusion of renal transplants with anti-human T-lymphocyte globulin (ATLG) ameliorates IRI and results in improved graft function. Methods: We performed a randomized, single-blinded, placebo-controlled trial involving 50 kidneys (KTx). Prior to implantation organs were perfused and incubated with ATLG (AP) (n = 24 kidney). Control organs (CP) were perfused with saline only (n = 26 kidney). Primary endpoint was defined as graft function reflected by serum creatinine at day 7 post transplantation (post-tx). Results: AP-KTx recipients illustrated significantly better graft function at day 7 post-tx as reflected by lower creatinine levels, whereas no treatment effect was observed after 12 months surveillance. During the early hospitalization phase, 16 of the 26 CP-KTx patients required dialysis during the first 7 days post-tx, whereas only 10 of the 24 AP-KTx patients underwent dialysis. No treatment-specific differences were detected for various lymphocytes subsets in the peripheral blood of patients. Additionally, mRNA analysis of 0-h biopsies post incubation with ATLG revealed no changes of intragraft inflammatory expression patterns between AP and CP organs. Conclusion: We here present the first clinical study on peri-operative organ perfusion with ATLG illustrating improved graft function in the early period post kidney transplantation. Clinical Trial Registration:www.ClinicalTrials.gov, NCT03377283
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Affiliation(s)
- Paul V Ritschl
- Department of Surgery, Charité-Universitätsmedizin Berlin, Berlin, Germany.,BIH Charité Clinical Scientist Program, Berlin Institute of Health, Berlin, Germany
| | - Julia Günther
- Department of Visceral, Center for Operative Medicine, Transplant and Thoracic Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | - Lena Hofhansel
- Department of Visceral, Center for Operative Medicine, Transplant and Thoracic Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | - Anja A Kühl
- iPATH.Berlin-Immunopathology for Experimental Models, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Arne Sattler
- Department of Surgery, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Stefanie Ernst
- Biostatistics Unit, Clinical Research Unit, Berlin Institute of Health, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | | | - Susanne Ebner
- Department of Visceral, Center for Operative Medicine, Transplant and Thoracic Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | - Sascha Weiss
- Department of Surgery, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Claudia Bösmüller
- Department of Visceral, Center for Operative Medicine, Transplant and Thoracic Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | - Annemarie Weissenbacher
- Department of Visceral, Center for Operative Medicine, Transplant and Thoracic Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | - Rupert Oberhuber
- Department of Visceral, Center for Operative Medicine, Transplant and Thoracic Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | - Benno Cardini
- Department of Visceral, Center for Operative Medicine, Transplant and Thoracic Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | - Robert Öllinger
- Department of Visceral, Center for Operative Medicine, Transplant and Thoracic Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | - Stefan Schneeberger
- Department of Visceral, Center for Operative Medicine, Transplant and Thoracic Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | - Matthias Biebl
- Department of Visceral, Center for Operative Medicine, Transplant and Thoracic Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | - Christian Denecke
- Department of Visceral, Center for Operative Medicine, Transplant and Thoracic Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | - Christian Margreiter
- Department of Visceral, Center for Operative Medicine, Transplant and Thoracic Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | - Thomas Resch
- Department of Visceral, Center for Operative Medicine, Transplant and Thoracic Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | - Felix Aigner
- Department of Surgery, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Manuel Maglione
- Department of Visceral, Center for Operative Medicine, Transplant and Thoracic Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | - Johann Pratschke
- Department of Surgery, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Katja Kotsch
- Department of Surgery, Charité-Universitätsmedizin Berlin, Berlin, Germany
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20
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Abstract
Mechanisms of rejection, new pharmacologic approaches, and genomic medicine are major foci for current research in transplantation. It is hoped that these new agents and personalized immunosuppression will provide for less toxic regimens that are effective in preventing both acute and chronic allograft rejection. Until new agents are available, practitioners must use various combinations of currently approved agents to find the best regimens for improved long-term outcomes.
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Affiliation(s)
- Curtis D Holt
- Clinical Research Program, UCLA Department of Surgery, Dumont-UCLA Transplant Center, David Geffen School of Medicine at UCLA, 650 CE Young Drive South, Room 77-123CHS, Los Angeles, CA 90095-7054, USA.
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21
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Abstract
Liver transplantation outcomes have significantly improved over the past few decades owing largely to the introduction of effective immunosuppression medications. Further comprehension of the unique immune microenvironment of the liver has led to the development of newer molecular targeted therapeutics. Understanding the mechanism of action and adverse effect profiles of these medications is crucial for appropriate management of posttransplant patients. In this review, the author describes the immunologic response elicited by liver transplantation, chronicles the various immunosuppressant drug classes, discusses the evidence behind their use, and evaluates the management of special subpopulations of posttransplantation patients.
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Affiliation(s)
- Renumathy Dhanasekaran
- Division of Gastroenterology and Hepatology, Stanford University, 750 Welch Road, Suite 210, Palo Alto, CA 94304, USA.
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22
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Ruan V, Czer LSC, Awad M, Kittleson M, Patel J, Arabia F, Esmailian F, Ramzy D, Chung J, De Robertis M, Trento A, Kobashigawa JA. Use of Anti-Thymocyte Globulin for Induction Therapy in Cardiac Transplantation: A Review. Transplant Proc 2017; 49:253-259. [PMID: 28219580 DOI: 10.1016/j.transproceed.2016.11.034] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2016] [Accepted: 11/16/2016] [Indexed: 01/20/2023]
Abstract
The most common causes of death after heart transplantation (HTx) include acute rejection and multi-organ failure in the early period and malignancy and cardiac allograft vasculopathy (CAV) in the late period. Polyclonal antibody preparations such as rabbit anti-thymocyte globulin (ATG) may reduce early acute rejection and the later occurrence of CAV after HTx. ATG therapy depletes T cells, modulates adhesion and cell-signaling molecules, interferes with dendritic cell function, and induces B-cell apoptosis and regulatory and natural killer T-cell expansion. Evidence from animal studies and from retrospective clinical studies in humans indicates that ATG can be used to delay calcineurin inhibitor (CNI) exposure after HTx, thus benefiting renal function, and to reduce the incidence of CAV and ischemia-reperfusion injury in the transplanted heart. ATG may reduce de novo antibody production after HTx. ATG does not appear to increase cytomegalovirus infection rates with longer prophylaxis (6-12 months). In addition, ATG may reduce the risk of lymphoproliferative disease and does not appear to confer an additive effect on acquiring lymphoma after HTx. Randomized, controlled trials may provide stronger evidence of ATG association with patient survival, graft rejection, renal protection through delayed CNI initiation, as well as other benefits. It can also help establish optimal dosing and patient criteria to maximize treatment benefits.
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Affiliation(s)
- V Ruan
- Division of Cardiology, Cedars-Sinai Medical Center, and Cedars-Sinai Heart Institute, Los Angeles, California
| | - L S C Czer
- Division of Cardiology, Cedars-Sinai Medical Center, and Cedars-Sinai Heart Institute, Los Angeles, California.
| | - M Awad
- Division of Cardiology, Cedars-Sinai Medical Center, and Cedars-Sinai Heart Institute, Los Angeles, California
| | - M Kittleson
- Division of Cardiology, Cedars-Sinai Medical Center, and Cedars-Sinai Heart Institute, Los Angeles, California
| | - J Patel
- Division of Cardiology, Cedars-Sinai Medical Center, and Cedars-Sinai Heart Institute, Los Angeles, California
| | - F Arabia
- Division of Cardiothoracic Surgery, Cedars-Sinai Medical Center, and Cedars-Sinai Heart Institute, Los Angeles, California
| | - F Esmailian
- Division of Cardiothoracic Surgery, Cedars-Sinai Medical Center, and Cedars-Sinai Heart Institute, Los Angeles, California
| | - D Ramzy
- Division of Cardiothoracic Surgery, Cedars-Sinai Medical Center, and Cedars-Sinai Heart Institute, Los Angeles, California
| | - J Chung
- Division of Cardiothoracic Surgery, Cedars-Sinai Medical Center, and Cedars-Sinai Heart Institute, Los Angeles, California
| | - M De Robertis
- Division of Cardiothoracic Surgery, Cedars-Sinai Medical Center, and Cedars-Sinai Heart Institute, Los Angeles, California
| | - A Trento
- Division of Cardiothoracic Surgery, Cedars-Sinai Medical Center, and Cedars-Sinai Heart Institute, Los Angeles, California
| | - J A Kobashigawa
- Division of Cardiology, Cedars-Sinai Medical Center, and Cedars-Sinai Heart Institute, Los Angeles, California
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23
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Botsis T, Foster M, Arya N, Kreimeyer K, Pandey A, Arya D. Application of Natural Language Processing and Network Analysis Techniques to Post-market Reports for the Evaluation of Dose-related Anti-Thymocyte Globulin Safety Patterns. Appl Clin Inform 2017; 8:396-411. [PMID: 28447098 PMCID: PMC6241747 DOI: 10.4338/aci-2016-10-ra-0169] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2016] [Accepted: 02/15/2017] [Indexed: 11/23/2022] Open
Abstract
OBJECTIVE To evaluate the feasibility of automated dose and adverse event information retrieval in supporting the identification of safety patterns. METHODS We extracted all rabbit Anti-Thymocyte Globulin (rATG) reports submitted to the United States Food and Drug Administration Adverse Event Reporting System (FAERS) from the product's initial licensure in April 16, 1984 through February 8, 2016. We processed the narratives using the Medication Extraction (MedEx) and the Event-based Text-mining of Health Electronic Records (ETHER) systems and retrieved the appropriate medication, clinical, and temporal information. When necessary, the extracted information was manually curated. This process resulted in a high quality dataset that was analyzed with the Pattern-based and Advanced Network Analyzer for Clinical Evaluation and Assessment (PANACEA) to explore the association of rATG dosing with post-transplant lymphoproliferative disorder (PTLD). RESULTS Although manual curation was necessary to improve the data quality, MedEx and ETHER supported the extraction of the appropriate information. We created a final dataset of 1,380 cases with complete information for rATG dosing and date of administration. Analysis in PANACEA found that PTLD was associated with cumulative doses of rATG >8 mg/kg, even in periods where most of the submissions to FAERS reported low doses of rATG. CONCLUSION We demonstrated the feasibility of investigating a dose-related safety pattern for a particular product in FAERS using a set of automated tools.
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Affiliation(s)
- Taxiarchis Botsis
- Taxiarchis Botsis, Office of Biostatistics & Epidemiology | Center for Biologics Evaluation and Research | FDA, 10903 New Hampshire Ave, WO71 - 1232, Silver Spring, MD 20993-0002, E-mail:
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24
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Burkhalter F, Schaub S, Bucher C, Gürke L, Bachmann A, Hopfer H, Dickenmann M, Steiger J, Binet I. A Comparison of Two Types of Rabbit Antithymocyte Globulin Induction Therapy in Immunological High-Risk Kidney Recipients: A Prospective Randomized Control Study. PLoS One 2016; 11:e0165233. [PMID: 27855166 PMCID: PMC5113896 DOI: 10.1371/journal.pone.0165233] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2016] [Accepted: 10/04/2016] [Indexed: 11/18/2022] Open
Abstract
Background Induction treatment with rabbit polyclonal antithymocyte globulins (ATGs) is frequent used in kidney transplant recipients with donorspecific HLA antibodies and shows acceptable outcomes. The two commonly used ATGs, Thymoglobulin and ATG-F have slightly different antigen profile and antibody concentrations. The two compounds have never been directly compared in a prospective trial in immunological high-risk recipients. Therefore we performed a prospective randomized controlled study comparing the two compounds in immunological high-risk kidney recipients in terms of safety and efficacy. Methods Immunological high-risk kidney recipients, defined as the presence of HLA DSA but negative CDC-B and T-cell crossmatches were randomized 1:1 to receive ATG-F or Thymoglobulin. Maintenance immunosuppressive therapy consisted of tacrolimus, mycophenolate mofetil and steroids. Results The per-protocol analysis included 35 patients. There was no immediate infusion reaction observed with both compounds. No PTLD or malignancy occurred during the follow-up in both groups. The incidence of viral and bacterial infections was similar in both groups (p = 0.62). The cumulative incidence of clinical and subclinical antibody mediated allograft rejection as well as T-cell mediated allograft rejection during the first year between ATG-F and Thymoglobulin was similar (35% versus 19%; p = 0.30 and 11% versus 18%; 0.54 respectively). The two-year graft function was similar with a median eGFR of 56 ml/min/1.73m2 (range 21–128) (ATG-F-group) and 51 ml/min/1.73m2 (range 22–132) (Thymo-group) (p = 0.69). Conclusion We found no significant differences between the compared study drugs for induction treatment in immunological high-risk patients regarding safety and efficacy during follow-up with good allograft function at 2 years after transplantation.
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Affiliation(s)
- F Burkhalter
- Clinic for Transplant Immunology and Nephrology, University Hospital Basel, Basel, Switzerland
| | - S Schaub
- Clinic for Transplant Immunology and Nephrology, University Hospital Basel, Basel, Switzerland
| | - Ch Bucher
- Nephrology and Transplantation Medicine, Kantonsspital St Gallen, St Gallen, Switzerland
| | - L Gürke
- Department of Vascular and Transplant Surgery, University Hospital Basel, Basel, Switzerland
| | - A Bachmann
- Department of Urology, Basel University Hospital, Basel, Switzerland
| | - H Hopfer
- Institute for Pathology, University Hospital Basel, Basel, Switzerland
| | - M Dickenmann
- Clinic for Transplant Immunology and Nephrology, University Hospital Basel, Basel, Switzerland
| | - J Steiger
- Clinic for Transplant Immunology and Nephrology, University Hospital Basel, Basel, Switzerland
| | - I Binet
- Nephrology and Transplantation Medicine, Kantonsspital St Gallen, St Gallen, Switzerland
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25
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Abstract
Immunosuppression strategies that selectively inhibit effector T cells while preserving and even enhancing CD4FOXP3 regulatory T cells (Treg) permit immune self-regulation and may allow minimization of immunosuppression and associated toxicities. Many immunosuppressive drugs were developed before the identity and function of Treg were appreciated. A good understanding of the interactions between Treg and immunosuppressive agents will be valuable to the effective design of more tolerable immunosuppression regimens. This review will discuss preclinical and clinical evidence regarding the influence of current and emerging immunosuppressive drugs on Treg homeostasis, stability, and function as a guideline for the selection and development of Treg-friendly immunosuppressive regimens.
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Affiliation(s)
- Akiko Furukawa
- Department of Surgery, University of California, San Francisco, San Francisco, CA, United States
| | - Steven A Wisel
- Department of Surgery, University of California, San Francisco, San Francisco, CA, United States
| | - Qizhi Tang
- Department of Surgery, University of California, San Francisco, San Francisco, CA, United States
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26
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Pan H, Gazarian A, Mollet I, Mathias V, Dubois V, Sobh M, Buff S, Dubernard JM, Michallet M, Michallet MC. Lymphodepletive effects of rabbit anti-pig thymocyte globulin in neonatal swines. Transpl Immunol 2016; 39:74-83. [DOI: 10.1016/j.trim.2016.08.005] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2016] [Revised: 08/18/2016] [Accepted: 08/20/2016] [Indexed: 12/29/2022]
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27
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Ruggeri A, Sun Y, Labopin M, Bacigalupo A, Lorentino F, Arcese W, Santarone S, Gülbas Z, Blaise D, Messina G, Ghavamzadeh A, Malard F, Bruno B, Diez-Martin JL, Koc Y, Ciceri F, Mohty M, Nagler A. Post-transplant cyclophosphamide versus anti-thymocyte globulin as graft- versus-host disease prophylaxis in haploidentical transplant. Haematologica 2016; 102:401-410. [PMID: 27758821 DOI: 10.3324/haematol.2016.151779] [Citation(s) in RCA: 104] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2016] [Accepted: 09/30/2016] [Indexed: 11/09/2022] Open
Abstract
Severe graft-versus-host disease is a major barrier for non-T-cell-depleted haploidentical stem cell transplantation. There is no consensus on the optimal graft-versus-host disease prophylaxis. This study compared the two most commonly used graft-versus-host disease prophylaxis regimens (post-transplant cyclophosphamide-based vs. the anti-thymocyte globulin-based) in adults with acute myeloid leukemia reported to the European Society for Blood and Bone Marrow Transplantation. A total of 308 patients were analyzed; 193 received post-transplant cyclophosphamide-based regimen and 115 anti-thymocyte globulin-based regimen as anti-graft-versus-host disease prophylaxis. The post-transplant cyclophosphamide-based regimen was more likely to be associated to bone marrow as graft source (60% vs. 40%; P=0.01). Patients in the post-transplant cyclophosphamide-based regimen group had significantly less grade 3-4 acute graft-versus-host disease than those in the anti-thymocyte globulin-based group (5% vs. 12%, respectively; P=0.01), comparable to chronic graft-versus-host disease. Multivariate analysis showed that non-relapse mortality was lower in the post-transplant cyclophosphamide-based regimen group [22% vs. 30%, Hazard ratio (HR) 1.77(95%CI: 1.09-2.86); P=0.02] with no difference in relapse incidence. Patients receiving post-transplant cyclophosphamide-based regimen had better graft-versus-host disease-free, relapse-free survival [HR 1.45 (95%CI: 1.04-2.02); P=0.03] and leukemia-free survival [HR 1.48 (95%CI: 1.03-2.12); P=0.03] than those in the anti-thymocyte globulin-based group. In the multivariate analysis, there was also a trend for a higher overall survival [HR 1.43 (95%CI: 0.98-2.09); P=0.06] for post-transplant cyclophosphamide-based regimen versus the anti-thymocyte globulin-based group. Notably, center experience was also associated with non-relapse mortality and graft-versus-host disease-free, relapse-free survival. Haplo-SCT using a post-transplant cyclophosphamide-based regimen can achieve better leukemia-free survival and graft-versus-host disease-free, relapse-free survival, lower incidence of graft-versus-host disease and non-relapse mortality as compared to anti-thymocyte globulin-based graft-versus-host disease prophylaxis in patients with acute myeloid leukemia.
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Affiliation(s)
- Annalisa Ruggeri
- Service d'Hématologie et Thérapie Cellulaire, Hôpital Saint Antoine, AP-HP, Paris, France
| | - Yuqian Sun
- Peking University People's Hospital, Peking University Institute of Hematology, Beijing, China
| | - Myriam Labopin
- Service d'Hématologie et Thérapie Cellulaire, Hôpital Saint Antoine, AP-HP, Paris, France.,INSERM, UMRs 938, Paris, France
| | | | | | - William Arcese
- Tor Vergata University, Stem Cell Transplant Unit, Policlinico Universitario Tor Vergata, Rome, Italy
| | - Stella Santarone
- Ospedale Civile Dipartimento di Ematologia, Medicina Trasfusionale e Biotecnologie, Pescara, Italy
| | - Zafer Gülbas
- Anadolu Medical Center Hospital, Bone Marrow Transplantation Department, Kocaeli, Turkey
| | - Didier Blaise
- Programme de Transplantation & Therapie Cellulaire, Institut Paoli Calmettes, Marseille, France
| | - Giuseppe Messina
- Centro Unico Regionale Trapianti, Alberto Neri, Bianchi-Melacrino-Morelli, Reggio Calabria, Italy
| | | | - Florent Malard
- Service d'Hématologie et Thérapie Cellulaire, Hôpital Saint Antoine, AP-HP, Paris, France
| | - Benedetto Bruno
- A.O.U Citta della Salute e della Scienza di Torino, Presidio Molinette, Torino, Italy
| | - Jose Luis Diez-Martin
- Instituto de Investigacion Sanitaria Gregorio Marañon, Division of Hematology, Hospital Gregorio Marañon, Madrid, Spain
| | - Yener Koc
- Medical Park Hospitals, Stem Cell Transplant Unit, Antalya, Turkey
| | - Fabio Ciceri
- Ospedale San Raffaele, Haematology and BMT, Milano, Italy
| | - Mohamad Mohty
- Service d'Hématologie et Thérapie Cellulaire, Hôpital Saint Antoine, AP-HP, Paris, France.,INSERM, UMRs 938, Paris, France.,Université Pierre et Marie Curie, Paris, France
| | - Arnon Nagler
- Université Pierre et Marie Curie, Paris, France.,Division of Hematology and Bone Marrow Transplantation, The Chaim Sheba Medical Center, Tel-Hashomer, Ramat-Gan, Israel; Tel Aviv University (TAU), Israel.,EBMT Paris Office, Hospital Saint Antoine, Paris, France
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28
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Rekers NV, de Fijter J, Claas FH, Eikmans M. Mechanisms and risk assessment of steroid resistance in acute kidney transplant rejection. Transpl Immunol 2016; 38:3-14. [DOI: 10.1016/j.trim.2016.07.005] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2016] [Accepted: 07/28/2016] [Indexed: 12/15/2022]
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29
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Stevens RB, Wrenshall LE, Miles CD, Farney AC, Jie T, Sandoz JP, Rigley TH, Osama Gaber A. A Double-Blind, Double-Dummy, Flexible-Design Randomized Multicenter Trial: Early Safety of Single- Versus Divided-Dose Rabbit Anti-Thymocyte Globulin Induction in Renal Transplantation. Am J Transplant 2016; 16:1858-67. [PMID: 26696251 PMCID: PMC5069643 DOI: 10.1111/ajt.13659] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2015] [Revised: 11/11/2015] [Accepted: 11/29/2015] [Indexed: 01/25/2023]
Abstract
A previous nonblinded, randomized, single-center renal transplantation trial of single-dose rabbit anti-thymocyte globulin induction (SD-rATG) showed improved efficacy compared with conventional divided-dose (DD-rATG) administration. The present multicenter, double-blind/double-dummy STAT trial (Single dose vs. Traditional Administration of Thymoglobulin) evaluated SD-rATG versus DD-rATG induction for noninferiority in early (7-day) safety and tolerability. Ninety-five patients (randomized 1:1) received 6 mg/kg SD-rATG or 1.5 mg/kg/dose DD-rATG, with tacrolimus-mycophenolate maintenance immunosuppression. The primary end point was a composite of fever, hypoxia, hypotension, cardiac complications, and delayed graft function. Secondary end points included 12-month patient survival, graft survival, and rejection. Target enrollment was 165 patients with an interim analysis scheduled after 80 patients. Interim analysis showed primary end point noninferiority of SD-rATG induction (p = 0.6), and a conditional probability of <1.73% of continued enrollment producing a significant difference (futility analysis), leading to early trial termination. Final analysis (95 patients) showed no differences in occurrence of primary end point events (p = 0.58) or patients with no, one, or more than one event (p = 0.81), or rejection, graft, or patient survival (p = 0.78, 0.47, and 0.35, respectively). In this rigorously blinded trial in adult renal transplantation, we have shown SD-rATG induction to be noninferior to DD-rATG induction in early tolerability and equivalent in 12-month safety. (Clinical Trials.gov #NCT00906204.).
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Affiliation(s)
- R. B. Stevens
- Department of SurgeryWright State UniversityDaytonOH
| | | | - C. D. Miles
- Department of Internal MedicineUniversity of Nebraska Medical CenterOmahaNE
| | - A. C. Farney
- Department of SurgeryWake Forest UniversityWinston‐SalemNC
| | - T. Jie
- Department of SurgeryUniversity of ArizonaTucsonAZ
| | - J. P. Sandoz
- Department of SurgeryWright State UniversityDaytonOH
| | - T. H. Rigley
- Department of SurgeryWright State UniversityDaytonOH
| | - A. Osama Gaber
- Houston Methodist Research InstituteHouston Methodist HospitalHoustonTX
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30
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Lee Y, Butani L, Glaser N, Nguyen S. Resolution of Graves' disease after renal transplantation. Pediatr Transplant 2016; 20:590-593. [PMID: 27106887 DOI: 10.1111/petr.12709] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/15/2016] [Indexed: 01/13/2023]
Abstract
We report a case of an adolescent boy with Down's syndrome and ESRD on hemodialysis who developed mild Graves' disease that was not amenable to radioablation, surgery, or ATDs. After 14 months of observation without resolution of Graves' disease, he successfully received a DDRT with a steroid minimization protocol. Thymoglobulin and a three-day course of steroids were used for induction and he was started on tacrolimus, MMF, and pravastatin for maintenance transplant immunosuppression. One month after transplantation, all biochemical markers and antibody profiling for Graves' disease had resolved and remain normal one yr later.
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Affiliation(s)
| | - Lavjay Butani
- Section of Nephrology, Department of Pediatrics, University of California, Davis, Sacramento, CA, USA
| | - Nicole Glaser
- Section of Endocrinology, Department of Pediatrics, University of California, Davis, Sacramento, CA, USA
| | - Stephanie Nguyen
- Section of Nephrology, Department of Pediatrics, University of California, Davis, Sacramento, CA, USA
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31
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Khan A, Nasr P, El-Charabaty E, El-Sayegh S. An Insight Into the Immunologic Events and Risk Assessment in Renal Transplantation. J Clin Med Res 2016; 8:367-72. [PMID: 27081421 PMCID: PMC4817575 DOI: 10.14740/jocmr2411w] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/18/2015] [Indexed: 12/30/2022] Open
Abstract
Organ transplantation has always been considered to be the optimal therapeutic intervention in patients with end-stage organ failure. In the US, approximately 615,000 patients are diagnosed with end-stage renal disease and less than 30% have received a kidney transplant. One of the crucial drawbacks in successful renal transplantation is allograft rejection. Survival rates among transplant recipients have greatly improved due to better understanding of transplant biology and more effective immunosuppressive agents. Post-transplant immune monitoring and optimization of the immunosuppressive therapy using non-invasive biomarkers can effectively predict impending graft rejection and may spare the need for renal biopsy. This article provides an insight into the immunomodulations of renal transplant recipients. It depicts the immune system including several types of kidney rejection and reviews the biomarkers that may serve in near future, as surveillance tools for graft monitoring. Finally, a summary on the main immunosuppressive drugs used in kidney transplant both in the induction and maintenance phases is also covered.
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Affiliation(s)
- Asif Khan
- Department of Medicine, Staten Island University Hospital, 475 Seaview Ave., Staten Island, NY 10305, USA
| | - Patricia Nasr
- Department of Medicine, Staten Island University Hospital, 475 Seaview Ave., Staten Island, NY 10305, USA
| | - Elie El-Charabaty
- Department of Nephrology, Staten Island University Hospital, 475 Seaview Ave., Staten Island, NY 10305, USA
| | - Suzanne El-Sayegh
- Department of Nephrology, Staten Island University Hospital, 475 Seaview Ave., Staten Island, NY 10305, USA
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Vacha M, Gommer J, Rege A, Sanoff S, Sudan D, Harris M. Effects of Ideal Versus Total Body Weight Dosage of Rabbit Antithymocyte Globulin on Outcomes of Kidney Transplant Patients With High Immunologic Risk. EXP CLIN TRANSPLANT 2016; 14:511-517. [PMID: 26742693 DOI: 10.6002/ect.2015.0197] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
OBJECTIVES The optimal dose of rabbit antithymocyte globulin induction therapy in kidney transplant recipients with high immunologic risk lacks consensus. The purpose of this study was to evaluate the effect of using ideal body weight rather than total body weight for the weight-based dose calculations in this patient population. MATERIALS AND METHODS Data were retrospectively collected on 89 adult patients who received rabbit antithymocyte globulin induction therapy for high immunologic risk kidney transplant. Hospital protocol changed from the use of cumulative rabbit antithymocyte globulin doses of 7.5 mg/kg total body weight to 7.5 mg/kg ideal body weight in 2009. Patients were separated into 2 cohorts based on the amount of rabbit antithymocyte globulin (in mg/kg total body weight) received. Rate of biopsy-proven acute rejection, patient survival, and allograft function were evaluated at 90 days and 1 year after transplant. Cost of induction therapy was also evaluated. RESULTS Baseline demographics were predominantly similar between the 2 cohorts. No significant difference in maintenance immunosuppression was identified. Rates of biopsy-proven acute rejection at 90 days and 1 year were similar between ideal and total body weight cohorts (4.2% vs 0% at 90 days, P = .5; 8.7% vs 0% at 1 year, P = .13). Patient survival and allograft function were also similar. Median cost of rabbit antithymocyte globulin induction therapy per patient was lower in the ideal body weight cohort, but this difference was not statistically significant ($17 542 vs $19 934; P = .3). CONCLUSIONS Our results suggest that use of ideal body weight for dose calculations of rabbit antithymocyte globulin induction therapy in high immunologic risk kidney transplant recipients at 7.5 mg/kg results in low rates of acute rejection with a safety profile similar to that shown with a total body weight dosage. Use of ideal body weight for lower cumulative doses may still need further evaluation in this patient population.
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Affiliation(s)
- Mary Vacha
- From the Department of Pharmacy, Duke University Hospital, Durham, North Carolina, USA
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De Pietri L, Serra V, Preziosi G, Rompianesi G, Begliomini B. Perioperative effects of high doses of intraoperative thymoglobulin induction in liver transplantation. World J Transplant 2015; 5:320-328. [PMID: 26722660 PMCID: PMC4689943 DOI: 10.5500/wjt.v5.i4.320] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2015] [Revised: 10/06/2015] [Accepted: 11/25/2015] [Indexed: 02/05/2023] Open
Abstract
AIM: To describe our single-centre experience in liver transplantation (LT) with the infusion of high perioperative thymoglobulin doses. The optimal dosage and timing of thymoglobulin® [antithymocyte globulin (ATG)] administration during LT remains controversial. Cytokine release syndrome, haemolytic anaemia, thrombocytopenia, neutropenia, fever and serum sickness are potential adverse effects associated with ATG infusion.
METHODS: Between December 2009 and December 2010, 16 adult non-randomized patients (ATG group), receiving a liver graft from a deceased donor, received an intraoperative infusion (4-6 h infusion) of thymoglobulin (3 mg/kg, ATG: Thymoglobuline®). These patients were compared (case control approach) with 16 patients who had a liver transplant without ATG treatment (control group) to evaluate the possible effects of intraoperative ATG infusion. The matching parameters were: Sex, recipient age (± 5 years), LT indication including viral status, MELD score (± 5 points), international normalized ratio and platelet count (as close as possible). The exclusion criteria for both groups included the following: Multi-organ or living donor transplant, immunosuppressive therapy before transplantation, contraindications to the administration of any thymocyte globulin, human immunodeficiency virus seropositivity, thrombocytopenia [platelet < 50000/μL] or leukopenia [white blood cells < 1000/μL]. The perioperative side effects (haemodynamic alterations, core temperature variations, colloids and crystalloids requirements, and surgical time) possibly related to ATG infusion and the thromboelastographic (TEG) evaluation of the ATG effects on coagulation, blood loss and blood product transfusion were analysed during the operation and the first three postoperative days.
RESULTS: Intraoperative ATG administration was associated with longer surgical procedures [560 ± 88 min vs 480 ± 83 min (control group), P = 0.013], an intraoperative core temperature more than 37 °C (50% of ATG patients vs 6.2% of control patients, P = 0.015), major intraoperative blood loss [3953 ± 3126 mL vs 1419 ± 940 mL (control group), P = 0.05], higher red blood cell [2092 ± 1856 mL ATG group vs 472 ± 632 mL (control group), P = 0.02], fresh frozen plasma [671 ± 1125 mL vs 143 ± 349 mL (control group), P = 0.015], and platelet [374 ± 537 mL vs 15.6 ± 62.5 mL (control group), P = 0.017] transfusion, and a higher requirement for catecholamines (0.08 ± 0.07 μg/kg per minutes vs 0.01 ± 0.38 μg/kg per minutes, respectively, in the ATG and control groups) for haemodynamic support. The TEG tracings changed to a straight line during ATG infusion (preanhepatic and anhepatic phases) in 81% of the patients from the ATG group compared to 6.25% from the control group (P < 0.001). Patients from the ATG group compared to controls had higher post-op core temperatures (38 °C ± 1.0 °C vs 37.3 °C ± 0.5 °C; P = 0.02), an increased need of noradrenaline (43.7% vs 6.25%, P = 0.037), received more platelet transfusions (31.5% vs 0%, P = 0.04) and required continuous renal replacement therapy (4 ATG patients vs none in the control group; P = 0.10). ATG infusion was considered the cause of a fatal anaphylactic shock and of a suspected adverse reaction that led to intravascular haemolysis and acute renal failure.
CONCLUSION: The side effects and the coagulation imbalance observed in patients receiving a high dosage of ATG suggest caution in the use of thymoglobulin during LT.
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Stevens RB, Foster KW, Miles CD, Kalil AC, Florescu DF, Sandoz JP, Rigley TH, Malik T, Wrenshall LE. A Randomized 2x2 Factorial Clinical Trial of Renal Transplantation: Steroid-Free Maintenance Immunosuppression with Calcineurin Inhibitor Withdrawal after Six Months Associates with Improved Renal Function and Reduced Chronic Histopathology. PLoS One 2015; 10:e0139247. [PMID: 26465152 PMCID: PMC4605789 DOI: 10.1371/journal.pone.0139247] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2015] [Accepted: 09/08/2015] [Indexed: 12/28/2022] Open
Abstract
INTRODUCTION The two most significant impediments to renal allograft survival are rejection and the direct nephrotoxicity of the immunosuppressant drugs required to prevent it. Calcineurin inhibitors (CNI), a mainstay of most immunosuppression regimens, are particularly nephrotoxic. Until less toxic antirejection agents become available, the only option is to optimize our use of those at hand. AIM To determine whether intensive rabbit anti-thymocyte globulin (rATG) induction followed by CNI withdrawal would individually or combined improve graft function and reduce graft chronic histopathology-surrogates for graft and, therefore, patient survival. As previously reported, a single large rATG dose over 24 hours was well-tolerated and associated with better renal function, fewer infections, and improved patient survival. Here we report testing whether complete CNI discontinuation would improve renal function and decrease graft pathology. METHODS Between April 20, 2004 and 4-14-2009 we conducted a prospective, randomized, non-blinded renal transplantation trial of two rATG dosing protocols (single dose, 6 mg/kg vs. divided doses, 1.5 mg/kg every other day x 4; target enrollment = 180). Subsequent maintenance immunosuppression consisted of tacrolimus, a CNI, and sirolimus, a mammalian target of rapamycin inhibitor. We report here the outcome of converting patients after six months either to minimized tacrolimus/sirolimus or mycophenolate mofetil/sirolimus. Primary endpoints were graft function and chronic histopathology from protocol kidney biopsies at 12 and 24 months. RESULTS CNI withdrawal (on-treatment analysis) associated with better graft function (p <0.001) and lower chronic histopathology composite scores in protocol biopsies at 12 (p = 0.003) and 24 (p = 0.013) months, without affecting patient (p = 0.81) or graft (p = 0.93) survival, or rejection rate (p = 0.17). CONCLUSION CNI (tacrolimus) withdrawal at six months may provide a strategy for decreased nephrotoxicity and improved long-term function in steroid-free low immunological risk renal transplant patients. TRIAL REGISTRATION ClinicalTrials.gov NCT00556933.
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Affiliation(s)
- R. Brian Stevens
- Department of Surgery, Wright State University Boonshoft School of Medicine, Dayton, Ohio, United States of America
- * E-mail:
| | - Kirk W. Foster
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska, United States of America
| | - Clifford D. Miles
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska, United States of America
| | - Andre C. Kalil
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska, United States of America
| | - Diana F. Florescu
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska, United States of America
| | - John P. Sandoz
- Department of Surgery, Wright State University Boonshoft School of Medicine, Dayton, Ohio, United States of America
| | - Theodore H. Rigley
- Department of Surgery, Wright State University Boonshoft School of Medicine, Dayton, Ohio, United States of America
| | - Tamer Malik
- Department of Surgery, Wright State University Boonshoft School of Medicine, Dayton, Ohio, United States of America
| | - Lucile E. Wrenshall
- Department of Surgery, Wright State University Boonshoft School of Medicine, Dayton, Ohio, United States of America
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Lin K, Chen S, Chen G. Role of Memory T Cells and Perspectives for Intervention in Organ Transplantation. Front Immunol 2015; 6:473. [PMID: 26441978 PMCID: PMC4568416 DOI: 10.3389/fimmu.2015.00473] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2015] [Accepted: 08/31/2015] [Indexed: 12/12/2022] Open
Abstract
Memory T cells are necessary for protective immunity against invading pathogens, especially under conditions of immunosuppression. However, their presence also threatens transplant survival, making transplantation a great challenge. Significant progress has been achieved in recent years in advancing our understanding of the role that memory T cells play in transplantation. This review focuses on the latest advances in our understanding of the involvement of memory T cells in graft rejection and transplant tolerance and discusses potential strategies for targeting memory T cells in order to minimize allograft rejection and optimize clinical outcomes.
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Affiliation(s)
- Kailin Lin
- Institute of Organ Transplantation, Tongji Hospital, Huazhong University of Science and Technology , Wuhan , China
| | - Song Chen
- Institute of Organ Transplantation, Tongji Hospital, Huazhong University of Science and Technology , Wuhan , China ; Key Laboratory of Organ Transplantation, Ministry of Education , Wuhan , China ; Key Laboratory of Organ Transplantation, Ministry of Public Health , Wuhan , China
| | - Gang Chen
- Institute of Organ Transplantation, Tongji Hospital, Huazhong University of Science and Technology , Wuhan , China ; Key Laboratory of Organ Transplantation, Ministry of Education , Wuhan , China ; Key Laboratory of Organ Transplantation, Ministry of Public Health , Wuhan , China
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36
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Huang W, Yu L, Cao T, Li Y, Liu Z, Li H, Bo J, Zhao Y, Jing Y, Wang S, Zhu H, Dou L, Wang Q, Gao C. The efficacy and safety of rabbit anti-thymocyte globulin vs rabbit anti-T-lymphocyte globulin in peripheral blood stem cell transplantation from unrelated donors. Leuk Lymphoma 2015; 57:355-363. [PMID: 26118935 DOI: 10.3109/10428194.2015.1045901] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
The comparative efficacy and safety of antithymocyte globulin (ATG) at fixed doses in patients undergoing allogeneic peripheral blood stem cell transplantation from unrelated donors (UR-PBSCT) has not been evaluated. In this study, the records of 56 patients and 54 patients who received pre-transplant ATG-Thymoglobulin (ATG-T) at a total dose of 10 mg/kg and ATG- Fresenius (ATG-F) at a total dose of 20 mg/kg, respectively, were retrospectively analyzed. ATG-F patients had a significantly lower probability of developing chronic graft-vs-host disease (cGVHD) than those treated with ATG-T (p = 0.04). ATG-F was associated with a non-significant trend towards lower relapse rates and higher survival at 3- and 5-years of follow-up compared with ATG-T. A significantly greater proportion of ATG-T patients experienced chills and high fever than ATG-F patients (p < 0.01). The current findings suggest that ATG-F may more effectively and safely prevent cGVHD without increasing relapse rates in patients undergoing UR-PBSCT.
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Affiliation(s)
- Wenrong Huang
- a Department of Hematology and BMT , Chinese PLA General Hospital , Beijing , PR China.,b Department of Hematology , Hainan Branch of Chinese PLA General Hospital , Hainan province , PR China
| | - Li Yu
- a Department of Hematology and BMT , Chinese PLA General Hospital , Beijing , PR China
| | - Tingting Cao
- a Department of Hematology and BMT , Chinese PLA General Hospital , Beijing , PR China
| | - Yanfen Li
- a Department of Hematology and BMT , Chinese PLA General Hospital , Beijing , PR China
| | - Zhanxiang Liu
- a Department of Hematology and BMT , Chinese PLA General Hospital , Beijing , PR China
| | - Honghua Li
- a Department of Hematology and BMT , Chinese PLA General Hospital , Beijing , PR China
| | - Jian Bo
- a Department of Hematology and BMT , Chinese PLA General Hospital , Beijing , PR China
| | - Yu Zhao
- a Department of Hematology and BMT , Chinese PLA General Hospital , Beijing , PR China
| | - Yu Jing
- a Department of Hematology and BMT , Chinese PLA General Hospital , Beijing , PR China
| | - Shuhong Wang
- a Department of Hematology and BMT , Chinese PLA General Hospital , Beijing , PR China
| | - Haiyan Zhu
- a Department of Hematology and BMT , Chinese PLA General Hospital , Beijing , PR China
| | - Liping Dou
- a Department of Hematology and BMT , Chinese PLA General Hospital , Beijing , PR China
| | - Qunshun Wang
- a Department of Hematology and BMT , Chinese PLA General Hospital , Beijing , PR China
| | - Chunji Gao
- a Department of Hematology and BMT , Chinese PLA General Hospital , Beijing , PR China
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Couzi L, Manook M, Perera R, Shaw O, Ahmed Z, Kessaris N, Dorling A, Mamode N. Difference in outcomes after antibody-mediated rejection between abo-incompatible and positive cross-match transplantations. Transpl Int 2015; 28:1205-15. [PMID: 26095452 DOI: 10.1111/tri.12621] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2015] [Revised: 04/07/2015] [Accepted: 06/08/2015] [Indexed: 02/06/2023]
Abstract
Graft survival seems to be worse in positive cross-match (HLAi) than in ABO-incompatible (ABOi) transplantation. However, it is not entirely clear why these differences exist. Sixty-nine ABOi, 27 HLAi and 10 combined ABOi+HLAi patients were included in this retrospective study, to determine whether the frequency, severity and the outcome of active antibody-mediated rejection (AMR) were different. Five-year death-censored graft survival was better in ABOi than in HLAi and ABOi+HLAi patients (99%, 69% and 64%, respectively, P = 0.0002). Features of AMR were found in 38%, 95% and 100% of ABOi, HLAi and ABOi+HLAi patients that had a biopsy, respectively (P = 0.0001 and P = 0.001). After active AMR, a declining eGFR and graft loss were observed more frequently in HLAi and HLAi+ABOi than in ABOi patients. The poorer prognosis after AMR in HLAi and ABOi+HLAi transplantations was not explained by a higher severity of histological lesions or by a less aggressive treatment. In conclusion, ABOi transplantation offers better results than HLAi transplantation, partly because AMR occurs less frequently but also because outcome after AMR is distinctly better. HLAi and combined ABOi+HLAi transplantations appear to have the same outcome, suggesting there is no synergistic effect between anti-A/B and anti-HLA antibodies.
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Affiliation(s)
- Lionel Couzi
- Department of Transplantation, Guy's and St Thomas' NHS Foundation Trust, London, UK
| | - Miriam Manook
- Department of Transplantation, Guy's and St Thomas' NHS Foundation Trust, London, UK.,Medical Research Council Centre for Transplantation, King's College London, London, UK
| | - Ranmith Perera
- Department of Histopathology, Guy's and St Thomas' NHS Foundation Trust, London, UK
| | - Olivia Shaw
- Clinical Transplant Laboratory, Guy's and St Thomas' NHS Foundation Trust, London, UK
| | - Zubir Ahmed
- Department of Transplantation, Guy's and St Thomas' NHS Foundation Trust, London, UK.,Medical Research Council Centre for Transplantation, King's College London, London, UK
| | - Nicos Kessaris
- Department of Transplantation, Guy's and St Thomas' NHS Foundation Trust, London, UK
| | - Anthony Dorling
- Department of Transplantation, Guy's and St Thomas' NHS Foundation Trust, London, UK.,Medical Research Council Centre for Transplantation, King's College London, London, UK
| | - Nizam Mamode
- Department of Transplantation, Guy's and St Thomas' NHS Foundation Trust, London, UK.,Medical Research Council Centre for Transplantation, King's College London, London, UK
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Mohty M, Bacigalupo A, Saliba F, Zuckermann A, Morelon E, Lebranchu Y. New directions for rabbit antithymocyte globulin (Thymoglobulin(®)) in solid organ transplants, stem cell transplants and autoimmunity. Drugs 2015; 74:1605-34. [PMID: 25164240 PMCID: PMC4180909 DOI: 10.1007/s40265-014-0277-6] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
In the 30 years since the rabbit antithymocyte globulin (rATG) Thymoglobulin® was first licensed, its use in solid organ transplantation and hematology has expanded progressively. Although the evidence base is incomplete, specific roles for rATG in organ transplant recipients using contemporary dosing strategies are now relatively well-identified. The addition of rATG induction to a standard triple or dual regimen reduces acute cellular rejection, and possibly humoral rejection. It is an appropriate first choice in patients with moderate or high immunological risk, and may be used in low-risk patients receiving a calcineurin inhibitor (CNI)-sparing regimen from time of transplant, or if early steroid withdrawal is planned. Kidney transplant patients at risk of delayed graft function may also benefit from the use of rATG to facilitate delayed CNI introduction. In hematopoietic stem cell transplantation, rATG has become an important component of conventional myeloablative conditioning regimens, following demonstration of reduced acute and chronic graft-versus-host disease. More recently, a role for rATG has also been established in reduced-intensity conditioning regimens. In autoimmunity, rATG contributes to the treatment of severe aplastic anemia, and has been incorporated in autograft projects for the management of conditions such as multiple sclerosis, Crohn’s disease, and systemic sclerosis. Finally, research is underway for the induction of tolerance exploiting the ability of rATG to induce immunosuppresive cells such as regulatory T-cells. Despite its long history, rATG remains a key component of the immunosuppressive armamentarium, and its complex immunological properties indicate that its use will expand to a wider range of disease conditions in the future.
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Affiliation(s)
- Mohamad Mohty
- Department of Hematology and Cellular Therapy, CHU Hôpital Saint Antoine, 184, rue du Faubourg Saint Antoine, 75571, Paris Cedex 12, France,
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Khan T. Delayed graft function in laparoscopic kidney transplantation: the importance of prolonged cold and warm ischemia. Am J Transplant 2015; 15:1444. [PMID: 25809841 DOI: 10.1111/ajt.13229] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2014] [Revised: 12/09/2014] [Accepted: 12/09/2014] [Indexed: 01/25/2023]
Affiliation(s)
- T Khan
- Department of Surgery, Prince Salman Armed Forces Hospital, Tabuk, Saudi Arabia
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Comparing Two Types of Rabbit ATG prior to Reduced Intensity Conditioning Allogeneic Hematopoietic SCT for Hematologic Malignancies. BONE MARROW RESEARCH 2015; 2015:980924. [PMID: 25874131 PMCID: PMC4385613 DOI: 10.1155/2015/980924] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/27/2014] [Revised: 01/06/2015] [Accepted: 01/31/2015] [Indexed: 01/06/2023]
Abstract
Different rabbit polyclonal antilymphocyte globulins (ATGs) are used in allogeneic hematopoietic stem cell transplantation (alloHSCT) to prevent graft-versus-host disease (GvHD). We compared 2 different ATGs in alloHSCT after reduced intensity conditioning (RIC) for hematological malignancies. We reviewed 30 alloHSCT for hematologic malignancies performed between 2007 and 2010 with fludarabine and i.v. busulfan as conditioning regimen. Patients alternatingly received Thymoglobulin or ATG-F. Median followup was 3.3 (2.5-4.5) years. Adverse events appeared to occur more frequently during Thymoglobulin infusion than during ATG-F infusion but without statistical significance (P = 0.14). There were also no differences in 3-year overall survival (OS), disease-free survival (DFS), relapse incidence, and transplant related mortality (TRM) in the Thymoglobulin versus ATG-F group: 45.7% versus 46.7%, 40% versus 33.7%, 40% versus 33.3%, and 20% versus 33.3%. The same held for graft failure, rejection, infectious complications, immune reconstitution, and acute or chronic GvHD. In patients transplanted for hematologic malignancies after RIC, the use of Thymoglobulin is comparable to that of ATG-F in all the aspects evaluated in the study. However due to the small number of patients in each group we cannot exclude a possible difference that may exist.
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A randomized 2×2 factorial trial, part 1: single-dose rabbit antithymocyte globulin induction may improve renal transplantation outcomes. Transplantation 2015; 99:197-209. [PMID: 25083614 PMCID: PMC4281164 DOI: 10.1097/tp.0000000000000250] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Supplemental digital content is available in the text. Background We conducted a randomized and unblinded 2×2 sequential-factorial trial, composed of an induction arm (part 1) comparing single-dose (SD) versus divided-dose rabbit antithymocyte globulin (rATG), and a maintenance arm (part 2) comparing tacrolimus minimization versus withdrawal. We report the long-term safety and efficacy of SD-rATG induction in the context of early steroid withdrawal and tacrolimus minimization or withdrawal. Methods Patients (n=180) received 6 mg/kg rATG, SD or four alternate-day doses (1.5 mg/kg/dose), with early steroid withdrawal and tacrolimus or sirolimus maintenance. After 6 months targeted maintenance levels were tacrolimus, 2 to 4 ng/mL and sirolimus, 4 to 6 ng/mL or, if calcineurin inhibitor–withdrawn, sirolimus 8 to 12 ng/mL with mycophenolate mofetil 2 g two times per day. Primary endpoints were renal function (abbreviated modification of diet in renal disease) and chronic graft histopathology (Banff). Secondary endpoints included patient survival, graft survival, biopsy-proven rejection, and infectious or noninfectious complications. Results Follow-up averaged longer than 4 years. Tacrolimus or sirolimus and mycophenolate mofetil exposure was identical between groups. The SD-rATG associated with improved renal function (2-36 months; P<0.001) in deceased donor recipients. The SD-rATG associated with quicker lymphocyte, CD4 T cell, and CD4-CD8 recovery and fewer infections. Cox multivariate hazard modeling showed divided-dose–rATG (P=0.019), deceased donor (P=0.003), serious infection (P=0.0.018), and lower lymphocyte count (P=0.001) associated with increased mortality. Patients with all four covariates showed a 27-fold increased likelihood of death (P=0.00002). Chronic graft histopathology, rejection rates, and death-censored graft survival were not significantly different between groups. Conclusion The SD-rATG induction improves the 3-year renal function in recipients of deceased donor kidneys. This benefit, along with possibly improved patient survival and fewer infections suggest that how rATG is administered may impact its efficacy and safety.
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Generation, cryopreservation, function and in vivo persistence of ex vivo expanded cynomolgus monkey regulatory T cells. Cell Immunol 2015; 295:19-28. [PMID: 25732601 DOI: 10.1016/j.cellimm.2015.02.006] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2014] [Revised: 02/05/2015] [Accepted: 02/06/2015] [Indexed: 12/16/2022]
Abstract
We expanded flow-sorted Foxp3(+) cynomolgus monkey regulatory T cells (Treg) >1000-fold after three rounds of stimulation with anti-CD3 mAb-loaded artificial antigen-presenting cells, rapamycin (first round only) and IL-2. The expanded Treg maintained their expression of Treg signature markers, CD25, CD27, CD39, Foxp3, Helios, and CTLA-4, as well as CXCR3, which plays an important role in T cell migration to sites of inflammation. In contrast to expanded effector T cells (Teff), expanded Treg produced minimal IFN-γ and IL-17 and no IL-2 and potently suppressed Teff proliferation. Following cryopreservation, thawed Treg were less viable than their freshly-expanded counterparts, although no significant changes in phenotype or suppressive ability were observed. Additional rounds of stimulation/expansion restored maximal viability. Furthermore, adoptively-transferred autologous Treg expanded from cryopreserved second round stocks and labeled with CFSE or VPD450 were detected in blood and secondary lymphoid tissues of normal or immunosuppressed recipients at least two months after their systemic infusion.
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Outcomes of peripheral blood stem cell transplantation patients from HLA-mismatched unrelated donor with antithymocyte globulin (ATG)-Thymoglobulin versus ATG-Fresenius: a single-center study. Med Oncol 2015; 32:465. [PMID: 25588925 DOI: 10.1007/s12032-014-0465-y] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2014] [Accepted: 12/16/2014] [Indexed: 10/24/2022]
Abstract
Although antithymocyte globulin (ATG) had been widely used in hematopoietic stem cell transplantation from unrelated donor due to its ability to prevent acute and chronic graft-versus-host disease (GVHD), the comparative efficacy and safety of ATG-Thymoglobulin (ATG-T) and ATG-Fresenius (ATG-F) in patients undergoing HLA-mismatched allogeneic peripheral blood stem cell transplantation from unrelated donors (UR-PBSCT) has not been evaluated. Retrospective analysis of patients who underwent HLA-mismatched UR-PBSCT between January 2003 and December 2013 and received pre-transplant ATG-T at a total dose of 10 mg/kg or ATG-F at a total dose of 20 mg/kg was performed. Patients who received ATG-T (n = 23) or ATG-F (n = 28) had similar baseline demographic, disease, and transplant characteristics. There were no significant between-groups differences in the probability of acute GVHD (P = 0.721) and chronic GVHD (P = 0.439). ATG-F was associated with nonsignificant trends toward higher disease-free survival at 3-year follow-up compared with ATG-T (45.7 ± 11.1 vs 61.3 ± 9.7 %, respectively, P = 0.07). A significantly greater proportion of ATG-T patients experienced high fever than ATG-F patients (P < 0.01) during ATG infusion. There was no difference in the rate of infection between the two treatment groups. There were less adverse effects comparing ATG-F with ATG-T. ATG-T at a total dose of 10 mg/kg and ATG-F at a total dose of 20 mg/kg had a similar clinical outcome in the setting of HLA-mismatched UR-PBSCT.
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Blank G, Welker C, Haarer J, Sterk M, Nadalin S, Yañez VAC, Joos TO, Menrad A, Snell D, LaCorcia G, Königsrainer A, Handgretinger R, Schilbach K. Selective, efficient modulation of activated CD4+ αβT cells by the novel humanized antibody GZ-αβTCR targeting human αβTCR. Bone Marrow Transplant 2014; 50:390-401. [DOI: 10.1038/bmt.2014.263] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2014] [Revised: 10/02/2014] [Accepted: 10/04/2014] [Indexed: 11/09/2022]
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Zuckermann A, Schulz U, Deuse T, Ruhpawar A, Schmitto JD, Beiras-Fernandez A, Hirt S, Schweiger M, Kopp-Fernandes L, Barten MJ. Thymoglobulin induction in heart transplantation: patient selection and implications for maintenance immunosuppression. Transpl Int 2014; 28:259-69. [PMID: 25363471 PMCID: PMC4359038 DOI: 10.1111/tri.12480] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2014] [Revised: 09/18/2014] [Accepted: 10/24/2014] [Indexed: 01/12/2023]
Abstract
Clinical data relating to rabbit antithymocyte globulin (rATG) induction in heart transplantation are far less extensive than for other immunosuppressants, or indeed for rATG in other indications. This was highlighted by the low grade of evidence and the lack of detailed recommendations for prescribing rATG in the International Society for Heart and Lung Transplantation (ISHLT) guidelines. The heart transplant population includes an increasing frequency of patients on mechanical circulatory support (MCS), often with ongoing infection and/or presensitization, who are at high immunological risk but also vulnerable to infectious complications. The number of patients with renal impairment is also growing due to lengthening waiting times, intensifying the need for strategies that minimize calcineurin inhibitor (CNI) toxicity. Additionally, the importance of donor-specific antibodies (DSA) in predicting graft failure is influencing immunosuppressive regimens. In light of these developments, and in view of the lack of evidence-based prescribing criteria, experts from Germany, Austria, and Switzerland convened to identify indications for rATG induction in heart transplantation and to develop an algorithm for its use based on patient characteristics.
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Affiliation(s)
- Andreas Zuckermann
- Department of Cardiac Surgery, Medical University of Vienna, Vienna, Austria
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Valdez-Ortiz R, Bestard O, Llaudó I, Franquesa M, Cerezo G, Torras J, Herrero-Fresneda I, Correa-Rotter R, Grinyó JM. Induction of suppressive allogeneic regulatory T cells via rabbit antithymocyte polyclonal globulin during homeostatic proliferation in rat kidney transplantation. Transpl Int 2014; 28:108-19. [PMID: 25208307 DOI: 10.1111/tri.12448] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2014] [Revised: 05/19/2014] [Accepted: 09/04/2014] [Indexed: 11/27/2022]
Abstract
Experimental studies have shown that rabbit antithymocyte polyclonal globulin (ATG) can expand human CD4+CD25++Foxp3+ cells (Tregs). We investigated the major biological effects of a self-manufactured rabbit polyclonal anti-rat thymoglobulin (rATG) in vitro, as well as its effects on different peripheral T-cell subsets. Moreover, we evaluated the allogeneic suppressive capacity of rATG-induced Tregs in an experimental rat renal transplant model. Our results show that rATG has the capacity to induce apoptosis in T lymphocyte lymphocytes as a primary mechanism of T-cell depletion. Our in vivo studies demonstrated a rapid but transient cellular depletion of the main T cell subsets, directly proportional to the rATG dose used, but not of the effector memory T cells, which required significantly higher rATG doses. After rATG administration, we observed a significant proliferation of Tregs in the peripheral blood of transplanted rats, leading to an increase in the Treg/T effector ratio. Importantly, rATG-induced Tregs displayed a strong donor-specific suppressive capacity when assessed in an antigen-specific allogeneic co-culture. All of these results were associated with better renal graft function in rats that received rATG. Our study shows that rATG has the biological capacity immunomodulatory to promote a regulatory alloimmune milieu during post-transplant homeostatic proliferation.
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Affiliation(s)
- Rafael Valdez-Ortiz
- Laboratory of Experimental Nephrology, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain; Nephrology Department, Hospital General de México, Mexico City, México; Renal Transplant Unit, Department of Nephrology, Hospital Universitari de Bellvitge, Barcelona, Spain
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Gunay Y, Inal A, Yener N, Sinanoglu O, Selvi O, Bircan HY. A novel mechanism of anti-T-lymphocyte globulin mediated by fractalkine in renal ischemia-reperfusion injury in rats. Transplant Proc 2014; 45:2461-8. [PMID: 23953563 DOI: 10.1016/j.transproceed.2013.02.118] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2012] [Revised: 01/18/2013] [Accepted: 02/16/2013] [Indexed: 11/16/2022]
Abstract
BACKGROUND Ischemia-reperfusion injury (IRI) is among the main challenges in kidney transplantation. It causes delayed graft function and graft loss in long-term follow-up studies. Anti-T lymphocyte globulin (ATG), a common induction immunosuppressive, has been used in kidney transplantation to prevent rejection. Fractalkine (FKN) is among the main chemokines involved in IRI. This study was designed to identify the relationship between ATG and FKN after warm ischemia in rat kidneys. METHODS Rats were divided into three groups: Control, IRI+normal saline(NS) and IRI+ATG. After IRI was initiated, rats received a dose of ATG or NS during surgery as well as two more doses at 24 and 48 hours after surgery. All rats were humanely killed at 72 hours. RESULTS The concentration of FKN as well as dendritic cells (DC) and macrophages were lower in both peripheral blood and the injured kidney among ATG-treated versus control rats. Additionally cell necrosis, cytoplasmic vacuolization, cast formation, and tubular dilatation were improved among ATG-treated rats. Serum creatinine levels were lower in rats that received ATG. CONCLUSION ATG depleted the concentration of FKN, which inhibits migrations of DCs and macrophages into the kidney, and reduces IRI-related pathology.
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Affiliation(s)
- Y Gunay
- Florence Nightingale Hospital, Liver Transplanation center, Istanbul, Turkey.
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Nashan B. Induction therapy and mTOR inhibition: minimizing calcineurin inhibitor exposure in de novo renal transplant patients. Clin Transplant 2014; 27 Suppl 25:16-29. [PMID: 23909498 DOI: 10.1111/ctr.12156] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/12/2013] [Indexed: 12/18/2022]
Abstract
Use of induction therapy with mTOR inhibitor maintenance immunosuppression to facilitate reduced calcineurin inhibitor (CNI) exposure in de novo kidney transplant patients has been explored in a series of randomized trials. These studies have typically employed interleukin-2 receptor antagonist (IL-2RA) induction, in low or standard immunological risk recipients. Although no study has directly compared mTOR inhibition plus reduced CNI exposure with or without induction, inclusion of IL-2RA induction appears to permit a substantial reduction in CNI exposure without the need for high mTOR inhibitor dosing. IL-2RA induction with an mTOR inhibitor and steroids has consistently shown similar efficacy to standard-exposure CNI with mycophenolic acid and steroids and may improve renal function among patients who remain on the mTOR inhibitor-based regimen. With modern mTOR inhibitor dosing, wound healing complications are of less concern and may be no more frequent than in mycophenolic acid-based regimens. The incidence of cytomegalovirus infection appears lower in patients receiving de novo mTOR inhibition. The available evidence demonstrates that IL-2RA induction with an mTOR inhibitor can successfully reduce CNI exposure by at least half without a penalty in terms of rejection in low- or moderate-risk de novo transplant recipients and may offer renal and antiviral benefits.
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Affiliation(s)
- Björn Nashan
- Department of Hepatobiliary Surgery and Visceral Transplantation, University Medical Center Eppendorf, Hamburg, Germany.
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Popow I, Leitner J, Grabmeier-Pfistershammer K, Majdic O, Zlabinger GJ, Kundi M, Steinberger P. A comprehensive and quantitative analysis of the major specificities in rabbit antithymocyte globulin preparations. Am J Transplant 2013; 13:3103-13. [PMID: 24168235 DOI: 10.1111/ajt.12514] [Citation(s) in RCA: 82] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2013] [Revised: 09/04/2013] [Accepted: 09/20/2013] [Indexed: 01/25/2023]
Abstract
Antithymocyte globulin (ATG) preparations are used for treatment and prevention of graft rejection episodes, graft versus host disease and aplastic anemia. The immunomodulatory and immuosuppressive properties of ATGs are mediated by their interaction with a large variety of antigens expressed on immune and nonimmune cell populations. We have conducted a comprehensive analysis on antibody specificities contained in rabbit ATGs in clinical use, ATG-Fresenius (ATG-F) and Thymoglobulin (THG). We have used retroviral expression cloning to identify novel ATG antigens and demonstrate that together with ATG antigens described earlier, these molecules account for the majority of ATG antibodies directed to human cells. Moreover, we have employed cell lines engineered to express antigens at high levels to quantify the antibodies directed to each ATG antigen. We have used cell lines expressing the T cell receptor complex, CD2 and CD28 to remove antibodies to these antigens from ATG preparations and demonstrate that this treatment abrogated the ability of ATGs to induce activation and forkhead box P3 expression in T cells. Comprehensive information and differences on the antigens targeted by ATG-F and THG as well as novel approaches to assess their functional properties are the basis for a better understanding of their immunomodulatory capacities and might eventually translate into improved ATG-based regimen.
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Affiliation(s)
- I Popow
- Division of Immune Receptors and T Cell Activation, Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University Vienna, Vienna, Austria
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Gitelman SE, Gottlieb PA, Rigby MR, Felner EI, Willi SM, Fisher LK, Moran A, Gottschalk M, Moore WV, Pinckney A, Keyes-Elstein L, Aggarwal S, Phippard D, Sayre PH, Ding L, Bluestone JA, Ehlers MR. Antithymocyte globulin treatment for patients with recent-onset type 1 diabetes: 12-month results of a randomised, placebo-controlled, phase 2 trial. Lancet Diabetes Endocrinol 2013; 1:306-16. [PMID: 24622416 PMCID: PMC6489466 DOI: 10.1016/s2213-8587(13)70065-2] [Citation(s) in RCA: 109] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
BACKGROUND Type 1 diabetes results from T-cell-mediated destruction of β cells. Findings from preclinical studies and pilot clinical trials suggest that antithymocyte globulin (ATG) might be effective for reducing this autoimmune response. We assessed the safety and efficacy of rabbit ATG in preserving islet function in participants with recent-onset type 1 diabetes, and report here our 12-month results. METHODS For this phase 2, randomised, placebo-controlled, clinical trial, we enrolled patients with recent-onset type 1 diabetes, aged 12-35 years, and with a peak C-peptide of 0.4 nM or greater on mixed meal tolerance test from 11 sites in the USA. We used a computer generated randomisation sequence to randomly assign patients (2:1, with permuted-blocks of size three or six and stratified by study site) to receive either 6.5 mg/kg ATG or placebo over a course of four days. All participants were masked and initially managed by an unmasked drug management team, which managed all aspects of the study until month 3. Thereafter, to maintain masking for diabetes management throughout the remainder of the study, participants received diabetes management from an independent, masked study physician and nurse educator. The primary endpoint was the baseline-adjusted change in 2-h area under the curve C-peptide response to mixed meal tolerance test from baseline to 12 months. Analyses were by intention to treat. This is a planned interim analysis of an on-going trial that will run for 24 months of follow-up. This study is registered with ClinicalTrials.gov, number NCT00515099. FINDINGS Between Sept 10, 2007, and June 1, 2011, we screened 154 individuals, randomly allocating 38 to ATG and 20 to placebo. We recorded no between-group difference in the primary endpoint: participants in the ATG group had a mean change in C-peptide area under the curve of -0.195 pmol/mL (95% CI -0.292 to -0.098) and those in the placebo group had a mean change of -0.239 pmol/mL (-0.361 to -0.118) in the placebo group (p=0.591). All except one participant in the ATG group had both cytokine release syndrome and serum sickness, which was associated with a transient rise in interleukin-6 and acute-phase proteins. Acute T cell depletion occurred in the ATG group, with slow reconstitution over 12 months. However, effector memory T cells were not depleted, and the ratio of regulatory to effector memory T cells declined in the first 6 months and stabilised thereafter. ATG-treated patients had 159 grade 3-4 adverse events, many associated with T-cell depletion, compared with 13 in the placebo group, but we detected no between-group difference in incidence of infectious diseases. INTERPRETATION Our findings suggest that a brief course of ATG does not result in preservation of β-cell function 12 months later in patients with new-onset type 1 diabetes. Generalised T-cell depletion in the absence of specific depletion of effector memory T cells and preservation of regulatory T cells seems to be an ineffective treatment for type 1 diabetes.
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Affiliation(s)
| | | | - Mark R Rigby
- Indiana University and Riley Children's Hospital, Indianapolis, Indianapolis, IN, USA
| | | | - Steven M Willi
- Children's Hospital of Philadelphia, Philadelphia, PA, USA
| | - Lynda K Fisher
- Children's Hospital of Los Angeles, Los Angeles, CA, USA
| | | | | | | | | | | | | | | | | | - Linna Ding
- National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA
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