|
1
|
Pham JA, Coronel MM. Unlocking Transplant Tolerance with Biomaterials. Adv Healthc Mater 2025; 14:e2400965. [PMID: 38843866 PMCID: PMC11834385 DOI: 10.1002/adhm.202400965] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2024] [Revised: 05/31/2024] [Indexed: 07/04/2024]
Abstract
For patients suffering from organ failure due to injury or autoimmune disease, allogeneic organ transplantation with chronic immunosuppression is considered the god standard in terms of clinical treatment. However, the true "holy grail" of transplant immunology is operational tolerance, in which the recipient exhibits a sustained lack of alloreactivity toward unencountered antigen presented by the donor graft. This outcome is resultant from critical changes to the phenotype and genotype of the immune repertoire predicated by the activation of specific signaling pathways responsive to soluble and mechanosensitive cues. Biomaterials have emerged as a medium for interfacing with and reprogramming these endogenous pathways toward tolerance in precise, minimally invasive, and spatiotemporally defined manners. By viewing seminal and contemporary breakthroughs in transplant tolerance induction through the lens of biomaterials-mediated immunomodulation strategies-which include intrinsic material immunogenicity, the depot effect, graft coatings, induction and delivery of tolerogenic immune cells, biomimicry of tolerogenic immune cells, and in situ reprogramming-this review emphasizes the stunning diversity of approaches in the field and spotlights exciting future directions for research to come.
Collapse
Affiliation(s)
- John‐Paul A. Pham
- Department of Biomedical EngineeringUniversity of MichiganAnn ArborMI48109USA
- Elizabeth Caswell Diabetes InstituteUniversity of MichiganAnn ArborMI48109USA
| | - María M. Coronel
- Department of Biomedical EngineeringUniversity of MichiganAnn ArborMI48109USA
- Elizabeth Caswell Diabetes InstituteUniversity of MichiganAnn ArborMI48109USA
| |
Collapse
|
|
2
|
Liao T, Shi X, Han F, Wang Y, Zeng W, Liu R, Yan Z, Xia R, Huang Z, Xu J, Miao Y. Blockade of BLyS inhibits B-cell responses and antibody production for the prevention of chronic transplant rejection. J Heart Lung Transplant 2024; 43:652-662. [PMID: 38070662 DOI: 10.1016/j.healun.2023.12.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2023] [Revised: 11/11/2023] [Accepted: 12/02/2023] [Indexed: 12/22/2023] Open
Abstract
BACKGROUND Chronic rejection, closely related to the activation of B cells and donor-specific antibody (DSA) production, has unsatisfactory therapeutic outcomes. B lymphocyte stimulator (BLyS) is a major regulatory factor that controls the activation and differentiation of B cells. However, it remains unclear whether BLyS blockade can regulate B and plasma cells in the transplantation setting and affect chronic rejection. Here, we investigated the efficacy of the BLyS inhibitors belimumab and telitacicept in controlling B-cell response and preventing chronic rejection. METHODS The effects of belimumab and telitacicept on B-cell activation, differentiation, and antibody production in vitro were determined. A chronic rejection model in mouse was established by allogeneic cardiac transplantation with CTLA4-Ig treatment. Allograft survival, histology, DSA levels, and B-cell responses were analyzed to evaluate the chronic rejection-preventive effects of belimumab and telitacicept. RESULTS In vitro experiments confirmed that belimumab and telitacicept inhibited B-cell activation and differentiation and reduced antibody production. In vivo experiments indicated that they significantly prolonged allograft survival, attenuated chronic rejection through significant suppression of myocardial ischemic necrosis and interstitial fibrosis, and reduced DSA-IgG levels, C4d deposition, and inflammatory cell infiltration. Furthermore, the frequencies of B cells, plasma cells, and IgG-producing cells in the recipients' spleen, lymph nodes, bone marrow, and blood were decreased after BLyS inhibitors treatment. CONCLUSIONS This study demonstrated that belimumab and telitacicept inhibit B-cell responses and antibody production and alleviate chronic transplant rejection. Therefore, BLyS inhibitors are expected to be used for the prevention of chronic rejection in clinical practice.
Collapse
Affiliation(s)
- Tao Liao
- Department of Transplantation, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Xiaoyi Shi
- Department of Transplantation, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Fei Han
- Research Institute of Organ Transplantation, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Yuchen Wang
- Department of Transplantation, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Wenli Zeng
- Department of Transplantation, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Rumin Liu
- Department of Transplantation, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Ziyan Yan
- Department of Transplantation, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Renfei Xia
- Department of Transplantation, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Zhengyu Huang
- Research Institute of Organ Transplantation, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Jian Xu
- Department of Transplantation, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Yun Miao
- Department of Transplantation, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.
| |
Collapse
|
|
3
|
Lee JH, Lee H, Kim K, Lee SW, Song JH, Hwang SD. Effect of Plasmapheresis on the Efficacy of Rituximab in Antibody-Mediated Rejection Patients. Transplant Proc 2024; 56:723-725. [PMID: 38383260 DOI: 10.1016/j.transproceed.2024.01.014] [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: 10/30/2023] [Accepted: 01/16/2024] [Indexed: 02/23/2024]
Abstract
BACKGROUND Rituximab and plasmapheresis (PP) suppress and eliminate antibody production in patients experiencing antibody-mediated rejection (AMR). Herein, we discuss a case where rituximab was less effective after PP for treating AMR. CASE A 55-year-old male patient underwent kidney transplantation. His renal function remained normal for 1 year. Subsequently, renal function declined, and (donor-specific antibodies showed positive results. A biopsy of the transplanted kidney revealed AMR. On the day of the biopsy, the medical staff administered 200 mg of rituximab, followed by IV immunoglobulin (IVIg) and PP the next day. The time interval between PP + IVIg treatment and rituximab was 12 h. As a result, the B-cell markers CD19 and CD20 did not decrease sufficiently, and the patient's creatinine and glomerular filtration rate muscles did not recover adequately. CONCLUSION We report a case in which PP was administered shortly after rituximab injection, resulting in insufficient B-cell inhibition due to the removal of rituximab.
Collapse
Affiliation(s)
- Jin Ho Lee
- Division of Nephrology, Department of Internal Medicine, Leesin Hemodialysis and Intervention Clinic, Busan, South Korea
| | - Heeryong Lee
- Division of Nephrology, Department of Internal Medicine, Leesin Hemodialysis and Intervention Clinic, Busan, South Korea
| | - Kipyo Kim
- Division of Nephrology and Hypertension, Department of Internal Medicine, Inha University College of Medicine, Incheon, South Korea
| | - Seoung Woo Lee
- Division of Nephrology and Hypertension, Department of Internal Medicine, Inha University College of Medicine, Incheon, South Korea
| | - Joon Ho Song
- Division of Nephrology and Hypertension, Department of Internal Medicine, Inha University College of Medicine, Incheon, South Korea
| | - Seun Deuk Hwang
- Division of Nephrology and Hypertension, Department of Internal Medicine, Inha University College of Medicine, Incheon, South Korea.
| |
Collapse
|
|
4
|
Dumortier J, Conti F, Hiriart JB, Dharancy S, Duvoux C, Besch C, Houssel-Debry P, Latournerie M, Chermak F, Meszaros M, Pageaux GP, Radenne S, Boillot O, Hardwigsen J, Kounis I, Kamar N, Saliba F, Erard D, Del Bello A. Treatment of donor-specific anti-HLA antibodies-mediated rejection after liver transplantation: A French nationwide retrospective study. Liver Transpl 2023; 29:1313-1322. [PMID: 37367954 DOI: 10.1097/lvt.0000000000000200] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Accepted: 05/25/2023] [Indexed: 06/28/2023]
Abstract
The deleterious effect of donor-specific anti-HLA antibodies (DSA) after liver transplantation (LT) has been increasingly recognized during the past decade. Antibody-mediated rejection (AMR) represents a rare but severe complication in the presence of DSA. However, little is known concerning the treatment of AMR after LT. The nationwide French study aimed to describe LT recipients who received specific treatment of AMR. We performed a multicenter retrospective study on 44 patients who were treated with B-cell targeting agents from January 2008 to December 2020. Median patient age at the time of AMR treatment was 51.6 years (range: 17.9-68.0). AMR was classified as acute (n = 19) or chronic (n = 25). The diagnosis of AMR was made after a median time of 16.8 months (range: 0.4-274.2) after LT. The main therapeutic combination was plasma exchange/rituximab/IVIG (n = 25, 56.8%). The median follow-up after the treatment of AMR was 32 months (range: 1-115). After the treatment, 1-, 5- and 10-year patient and graft survivals were 77%, 55.9%, and 55.9%, and 69.5%, 47.0%, and 47.0%, respectively. Initial total bilirubin (Q1-Q3 vs. Q4) was significantly associated with patient survival (log-rank test, p = 0.005) and graft survival (log-rank test, p = 0.002). After a median follow-up of 21 months (range: 12-107), DSA became undetectable in 15/38 patients (39.5%) with available DSA monitoring. In conclusion, specific treatment of AMR in LT recipients has slowly emerged in France during the past decade and has probably been considered in the most severe patients; this explains the global poor outcome, even if the outcome was favorable in some cases.
Collapse
Affiliation(s)
- Jérôme Dumortier
- Hospices Civils de Lyon, Hôpital Edouard Herriot, Fédération des Spécialités digestives, et Université Claude Bernard Lyon 1, Lyon, France
| | - Filomena Conti
- APHP, Hôpital de la Pitié Salpêtrière, Service d'hépatologie et transplantation hépatique, Paris, France
| | - Jean-Baptiste Hiriart
- CHU de Bordeaux, Hôpital Haut-Lévêque, Service de Chirurgie hépatobiliaire et de transplantation hépatique, Bordeaux, France
| | - Sébastien Dharancy
- CHU Lille, Hôpital Claude Huriez, Service des maladies de l'appareil digestif, Lille, France
| | | | - Camille Besch
- CHRU Hautepierre, Service de chirurgie hépato-bilio-pancréatique et transplantation hépatique, Strasbourg, France
| | - Pauline Houssel-Debry
- Hôpital Universitaire de Pontchaillou, Service d'Hépatologie et Transplantation hépatique, Rennes, France
| | - Marianne Latournerie
- CHU Dijon, Service d'Hépato-gastroentérologie et oncologie digestive, Inserm EPICAD LNC-UMR1231, Université de Bourgogne-Franche Comté, Dijon, France
| | - Faiza Chermak
- CHU de Bordeaux, Hôpital Haut-Lévêque, Service de Chirurgie hépatobiliaire et de transplantation hépatique, Bordeaux, France
| | - Magdalena Meszaros
- CHU Saint Eloi, Département d'hépato-gatroentérologie et transplantation hépatique, et Université de Montpellier, Montpellier, France
| | - Georges-Philippe Pageaux
- CHU Saint Eloi, Département d'hépato-gatroentérologie et transplantation hépatique, et Université de Montpellier, Montpellier, France
| | - Sylvie Radenne
- Hospices civils de Lyon, Hôpital de la Croix Rousse, Service d'Hépato-Gastroentérologie, Lyon, France
| | - Olivier Boillot
- Hospices Civils de Lyon, Hôpital Edouard Herriot, Fédération des Spécialités digestives, et Université Claude Bernard Lyon 1, Lyon, France
| | - Jean Hardwigsen
- APHM, Hôpital La Timone, Service chirurgie générale et transplantation hépatique Marseille, France
| | - Ilias Kounis
- AP-HP, Hôpital Paul Brousse, Centre Hépato-Biliaire, INSERM, Unité 1193, Hepatinov, et Université Paris Saclay, Villejuif, France
| | - Nassim Kamar
- CHU Rangueil, Département de Néphrologie et Transplantation d'Organes, Toulouse, France
| | - Faouzi Saliba
- AP-HP, Hôpital Paul Brousse, Centre Hépato-Biliaire, INSERM, Unité 1193, Hepatinov, et Université Paris Saclay, Villejuif, France
| | - Domitille Erard
- Hospices civils de Lyon, Hôpital de la Croix Rousse, Service d'Hépato-Gastroentérologie, Lyon, France
| | - Arnaud Del Bello
- CHU Rangueil, Département de Néphrologie et Transplantation d'Organes, Toulouse, France
| |
Collapse
|
|
5
|
Matsumoto H, Suzuki H, Yamanaka T, Kaiho T, Hata A, Inage T, Ito T, Kamata T, Tanaka K, Sakairi Y, Motohashi S, Yoshino I. Anti-CD20 Antibody and Calcineurin Inhibitor Combination Therapy Effectively Suppresses Antibody-Mediated Rejection in Murine Orthotopic Lung Transplantation. Life (Basel) 2023; 13:2042. [PMID: 37895424 PMCID: PMC10608275 DOI: 10.3390/life13102042] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2023] [Revised: 10/07/2023] [Accepted: 10/10/2023] [Indexed: 10/29/2023] Open
Abstract
Antibody-mediated rejection (AMR) is a risk factor for chronic lung allograft dysfunction, which impedes long-term survival after lung transplantation. There are no reports evaluating the efficacy of the single use of anti-CD20 antibodies (aCD20s) in addition to calcineurin inhibitors in preventing AMR. Thus, this study aimed to evaluate the efficacy of aCD20 treatment in a murine orthotopic lung transplantation model. Murine left lung transplantation was performed using a major alloantigen strain mismatch model (BALBc (H-2d) → C57BL/6 (BL/6) (H-2b)). There were four groups: isograft (BL/6→BL/6) (Iso control), no-medication (Allo control), cyclosporine A (CyA) treated, and CyA plus murine aCD20 (CyA+aCD20) treated groups. Severe neutrophil capillaritis, arteritis, and positive lung C4d staining were observed in the allograft model and CyA-only-treated groups. These findings were significantly improved in the CyA+aCD20 group compared with those in the Allo control and CyA groups. The B cell population in the spleen, lymph node, and graft lung as well as the levels of serum donor-specific IgM and interferon γ were significantly lower in the CyA+aCD20 group than in the CyA group. Calcineurin inhibitor-mediated immunosuppression combined with aCD20 therapy effectively suppressed AMR in lung transplantation by reducing donor-specific antibodies and complement activation.
Collapse
Affiliation(s)
- Hiroki Matsumoto
- Department of General Thoracic Surgery, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan; (H.M.); (T.Y.); (T.K.); (T.I.); (K.T.); (Y.S.); (I.Y.)
- Department of Thoracic Surgery, Kimitsu Chuo Hospital, 1010 Sakurai, Kisarazu 292-8535, Japan
| | - Hidemi Suzuki
- Department of General Thoracic Surgery, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan; (H.M.); (T.Y.); (T.K.); (T.I.); (K.T.); (Y.S.); (I.Y.)
| | - Takahiro Yamanaka
- Department of General Thoracic Surgery, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan; (H.M.); (T.Y.); (T.K.); (T.I.); (K.T.); (Y.S.); (I.Y.)
| | - Taisuke Kaiho
- Department of General Thoracic Surgery, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan; (H.M.); (T.Y.); (T.K.); (T.I.); (K.T.); (Y.S.); (I.Y.)
| | - Atsushi Hata
- Department of General Thoracic Surgery, Chiba Cancer Center, Chiba 260-8717, Japan; (A.H.); (T.I.)
| | - Terunaga Inage
- Department of General Thoracic Surgery, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan; (H.M.); (T.Y.); (T.K.); (T.I.); (K.T.); (Y.S.); (I.Y.)
| | - Takamasa Ito
- Department of General Thoracic Surgery, Chiba Cancer Center, Chiba 260-8717, Japan; (A.H.); (T.I.)
| | - Toshiko Kamata
- Department of Thoracic Surgery, International University of Health and Welfare Atami Hospital, Shizuoka 413-0012, Japan;
| | - Kazuhisa Tanaka
- Department of General Thoracic Surgery, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan; (H.M.); (T.Y.); (T.K.); (T.I.); (K.T.); (Y.S.); (I.Y.)
| | - Yuichi Sakairi
- Department of General Thoracic Surgery, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan; (H.M.); (T.Y.); (T.K.); (T.I.); (K.T.); (Y.S.); (I.Y.)
| | - Shinichiro Motohashi
- Department of Medical Immunology, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan;
| | - Ichiro Yoshino
- Department of General Thoracic Surgery, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan; (H.M.); (T.Y.); (T.K.); (T.I.); (K.T.); (Y.S.); (I.Y.)
- Department of General Thoracic Surgery, International University of Health and Welfare Narita Hospital, Chiba 286-8520, Japan
| |
Collapse
|
|
6
|
Parajuli S, Zhong W, Pantha M, Sokup M, Aziz F, Garg N, Mohamed M, Mandelbrot D. The Trend of Serum Creatinine Does Not Predict Follow-Up Biopsy Findings Among Kidney Transplant Recipients With Antibody-Mediated Rejection. Transplant Direct 2023; 9:e1489. [PMID: 37250486 PMCID: PMC10212615 DOI: 10.1097/txd.0000000000001489] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Accepted: 03/23/2023] [Indexed: 05/31/2023] Open
Abstract
UNLABELLED Traditionally, antibody-mediated rejection (AMR) has been suspected mainly by a rise in serum creatinine (Scr) and confirmed by allograft biopsy. There is limited literature describing the trend of Scr after treatment, and how that trend might differ between patients with histological response and with no response to treatment. METHODS We included all cases of AMR at our program between March 2016 and July 2020 who had a follow-up biopsy after the index biopsy, with initial diagnosis of AMR. We trended the Scr and change in Scr (delta Scr) and its association with being a responder (microvascular inflammation, MVI ≤1) or nonresponder (MVI >1), as well as graft failure. RESULTS A total of 183 kidney transplant recipients were included, 66 in the responder group and 177 in the nonresponder group. The MVI scores and sum chronicity scores, along with transplant glomerulopathy scores, were higher in the nonresponder group. However, Scr at index biopsy was similar in responders (1.74 ± 0.70) versus nonresponders (1.83 ± 0.65; P = 0.39), as were the delta Scr at various time points. After adjustment for multiple variables, delta Scr was not associated with being a nonresponder. Also, delta Scr value at follow-up biopsy compared with index biopsy among responders was 0 ± 0.67 (P = 0.99) and among nonresponders was -0.01 ± 0.61 (P = 0.89). Being a nonresponder was significantly associated with an increased risk of graft failure at the last follow-up in univariate analysis but was not in multivariate analysis (hazard ratio 1.35; 95% confidence interval, 0.58-3.17; P = 0.49). CONCLUSIONS We found that Scr is not a good predictor of the resolution of MVI, supporting the utility of follow-up biopsies after treatment of AMR.
Collapse
Affiliation(s)
- Sandesh Parajuli
- Division of Nephrology, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI
| | - Weixiong Zhong
- Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI
| | - Monika Pantha
- Division of Nephrology, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI
| | - Megan Sokup
- Division of Nephrology, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI
| | - Fahad Aziz
- Division of Nephrology, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI
| | - Neetika Garg
- Division of Nephrology, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI
| | - Maha Mohamed
- Division of Nephrology, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI
| | - Didier Mandelbrot
- Division of Nephrology, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI
| |
Collapse
|
|
7
|
Okada M, Narumi S, Hasegawa Y, Futamura K, Hiramitsu T, Ichimori T, Goto N, Kobayashi T, Uchida K, Takeda A, Watarai Y. Optimal dose of rituximab in ABO-incompatible kidney transplantation in patients with low anti-A/B antibody titers: A single-center retrospective cohort study. Clin Transplant 2023; 37:e14915. [PMID: 36634703 DOI: 10.1111/ctr.14915] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2022] [Revised: 11/28/2022] [Accepted: 01/07/2023] [Indexed: 01/14/2023]
Abstract
BACKGROUND The clinical outcomes of ABO-incompatible (ABOi) kidney transplantation have improved with the introduction of desensitization therapy with rituximab. However, rituximab prevents not only antibody-mediated rejection (AMR) but also increases the risk of adverse events, such as infection. For ABOi kidney transplantation in patients with low anti-A/B antibody titers, we previously used a rituximab-free desensitization protocol and then initiated a single dose of 100 mg rituximab in 2016. We retrospectively compared the outcomes of ABOi kidney transplantation in patients with low anti-A/B antibody titers before and after the introduction of rituximab. METHODS ABOi kidney transplantations (n = 142) in patients with low anti-A/B antibody titers between 2007 and 2021 were included. Patients were divided into two groups (with and without rituximab) for desensitization. The primary outcomes were the incidence of acute AMR and infection. RESULTS Sixty-six patients were desensitized without rituximab (rituximab-free group), and 76 were pretreated with 100 mg rituximab (rituximab group) before transplantation. The incidence of acute AMR was significantly lower in the rituximab group than in the rituximab-free group (.0% [0/76] vs. 7.6% [5/66], respectively; p = .047). Post-transplantation anti-A/B antibody titers were also lower in the rituximab group than in the rituximab-free group. There was no significant difference in the incidence of adverse events, including infections, between the two groups. CONCLUSION In ABOi kidney transplantation patients with low anti-A/B antibody titers, the desensitization protocol with a single dose of 100 mg rituximab was effective in preventing acute AMR without increasing the risk of other adverse events.
Collapse
Affiliation(s)
- Manabu Okada
- Department of Transplant Surgery, Japanese Red Cross Aichi Medical Center Nagoya Daini Hospital, Nagoya, Japan.,Department of Transplant Nephrology, Japanese Red Cross Aichi Medical Center Nagoya Daini Hospital, Nagoya, Japan
| | - Shunji Narumi
- Department of Transplant Surgery, Japanese Red Cross Aichi Medical Center Nagoya Daini Hospital, Nagoya, Japan.,Department of Transplant Nephrology, Japanese Red Cross Aichi Medical Center Nagoya Daini Hospital, Nagoya, Japan
| | - Yuki Hasegawa
- Department of Transplant Surgery, Japanese Red Cross Aichi Medical Center Nagoya Daini Hospital, Nagoya, Japan.,Department of Transplant Nephrology, Japanese Red Cross Aichi Medical Center Nagoya Daini Hospital, Nagoya, Japan
| | - Kenta Futamura
- Department of Transplant Surgery, Japanese Red Cross Aichi Medical Center Nagoya Daini Hospital, Nagoya, Japan.,Department of Transplant Nephrology, Japanese Red Cross Aichi Medical Center Nagoya Daini Hospital, Nagoya, Japan
| | - Takahisa Hiramitsu
- Department of Transplant Surgery, Japanese Red Cross Aichi Medical Center Nagoya Daini Hospital, Nagoya, Japan.,Department of Transplant Nephrology, Japanese Red Cross Aichi Medical Center Nagoya Daini Hospital, Nagoya, Japan
| | - Toshihiro Ichimori
- Department of Transplant Surgery, Japanese Red Cross Aichi Medical Center Nagoya Daini Hospital, Nagoya, Japan.,Department of Transplant Nephrology, Japanese Red Cross Aichi Medical Center Nagoya Daini Hospital, Nagoya, Japan
| | - Norihiko Goto
- Department of Transplant Surgery, Japanese Red Cross Aichi Medical Center Nagoya Daini Hospital, Nagoya, Japan.,Department of Transplant Nephrology, Japanese Red Cross Aichi Medical Center Nagoya Daini Hospital, Nagoya, Japan
| | - Takaaki Kobayashi
- Department of Renal Transplant Surgery, Aichi Medical University School of Medicine, Nagakute, Japan
| | - Kazuharu Uchida
- Department of Renal Transplant Surgery, Masuko Memorial Hospital, Nagoya, Japan
| | - Asami Takeda
- Department of Nephrology, Japanese Red Cross Aichi Medical Center Nagoya Daini Hospital, Nagoya, Japan
| | - Yoshihiko Watarai
- Department of Transplant Surgery, Japanese Red Cross Aichi Medical Center Nagoya Daini Hospital, Nagoya, Japan.,Department of Transplant Nephrology, Japanese Red Cross Aichi Medical Center Nagoya Daini Hospital, Nagoya, Japan
| |
Collapse
|
|
8
|
McGovern KE, Sonar SA, Watanabe M, Coplen CP, Bradshaw CM, Nikolich JŽ. The aging of the immune system and its implications for transplantation. GeroScience 2023:10.1007/s11357-022-00720-2. [PMID: 36626019 PMCID: PMC9838392 DOI: 10.1007/s11357-022-00720-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2022] [Accepted: 12/21/2022] [Indexed: 01/11/2023] Open
Abstract
By the last third of life, most mammals, including humans, exhibit a decline in immune cell numbers, immune organ structure, and immune defense of the organism, commonly known as immunosenescence. This decline leads to clinical manifestations of increased susceptibility to infections, particularly those caused by emerging and reemerging microorganisms, which can reach staggering levels-infection with SARS-CoV-2 has been 270-fold more lethal to older adults over 80 years of age, compared to their 18-39-year-old counterparts. However, while this would be expected to be beneficial to situations where hyporeactivity of the immune system may be desirable, this is not always the case. Here, we discuss the cellular and molecular underpinnings of immunosenescence as they pertain to outcomes of solid organ and hematopoietic transplantation.
Collapse
Affiliation(s)
- Kathryn E McGovern
- Department of Immunobiology, University of Arizona, Tucson, AZ, 85724, USA
- Arizona Center On Aging, The University of Arizona, University of Arizona College of Medicine-Tucson, Tucson, AZ, 85724, USA
- BIO5 Institute, University of Arizona, Tucson, AZ, USA
| | - Sandip A Sonar
- Department of Immunobiology, University of Arizona, Tucson, AZ, 85724, USA
- Arizona Center On Aging, The University of Arizona, University of Arizona College of Medicine-Tucson, Tucson, AZ, 85724, USA
| | - Makiko Watanabe
- Department of Immunobiology, University of Arizona, Tucson, AZ, 85724, USA
- Arizona Center On Aging, The University of Arizona, University of Arizona College of Medicine-Tucson, Tucson, AZ, 85724, USA
| | - Christopher P Coplen
- Department of Immunobiology, University of Arizona, Tucson, AZ, 85724, USA
- Arizona Center On Aging, The University of Arizona, University of Arizona College of Medicine-Tucson, Tucson, AZ, 85724, USA
| | - Christine M Bradshaw
- Department of Immunobiology, University of Arizona, Tucson, AZ, 85724, USA
- Arizona Center On Aging, The University of Arizona, University of Arizona College of Medicine-Tucson, Tucson, AZ, 85724, USA
| | - Janko Ž Nikolich
- Department of Immunobiology, University of Arizona, Tucson, AZ, 85724, USA.
- Arizona Center On Aging, The University of Arizona, University of Arizona College of Medicine-Tucson, Tucson, AZ, 85724, USA.
- BIO5 Institute, University of Arizona, Tucson, AZ, USA.
- The Aegis Consortium for Pandemic-free Future, University of Arizona Health Sciences, University of Arizona, Tucson, 85719, USA.
| |
Collapse
|
|
9
|
Nishiura H, Takahashi M, Iwai T, Uchida J, Nakamura Y. Analysis of Risk Factors for Infusion-Related Reactions Following Rituximab Administration in Patients with Desensitization before Renal Transplantation. Biol Pharm Bull 2023; 46:1332-1337. [PMID: 37661411 DOI: 10.1248/bpb.b23-00157] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/05/2023]
Abstract
Infusion-related reactions (IRRs) are the major side effects of rituximab administration. Although several studies have reported predictive markers for IRRs in patients with malignancies, there are no such reports for patients without malignancies. Accordingly, we aimed to clarify the predictive markers for rituximab-induced IRRs in renal transplant recipients. This retrospective study included 116 inpatients aged ≥18 years who received an initial dose of 150 mg/m2 of rituximab for desensitization before renal transplantation with loxoprofen and diphenhydramine before rituximab infusion between June 2007 and February 2022. Overall, 45 patients were evaluated and 71 patients were excluded in this study. IRRs were observed in 12 (26.7%) patients. The proportion of men in the IRRs group was significantly higher than that in the non-IRRs group (p = 0.023). Additionally, body weight, body surface area (BSA), and body mass index (BMI) were significantly higher in the IRRs group than in the non-IRRs group (body weight, p = 0.0058; BSA, p = 0.0051; BMI, p = 0.017). Their cutoff values for predicting rituximab-induced IRRs, based on the receiver-operating characteristic curve, were 74.850 kg, 1.910 m2 and 24.164 kg/m2, respectively. In conclusion, the male sex, high actual body weight, BSA, and BMI may be new predictive markers for rituximab-induced IRRs in renal transplant recipients. Therefore, clinicians should carefully monitor patients who receive rituximab before renal transplantation and present with the predictive markers.
Collapse
Affiliation(s)
| | | | - Tomoaki Iwai
- Department of Urology, Osaka Metropolitan University Graduate School of Medicine
| | - Junji Uchida
- Department of Urology, Osaka Metropolitan University Graduate School of Medicine
| | | |
Collapse
|
|
10
|
Bernard J, Sellier-Leclerc AL, Demède D, Chamouard V, Ranchin B, Bacchetta J. Rituximab as induction therapy in pediatric kidney transplantation: A single-center experience in four patients. Pediatr Transplant 2022; 26:e14329. [PMID: 35655369 DOI: 10.1111/petr.14329] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2022] [Revised: 05/03/2022] [Accepted: 05/11/2022] [Indexed: 11/30/2022]
Abstract
BACKGROUND The anti-CD20 rituximab is often used in the treatment of children with steroid-resistant nephrotic syndrome or EBV-induced post-transplant lymphoproliferative disorder. This single-center series reports the use of rituximab as induction therapy in pediatric kidney transplantation. METHODS Four children who received rituximab as induction therapy for kidney transplantation since 2016 were retrospectively analyzed. Clinical and laboratory data were extracted from medical records. RESULTS The patients (2 boys and 2 girls) were aged from 6.1 to 11.9 years and were treated with rituximab on the day of the transplantation procedure; all the transplants came from deceased donors. In all patients, rituximab was used because of positive EBV viral loads before kidney transplantation. Viral loads remained undetectable for the first 6 months after the transplantation procedure and remained below the 4.5 log threshold thereafter. After a median follow-up of 2.3 years, none of the patients displayed rejection or de novo donor-specific antibodies; the glomerular filtration rate remained above 70 ml/min/1.73 m2 . No post-transplant lymphoproliferative disorder was observed. CONCLUSION The results suggest that rituximab can be used as induction therapy to prevent EBV replication and its complications in case of positive viral load prior to kidney transplantation.
Collapse
Affiliation(s)
- Josselin Bernard
- Pediatric Department, University Hospital of Nantes, Nantes, France.,Pediatric Nephrology, Rheumatology and Dermatology Unit, Reference Center for Rare Renal Diseases, Hôpital Femme Mère Enfant, Rare Disease Networks ORKID and ERK-Net, Hospices Civils de Lyon, Bron, France
| | - Anne-Laure Sellier-Leclerc
- Pediatric Nephrology, Rheumatology and Dermatology Unit, Reference Center for Rare Renal Diseases, Hôpital Femme Mère Enfant, Rare Disease Networks ORKID and ERK-Net, Hospices Civils de Lyon, Bron, France
| | - Delphine Demède
- Pediatric Surgery Department, Hôpital Femme Mère Enfant, Hospices Civils de Lyon, Bron, France
| | - Valérie Chamouard
- Pharmacy Department, Groupement Hospitalier Est, Hospices Civils de Lyon, Bron, France
| | - Bruno Ranchin
- Pediatric Nephrology, Rheumatology and Dermatology Unit, Reference Center for Rare Renal Diseases, Hôpital Femme Mère Enfant, Rare Disease Networks ORKID and ERK-Net, Hospices Civils de Lyon, Bron, France
| | - Justine Bacchetta
- Pediatric Nephrology, Rheumatology and Dermatology Unit, Reference Center for Rare Renal Diseases, Hôpital Femme Mère Enfant, Rare Disease Networks ORKID and ERK-Net, Hospices Civils de Lyon, Bron, France.,Pediatric Surgery Department, Hôpital Femme Mère Enfant, Hospices Civils de Lyon, Bron, France.,Pharmacy Department, Groupement Hospitalier Est, Hospices Civils de Lyon, Bron, France.,Lyon Est Medical School, Lyon 1 University, Lyon, France
| |
Collapse
|
|
11
|
Zhou Q, Li T, Wang K, Zhang Q, Geng Z, Deng S, Cheng C, Wang Y. Current status of xenotransplantation research and the strategies for preventing xenograft rejection. Front Immunol 2022; 13:928173. [PMID: 35967435 PMCID: PMC9367636 DOI: 10.3389/fimmu.2022.928173] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2022] [Accepted: 07/07/2022] [Indexed: 12/13/2022] Open
Abstract
Transplantation is often the last resort for end-stage organ failures, e.g., kidney, liver, heart, lung, and pancreas. The shortage of donor organs is the main limiting factor for successful transplantation in humans. Except living donations, other alternatives are needed, e.g., xenotransplantation of pig organs. However, immune rejection remains the major challenge to overcome in xenotransplantation. There are three different xenogeneic types of rejections, based on the responses and mechanisms involved. It includes hyperacute rejection (HAR), delayed xenograft rejection (DXR) and chronic rejection. DXR, sometimes involves acute humoral xenograft rejection (AHR) and cellular xenograft rejection (CXR), which cannot be strictly distinguished from each other in pathological process. In this review, we comprehensively discussed the mechanism of these immunological rejections and summarized the strategies for preventing them, such as generation of gene knock out donors by different genome editing tools and the use of immunosuppressive regimens. We also addressed organ-specific barriers and challenges needed to pave the way for clinical xenotransplantation. Taken together, this information will benefit the current immunological research in the field of xenotransplantation.
Collapse
Affiliation(s)
- Qiao Zhou
- Department of Rheumatology and Immunology, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
- Clinical Immunology Translational Medicine Key Laboratory of Sichuan Province, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
- Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, China
| | - Ting Li
- Department of Rheumatology, Wenjiang District People’s Hospital, Chengdu, China
| | - Kaiwen Wang
- School of Medicine, Faculty of Medicine and Health, The University of Leeds, Leeds, United Kingdom
| | - Qi Zhang
- School of Medicine, University of Electronics and Technology of China, Chengdu, China
| | - Zhuowen Geng
- School of Medicine, Faculty of Medicine and Health, The University of Leeds, Leeds, United Kingdom
| | - Shaoping Deng
- Clinical Immunology Translational Medicine Key Laboratory of Sichuan Province, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
- Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, China
- Institute of Organ Transplantation, Sichuan Academy of Medical Science and Sichuan Provincial People’s Hospital, Chengdu, China
| | - Chunming Cheng
- Department of Radiation Oncology, James Comprehensive Cancer Center and College of Medicine at The Ohio State University, Columbus, OH, United States
- *Correspondence: Chunming Cheng, ; Yi Wang,
| | - Yi Wang
- Department of Critical Care Medicine, Sichuan Academy of Medical Science and Sichuan Provincial People's Hospital, Chengdu, China
- *Correspondence: Chunming Cheng, ; Yi Wang,
| |
Collapse
|
|
12
|
Lee YH, Sato Y, Saito M, Fukuma S, Saito M, Yamamoto S, Komatsuda A, Fujiyama N, Satoh S, Lee SH, Boor P, Habuchi T, Floege J, Yanagita M. Advanced Tertiary Lymphoid Tissues in Protocol Biopsies are Associated with Progressive Graft Dysfunction in Kidney Transplant Recipients. J Am Soc Nephrol 2022; 33:186-200. [PMID: 34725107 PMCID: PMC8763171 DOI: 10.1681/asn.2021050715] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2021] [Accepted: 09/13/2021] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND Tertiary lymphoid tissues (TLTs) are ectopic lymphoid tissues found in chronically inflamed organs. Although studies have documented TLT formation in transplanted kidneys, the clinical relevance of these TLTs remains controversial. We examined the effects of TLTs on future graft function using our histologic TLT maturity stages and the association between TLTs and Banff pathologic scores. We also analyzed the risk factors for the development of TLTs. METHODS Serial protocol biopsy samples (0 hour, 1, 6, and 12 months) without rejection were retrospectively analyzed from 214 patients who underwent living donor kidney transplantation. TLTs were defined as lymphocyte aggregates with signs of proliferation and their stages were determined by the absence (stage I) or presence (stage II) of follicular dendritic cells. RESULTS Only 4% of patients exhibited TLTs at the 0-hour biopsy. Prevalence increased to almost 50% at the 1-month biopsy, and then slightly further for 12 months. The proportion of advanced stage II TLTs increased gradually, reaching 19% at the 12-month biopsy. Presence of stage II TLTs was associated with higher risk of renal function decline after transplantation compared with patients with no TLT or stage I TLTs. Stage II TLTs were associated with more severe tubulitis and interstitial fibrosis/tubular atrophy at 12 months and predicted poorer graft function independently from the degree of interstitial inflammation. Pretransplantation rituximab treatment dramatically attenuated the development of stage II TLTs. CONCLUSIONS TLTs are commonly found in clinically stable transplanted kidneys. Advanced stage II TLTs are associated with progressive graft dysfunction, independent of interstitial inflammation.
Collapse
Affiliation(s)
- Yu Ho Lee
- Department of Nephrology, Graduate School of Medicine, Kyoto University, Kyoto, Japan,Division of Nephrology, Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam, Republic of Korea
| | - Yuki Sato
- Department of Nephrology, Graduate School of Medicine, Kyoto University, Kyoto, Japan,Medical Innovation Center TMK Project, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Mitsuru Saito
- Department of Urology, Graduate School of Medicine, Akita University, Akita, Japan
| | - Shingo Fukuma
- Human Health Sciences, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Masaya Saito
- Department of Hematology, Nephrology, and Rheumatology, Graduate School of Medicine, Akita University, Akita, Japan
| | - Shigenori Yamamoto
- Department of Nephrology, Graduate School of Medicine, Kyoto University, Kyoto, Japan,Medical Innovation Center TMK Project, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Atsushi Komatsuda
- Department of Hematology, Nephrology, and Rheumatology, Graduate School of Medicine, Akita University, Akita, Japan
| | - Nobuhiro Fujiyama
- Center for Kidney Disease and Transplantation, Akita University Hospital, Akita, Japan
| | - Shigeru Satoh
- Center for Kidney Disease and Transplantation, Akita University Hospital, Akita, Japan
| | - Sang-Ho Lee
- Division of Nephrology, Department of Internal Medicine, Kyung Hee University, Seoul, Republic of Korea
| | - Peter Boor
- Institute of Pathology, RWTH University of Aachen, Germany, Aachen, Germany,Division of Nephrology, RWTH University of Aachen, Germany, Aachen, Germany,Electron Microscopy Facility, RWTH University of Aachen, Aachen, Germany
| | - Tomonori Habuchi
- Department of Urology, Graduate School of Medicine, Akita University, Akita, Japan
| | - Jürgen Floege
- Division of Nephrology, RWTH University of Aachen, Germany, Aachen, Germany
| | - Motoko Yanagita
- Department of Nephrology, Graduate School of Medicine, Kyoto University, Kyoto, Japan,Institute for the Advanced Study of Human Biology (ASHBi), Kyoto University, Kyoto, Japan
| |
Collapse
|
|
13
|
Bikhet M, Iwase H, Yamamoto T, Jagdale A, Foote JB, Ezzelarab M, Anderson DJ, Locke JE, Eckhoff DE, Hara H, Cooper DKC. What Therapeutic Regimen Will Be Optimal for Initial Clinical Trials of Pig Organ Transplantation? Transplantation 2021; 105:1143-1155. [PMID: 33534529 DOI: 10.1097/tp.0000000000003622] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
We discuss what therapeutic regimen might be acceptable/successful in the first clinical trial of genetically engineered pig kidney or heart transplantation. As regimens based on a calcineurin inhibitor or CTLA4-Ig have proved unsuccessful, the regimen we administer to baboons is based on induction therapy with antithymocyte globulin, an anti-CD20 mAb (Rituximab), and cobra venom factor, with maintenance therapy based on blockade of the CD40/CD154 costimulation pathway (with an anti-CD40 mAb), with rapamycin, and a corticosteroid. An anti-inflammatory agent (etanercept) is administered for the first 2 wk, and adjuvant therapy includes prophylaxis against thrombotic complications, anemia, cytomegalovirus, and pneumocystis. Using this regimen, although antibody-mediated rejection certainly can occur, we have documented no definite evidence of an adaptive immune response to the pig xenograft. This regimen could also form the basis for the first clinical trial, except that cobra venom factor will be replaced by a clinically approved agent, for example, a C1-esterase inhibitor. However, none of the agents that block the CD40/CD154 pathway are yet approved for clinical use, and so this hurdle remains to be overcome. The role of anti-inflammatory agents remains unproven. The major difference between this suggested regimen and those used in allotransplantation is the replacement of a calcineurin inhibitor with a costimulation blockade agent, but this does not appear to increase the complications of the regimen.
Collapse
Affiliation(s)
- Mohamed Bikhet
- Xenotransplantation Program, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL
| | - Hayato Iwase
- Xenotransplantation Program, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL
| | - Takayuki Yamamoto
- Xenotransplantation Program, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL
| | - Abhijit Jagdale
- Xenotransplantation Program, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL
| | - Jeremy B Foote
- Department of Microbiology and Animal Resources Program, University of Alabama at Birmingham, Birmingham, AL
| | - Mohamed Ezzelarab
- Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA
| | - Douglas J Anderson
- Division of Transplantation, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL
| | - Jayme E Locke
- Division of Transplantation, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL
| | - Devin E Eckhoff
- Division of Transplantation, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL
| | - Hidetaka Hara
- Xenotransplantation Program, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL
| | - David K C Cooper
- Xenotransplantation Program, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL
| |
Collapse
|
|
14
|
Schmitz R, Fitch ZW, Schroder PM, Choi AY, Jackson AM, Knechtle SJ, Kwun J. B cells in transplant tolerance and rejection: friends or foes? Transpl Int 2021; 33:30-40. [PMID: 31705678 DOI: 10.1111/tri.13549] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2019] [Revised: 10/21/2019] [Accepted: 11/04/2019] [Indexed: 12/14/2022]
Abstract
Our understanding of the role of B cells in organ transplantation remains incomplete and continues to grow. The majority of research has focused on the detrimental role of antibodies that drive the development of pathogenesis of the transplanted organ. However, it has been shown that not all donor-specific antibodies are harmful and in some circumstances can even promote tolerance through the mechanism of accommodation. Furthermore, B cells can have effects on transplanted organs through their interaction with T cells, namely antigen presentation, cytokine production, and costimulation. More recently, the role and importance of Bregs was introduced to the field of transplantation. Due to this functional and ontogenetic heterogeneity, targeting B cells in transplantation may bring undesired immunologic side effects including increased rejection. Therefore, the selective control of B cells that contribute to the humoral response against donor antigens will continue to be an important and challenging area of research and potentially lead to improved long-term transplant outcomes.
Collapse
Affiliation(s)
- Robin Schmitz
- Department of Surgery, Duke Transplant Center, Duke University Medical Center, Durham, NC, USA
| | - Zachary W Fitch
- Department of Surgery, Duke Transplant Center, Duke University Medical Center, Durham, NC, USA
| | - Paul M Schroder
- Department of Surgery, Duke Transplant Center, Duke University Medical Center, Durham, NC, USA
| | - Ashley Y Choi
- Department of Surgery, Duke Transplant Center, Duke University Medical Center, Durham, NC, USA
| | - Annette M Jackson
- Department of Surgery, Duke Transplant Center, Duke University Medical Center, Durham, NC, USA
| | - Stuart J Knechtle
- Department of Surgery, Duke Transplant Center, Duke University Medical Center, Durham, NC, USA
| | - Jean Kwun
- Department of Surgery, Duke Transplant Center, Duke University Medical Center, Durham, NC, USA
| |
Collapse
|
|
15
|
Impact of rituximab on the T-cell flow cytometric crossmatch. Transpl Immunol 2020; 64:101360. [PMID: 33359130 DOI: 10.1016/j.trim.2020.101360] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2020] [Revised: 12/13/2020] [Accepted: 12/16/2020] [Indexed: 12/30/2022]
Abstract
Rituximab is frequently used in the setting of ABO-incompatible renal transplants, and highly sensitized patients. Its interference with B-cell flow cytometric crossmatch (B-FCXM) is well known. However, its effect on the T-cell flow cytometric crossmatch (T-FCXM) has not been described. We aimed to evaluate the effect of rituximab on the T-FCXM using non-pronase and pronase treated donor lymphocytes and compare results with the single antigen bead (SAB) assay. In this retrospective study, 28 patients on rituximab therapy were evaluated against 30 donors. Using non-pronase treated donor lymphocytes, all 30 FCXMs showed strong B-cell positivity {median (IQR) B-cell ratio: 184.65 (253.17)} which significantly reduced {1.0 (1.18); p < 0.00001} with pronase treatment. 'T-cell tailing' phenomenon was observed in 17/30 FCXMs in the non-pronase group as a 'tail of T-cells', indicating a rare sub-population. However, it disappeared in the pronase-treated group. SAB assay did not show donor-specific antibodies (DSA) in all 17 patients with 'T-cell tailing' phenomenon. Although, rituximab is described to impact only B-FCXM, we have consistently found 'T-cell tailing' in 57% of T-FCXMs, which clears with pronase treatment. The 'T-cell tailing' led to weak positive T-FCMX ratios due to increased MFI in the FL1 channel. However, the absence of DSA in all recipients reinforces the fact that this is a false positive finding and should not be misconstrued as a possible class I DSA. Structural homology of Fc receptors on activated T-cells to CD20 could be a possible explanation of the same and provide insight into a novel mechanism of action of rituximab.
Collapse
|
|
16
|
Yoshinaga K, Araki M, Wada K, Maruyama Y, Mitsui Y, Sadahira T, Kubota R, Nishimura S, Kobayashi Y, Takeuchi H, Tanabe K, Kitagawa M, Morinaga H, Uchida HA, Kitamura S, Sugiyama H, Wada J, Watanabe M, Watanabe T, Nasu Y. Low-dose rituximab induction therapy is effective in immunological high-risk renal transplantation without increasing cytomegalovirus infection. Int J Urol 2020; 27:1136-1142. [PMID: 33012030 DOI: 10.1111/iju.14382] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2020] [Accepted: 08/17/2020] [Indexed: 11/30/2022]
Abstract
OBJECTIVES To analyze the effect and impact of low-dose rituximab induction therapy on cytomegalovirus infection in living-donor renal transplantation. METHODS A total of 92 recipients undergoing living-donor renal transplantation at Okayama University Hospital from May 2009 to August 2018 were evaluated retrospectively. Indications for preoperative rituximab (200 mg/body) were the following: (i) ABO major mismatch; (ii) ABO minor mismatch; (iii) donor-specific anti-human leukocyte antigen antibody-positive; and (iv) focal segmental glomerulosclerosis. We excluded four recipients who were followed <3 months, five who received >200 mg/body rituximab and seven who received prophylactic therapy for cytomegalovirus. RESULTS There were 59 patients in the rituximab group and 17 in the non-rituximab group. Groups differed significantly in age (median age 53 vs 37 years, respectively; P = 0.04), but not in sex (male 64% vs 65%, P = 1.00), focal segmental glomerulosclerosis (3% vs 0%, P = 1.00) or percentage of cytomegalovirus-seronegative recipients of renal allografts from cytomegalovirus-seropositive donors (12% vs 18%, P = 0.68). The estimated glomerular filtration rate did not differ significantly between groups until 24 months after transplantation. Cytomegalovirus clinical symptoms (10% vs 24%, P = 0.22), including fever ≥38°C (5% vs 12%, P = 0.31) and gastrointestinal symptoms (5% vs 12%, P = 0.31), and the 5-year survival rates of death-censored graft loss (90% vs 83%, P = 0.43) did not differ significantly between groups. CONCLUSIONS Low-dose rituximab induction therapy is effective in immunological high-risk recipients without increasing cytomegalovirus infection in the absence of valganciclovir prophylaxis.
Collapse
Affiliation(s)
- Kasumi Yoshinaga
- Departments of, Department of, Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Science, Okayama, Japan
| | - Motoo Araki
- Departments of, Department of, Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Science, Okayama, Japan
| | - Koichiro Wada
- Departments of, Department of, Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Science, Okayama, Japan
| | - Yuki Maruyama
- Departments of, Department of, Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Science, Okayama, Japan
| | - Yosuke Mitsui
- Departments of, Department of, Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Science, Okayama, Japan
| | - Takuya Sadahira
- Departments of, Department of, Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Science, Okayama, Japan
| | - Risa Kubota
- Departments of, Department of, Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Science, Okayama, Japan
| | - Shingo Nishimura
- Departments of, Department of, Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Science, Okayama, Japan
| | - Yasuyuki Kobayashi
- Departments of, Department of, Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Science, Okayama, Japan
| | - Hidemi Takeuchi
- Department of, Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Science, Okayama, Japan
| | - Katsuyuki Tanabe
- Department of, Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Science, Okayama, Japan
| | - Masashi Kitagawa
- Department of, Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Science, Okayama, Japan
| | - Hiroshi Morinaga
- Department of, Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Science, Okayama, Japan
| | - Haruhito Adam Uchida
- Department of, Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Science, Okayama, Japan
| | - Shinji Kitamura
- Department of, Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Science, Okayama, Japan
| | - Hitoshi Sugiyama
- Department of, Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Science, Okayama, Japan
| | - Jun Wada
- Department of, Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Science, Okayama, Japan
| | - Masami Watanabe
- Departments of, Department of, Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Science, Okayama, Japan
| | - Toyohiko Watanabe
- Departments of, Department of, Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Science, Okayama, Japan
| | - Yasutomo Nasu
- Departments of, Department of, Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Science, Okayama, Japan
| |
Collapse
|
|
17
|
Rogers DL, Ruiz JC, Baze WB, McClure GB, Smith C, Urbanowski R, Boston T, Simmons JH, Williams L, Abee CR, Vanchiere JA. Epidemiological and molecular characterization of a novel adenovirus of squirrel monkeys after fatal infection during immunosuppression. Microb Genom 2020; 6:mgen000395. [PMID: 32614763 PMCID: PMC7643968 DOI: 10.1099/mgen.0.000395] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2020] [Accepted: 05/29/2020] [Indexed: 11/18/2022] Open
Abstract
Adenoviruses are a frequent cause of acute upper respiratory tract infections that can also cause disseminated disease in immunosuppressed patients. We identified a novel adenovirus, squirrel monkey adenovirus 1 (SqMAdV-1), as the cause of fatal infection in an immunocompromised squirrel monkey (Saimiri boliviensis) at the Keeling Center for Comparative Medicine and Research (KCCMR). Sequencing of SqMAdV-1 revealed that it is most closely related (80.4 % pairwise nucleotide identity) to the titi monkey (Plecturocebus cupreus) adenovirus (TMAdV). Although identified in the titi monkey, TMAdV is highly lethal in these monkeys, and they are not thought to be the natural host. While SqMAdV-1 is similar to other primate adenoviruses in size and genomic characteristics, a nucleotide polymorphism at the expected stop codon of the DNA polymerase gene results in a 126 amino acid extension at the carboxy terminus, a feature not previously observed among other primate adenoviruses. PCR testing and partial sequencing of 95 archived faecal samples from other squirrel monkeys (Saimiri boliviensis and Saimiri sciureus) housed at the KCCMR revealed the presence of three distinct, and apparently endemic species of adenoviruses. A grouping of ten squirrel monkey adenovirus variants has high similarity to SqMAdV-1. A single adenovirus variant (designated SqMAdV-3), detected in five monkeys, has similarity to tufted capuchin (Sapajus apella) adenoviruses. The largest group of adenovirus variants detected (designated SqMAdV-2.0-2.16) has very high similarity (93-99 %) to the TMAdV, suggesting that squirrel monkeys may be the natural host of the TMAdV.
Collapse
Affiliation(s)
- Donna L. Rogers
- Department of Pediatrics, Louisiana State University Health Sciences Center, Shreveport, LA, USA
| | - Julio C. Ruiz
- Keeling Center for Comparative Medicine Research, Department of Comparative Medicine, The University of Texas MD Anderson Cancer Center, Bastrop, TX, USA
| | - Wallace B. Baze
- Keeling Center for Comparative Medicine Research, Department of Comparative Medicine, The University of Texas MD Anderson Cancer Center, Bastrop, TX, USA
| | - Gloria B. McClure
- Department of Pediatrics, Louisiana State University Health Sciences Center, Shreveport, LA, USA
| | - Carolyn Smith
- Department of Pediatrics, Louisiana State University Health Sciences Center, Shreveport, LA, USA
| | - Ricky Urbanowski
- Department of Pediatrics, Louisiana State University Health Sciences Center, Shreveport, LA, USA
| | - Theresa Boston
- Department of Pediatrics, Louisiana State University Health Sciences Center, Shreveport, LA, USA
| | - Joe H. Simmons
- Keeling Center for Comparative Medicine Research, Department of Comparative Medicine, The University of Texas MD Anderson Cancer Center, Bastrop, TX, USA
| | - Lawrence Williams
- Keeling Center for Comparative Medicine Research, Department of Comparative Medicine, The University of Texas MD Anderson Cancer Center, Bastrop, TX, USA
| | - Christian R. Abee
- Keeling Center for Comparative Medicine Research, Department of Comparative Medicine, The University of Texas MD Anderson Cancer Center, Bastrop, TX, USA
| | - John A. Vanchiere
- Department of Pediatrics, Louisiana State University Health Sciences Center, Shreveport, LA, USA
- Keeling Center for Comparative Medicine Research, Department of Comparative Medicine, The University of Texas MD Anderson Cancer Center, Bastrop, TX, USA
| |
Collapse
|
|
18
|
Degner KR, Wilson NA, Reese SR, Parajuli S, Aziz F, Garg N, Mohamed M, Singh T, Mandelbrot DA, Panzer SE, Redfield RR, Van Hyfte K, Zhong W, Hidalgo LG, Djamali A. Short-term Immunopathological Changes Associated with Pulse Steroids/IVIG/Rituximab Therapy in Late Kidney Allograft Antibody Mediated Rejection. KIDNEY360 2020; 1:389-398. [PMID: 34476406 PMCID: PMC8409258 DOI: 10.34067/kid.0001082019] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/20/2019] [Accepted: 03/11/2020] [Indexed: 01/07/2023]
Abstract
BACKGROUND B-cell depletion is a common treatment of antibody-mediated rejection (ABMR). We sought to determine the specific immunopathologic effects of this therapeutic approach in kidney transplantation. METHODS This was a prospective observational study of kidney transplant recipients diagnosed with late ABMR (>3 months after transplant). Patients received treatment with pulse steroids, IVIG, and rituximab. Donor specific HLA antibodies (DSA), kidney allograft pathology, renal function, immune cell phenotypes, and 47 circulating cytokines were assessed at baseline and at three months. RESULTS We enrolled 23 patients in this study between April 2015 and March 2019. The majority of patients were male (74%) and Caucasian (78%) with an average age of 45.6±13.8 years. ABMR was diagnosed at 6.8±5.9 years (4 months-25 years) post-transplant. Treatment was associated with a significant decline in circulating HLA class I DSA (P=0.003) and class II DSA (P=0.002) and peritubular capillaritis (ptc, P=0.04) compared to baseline. Serum creatinine, BUN, eGFR, and proteinuria (UPC) remained stable. Circulating B-cells were depleted to barely detectable levels (P≤0.001), whereas BAFF (P=0.001), APRIL (P<0.001), and IL-10 (P=0.02), levels increased significantly post-treatment. Notably, there was a significant rise in circulating CD4+ (P=0.02) and CD8+ T-cells (P=0.003). We also noted a significant correlation between circulating cytotoxic CD8+ T-cells and BAFF (P=0.05), regulatory T-cells and IL10 (P=0.002), and HLA class I DSA (P=0.005). CONCLUSIONS Short-term pulse steroids/IVIG/rituximab therapy was associated with inhibition of ABMR (DSA and ptc), stabilization of kidney function, and increased regulatory B-cell and T-cell survival cytokines. Additional studies are needed to understand the implications of B cell-depletion on the crosstalk between T-cells, B-cells, and humoral components that regulate ABMR.
Collapse
Affiliation(s)
- Kenna R. Degner
- Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - Nancy A. Wilson
- Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
- Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - Shannon R. Reese
- Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - Sandesh Parajuli
- Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - Fahad Aziz
- Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - Neetika Garg
- Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - Maha Mohamed
- Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - Tripti Singh
- Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - Didier A. Mandelbrot
- Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - Sarah E. Panzer
- Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - Robert R. Redfield
- Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - Kristin Van Hyfte
- The Office of Clinical Trials, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - Weixiong Zhong
- Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - Luis G. Hidalgo
- Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - Arjang Djamali
- Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
- Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| |
Collapse
|
|
19
|
Shiu KY, Stringer D, McLaughlin L, Shaw O, Brookes P, Burton H, Wilkinson H, Douthwaite H, Tsui TL, Mclean A, Hilton R, Griffin S, Geddes C, Ball S, Baker R, Roufosse C, Horsfield C, Dorling A. Effect of Optimized Immunosuppression (Including Rituximab) on Anti-Donor Alloresponses in Patients With Chronically Rejecting Renal Allografts. Front Immunol 2020; 11:79. [PMID: 32117242 PMCID: PMC7012933 DOI: 10.3389/fimmu.2020.00079] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2019] [Accepted: 01/13/2020] [Indexed: 12/22/2022] Open
Abstract
RituxiCAN-C4 combined an open-labeled randomized controlled trial (RCT) in 7 UK centers to assess whether rituximab could stabilize kidney function in patients with chronic rejection, with an exploratory analysis of how B cell-depletion influenced T cell anti-donor responses relative to outcome. Between January 2007 and March 2015, 59 recruits were enrolled after screening, 23 of whom consented to the embedded RCT. Recruitment was halted when in a pre-specified per protocol interim analysis, the RCT was discovered to be significantly underpowered. This report therefore focuses on the exploratory analysis, in which we confirmed that when B cells promoted CD4+ anti-donor IFNγ production assessed by ELISPOT, this associated with inferior clinical outcome; these patterns were inhibited by optimized immunosuppression but not rituximab. B cell suppression of IFNγ production, which associated with number of transitional B cells and correlated with slower declines in kidney function was abolished by rituximab, which depleted transitional B cells for prolonged periods. We conclude that in this patient population, optimized immunosuppression but not rituximab promotes anti-donor alloresponses associated with favorable outcomes. Clinical Trial Registration: Registered with EudraCT (2006-002330-38) and www.ClinicalTrials.gov, identifier: NCT00476164.
Collapse
Affiliation(s)
- Kin Yee Shiu
- Department of Inflammation Biology, MRC Centre for Transplantation, Guy's Hospital, King's College London, London, United Kingdom
| | - Dominic Stringer
- Biostatistics and Health Informatics, The Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom
| | - Laura McLaughlin
- Department of Inflammation Biology, MRC Centre for Transplantation, Guy's Hospital, King's College London, London, United Kingdom
| | - Olivia Shaw
- Viapath Analytics LLP, London, United Kingdom
| | - Paul Brookes
- Histocompatibility and Immunogenetics, Imperial College Healthcare NHS Trust, London, United Kingdom
| | - Hannah Burton
- Department of Inflammation Biology, MRC Centre for Transplantation, Guy's Hospital, King's College London, London, United Kingdom
| | - Hannah Wilkinson
- Department of Inflammation Biology, MRC Centre for Transplantation, Guy's Hospital, King's College London, London, United Kingdom
| | - Harriet Douthwaite
- Department of Inflammation Biology, MRC Centre for Transplantation, Guy's Hospital, King's College London, London, United Kingdom
| | - Tjir-Li Tsui
- Department of Inflammation Biology, MRC Centre for Transplantation, Guy's Hospital, King's College London, London, United Kingdom
| | - Adam Mclean
- Imperial College Renal and Transplant Centre, Imperial College Healthcare NHS Trust, London, United Kingdom
| | - Rachel Hilton
- Department of Nephrology and Transplantation, Guy's and St. Thomas' NHS Foundation Trust, London, United Kingdom
| | - Sian Griffin
- Department of Nephrology, University Hospital of Wales, Cardiff, United Kingdom
| | - Colin Geddes
- Renal Unit, Western Infirmary, NHS Greater Glasgow and Clyde Trust, Glasgow, United Kingdom
| | - Simon Ball
- Department of Nephrology, University Hospital Birmingham, Birmingham, United Kingdom
| | - Richard Baker
- Renal Unit, St. James's University Hospital, Leeds, United Kingdom
| | - Candice Roufosse
- Histocompatibility and Immunogenetics, Imperial College Healthcare NHS Trust, London, United Kingdom
| | - Catherine Horsfield
- Department of Histopathology, Guy's and St. Thomas' NHS Foundation Trust, London, United Kingdom
| | - Anthony Dorling
- Department of Inflammation Biology, MRC Centre for Transplantation, Guy's Hospital, King's College London, London, United Kingdom
| |
Collapse
|
|
20
|
Maenosono R, Unagami K, Kakuta Y, Furusawa M, Okumi M, Azuma H, Ishida H, Tanabe K. Association between response to rituximab and antibody-mediated rejection in ABO-incompatible living kidney transplantation. Int J Urol 2019; 26:1114-1120. [PMID: 31522467 DOI: 10.1111/iju.14108] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2019] [Accepted: 08/11/2019] [Indexed: 01/01/2023]
Abstract
OBJECTIVES To examine the association of response to rituximab and the incidence of antibody-mediated rejection in preconditioning of rituximab and plasma exchange without post-transplant plasmapheresis in patients undergoing ABO-incompatible living kidney transplantation. METHODS A total of 115 patients who underwent ABO-incompatible living kidney transplantation at Tokyo Women's Medical University Hospital, Tokyo, Japan, were divided into two groups based on the response to rituximab: good response (n = 75) or poor response (n = 40). The rituximab good response and poor response patients were defined as patients whose CD19+ cells were non-detected (0%) and detected on the day of transplantation (2-5 days, median 3 days, after rituximab administration), respectively. RESULTS Rituximab response and anti-A/B blood antibody titer after plasmapheresis were significant risk factors for antibody-mediated rejection (P = 0.036, 0.045, respectively). The occurrence of antibody-mediated rejection was higher in the poor response group than in the good response group (22.5% vs 8.0%; P = 0.028). The 14-day, 3-month and 1-year cumulative incidence of antibody-mediated rejection was 2.7%, 5.3% and 8.0% in the good response group, and 17.5%, 20.0% and 22.5% in the poor response group after ABO-incompatible living kidney transplantation. The patient survival was not significantly different between the two groups. However, graft survival 1 month after transplantation was lower in the poor response group. There is no significant difference in graft function and in the incidence of complications, including infection, after transplantation between the two groups. CONCLUSIONS Antibody-mediated rejection after ABO-incompatible living kidney transplantation was significantly associated with the response to rituximab in our preconditioning protocol.
Collapse
Affiliation(s)
- Ryoichi Maenosono
- Department of Urology, Tokyo Women's Medical University, Tokyo, Japan.,Department of Urology, Osaka Medical College, Osaka, Japan
| | - Kohei Unagami
- Department of Organ Transplant Medicine, Tokyo Women's Medical University, Tokyo, Japan
| | - Yoichi Kakuta
- Department of Urology, Tokyo Women's Medical University, Tokyo, Japan
| | - Miyuki Furusawa
- Department of Urology, Tokyo Women's Medical University, Tokyo, Japan
| | - Masayoshi Okumi
- Department of Urology, Tokyo Women's Medical University, Tokyo, Japan
| | - Haruhito Azuma
- Department of Urology, Osaka Medical College, Osaka, Japan
| | - Hideki Ishida
- Department of Organ Transplant Medicine, Tokyo Women's Medical University, Tokyo, Japan
| | - Kazunari Tanabe
- Department of Urology, Tokyo Women's Medical University, Tokyo, Japan
| |
Collapse
|
|
21
|
Kidney transplantation in ANCA-associated vasculitis. J Nephrol 2019; 32:919-926. [DOI: 10.1007/s40620-019-00642-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2019] [Accepted: 08/14/2019] [Indexed: 02/04/2023]
|
|
22
|
Association Between Peripheral Blood CD19-Positive Rate and Antibody-Mediated Rejection Following Rituximab Administration in Kidney Transplant Recipients. Transplant Direct 2019; 5:e467. [PMID: 31334341 PMCID: PMC6616141 DOI: 10.1097/txd.0000000000000907] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2019] [Revised: 05/02/2019] [Accepted: 05/04/2019] [Indexed: 11/26/2022] Open
Abstract
Background. Rituximab is used widely for desensitization in ABO-incompatible and donor-specific antibody-positive kidney transplantation. However, data about the effects of individual differences in rituximab-induced B-cell suppression on antibody-mediated rejection (AMR) remain unknown. We aimed to assess the association between CD19-positive rate and AMR following rituximab administration after kidney transplantation. Methods. Overall, 42 patients who underwent rituximab therapy for pretransplant desensitization in ABO-incompatible (n = 33) and donor-specific antibody-positive (n = 15) kidney transplantation were observed retrospectively. To predict AMR incidence, the peripheral blood CD19-positive rate was determined and classified into short- and long-acting groups. AMR incidence, allograft function, complications, and rituximab dose were compared. Results. Eight patients (19%) had AMR within 39.2 months after transplantation. The CD19-positive rate cutoff value to predict AMR incidence was 4.4%, 6.4%, and 7.7% at 6, 12, and 18 months after transplantation, respectively. When comparing the short- and long-acting groups stratified according to the CD19-positive rate cutoff value, AMR incidence was significantly higher in the short-acting group than in the long-acting group at 6 (71.4% vs 8.6%), 12 (70.0% vs 3.1%), and 18 (58.3% vs 3.3%) months after transplantation. The CD19-positive rate for all patients with AMR exceeded the cutoff value 6, 12, or 18 months. Conversely, serum creatinine level, tacrolimus trough-level, cytomegalovirus antigenemia-positive rate, neutropenia incidence rate, and total dose of rituximab before transplantation showed no significant differences between the 2 groups. Conclusions. The risk of AMR was higher in patients with short-term B-cell suppression following rituximab administration. Additional rituximab administration after transplantation may prevent AMR in patients with a CD19-positive rate higher than the cutoff value.
Collapse
|
|
23
|
Liu M, Husain S, Famure O, Li Y, Kim SJ. Incidence, Risk Factors, Clinical Management, and Outcomes of Posttransplant Lymphoproliferative Disorder in Kidney Transplant Recipients. Prog Transplant 2019; 29:185-193. [PMID: 30845885 DOI: 10.1177/1526924819835834] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
BACKGROUND Posttransplant lymphoproliferative disorder (PTLD) is a severe complication after kidney transplantation. This study examined the incidence, risk factors, clinical management, and outcomes of PTLD in a cohort of kidney transplant recipients. DESIGN This single-center cohort study included 1642 patients transplanted from January 1, 2000, to December 31, 2012, with follow-up until December 31, 2013. The incidence and risk factors for PTLD were examined using a Cox proportional hazards model. A Cox model was also used to assess the association of PTLD and graft outcomes. RESULTS Sixteen recipients developed PTLD over follow-up. The incidence rate was 0.18 (95% confidence interval [CI]: 0.11-0.29) cases per 100 person-years. Four were from Epstein-Barr virus (EBV) mismatched (D+/R-) transplants and 12 from EBV-positive recipients (R+). Recipients with D+/R- matches were at a significantly higher risk of developing PTLD than R+ (hazard ratio [HR]: 7.52 [95% CI: 2.42-23.32]). Fifteen cases had immunosuppression reduced, 11 cases were supplemented with rituximab or ganciclovir, 6 cases required chemotherapy or radiation, and 6 cases had tumors excised. By the end of follow-up, 6 patients went into remission, 5 returned to chronic dialysis, and 5 patients died. Patients with PTLD were significantly more likely to have total graft failure (return to chronic dialysis, preemptive retransplant, or death with graft function) than patients without PTLD (HR: 3.41 [95% CI: 1.72-6.78). DISCUSSION Epstein-Barr virus mismatch continues to be a strong risk factor for developing PTLD after kidney transplantation. Recipients with PTLD have a poor prognosis, as the optimal management remains to be elucidated.
Collapse
Affiliation(s)
- Michelle Liu
- 1 Multi-Organ Transplant Program, University Health Network, Toronto, Ontario, Canada
| | - Shahid Husain
- 1 Multi-Organ Transplant Program, University Health Network, Toronto, Ontario, Canada.,2 Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Olusegun Famure
- 1 Multi-Organ Transplant Program, University Health Network, Toronto, Ontario, Canada
| | - Yanhong Li
- 1 Multi-Organ Transplant Program, University Health Network, Toronto, Ontario, Canada
| | - S Joseph Kim
- 1 Multi-Organ Transplant Program, University Health Network, Toronto, Ontario, Canada.,2 Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| |
Collapse
|
|
24
|
Oleinika K, Mauri C, Salama AD. Effector and regulatory B cells in immune-mediated kidney disease. Nat Rev Nephrol 2018; 15:11-26. [DOI: 10.1038/s41581-018-0074-7] [Citation(s) in RCA: 61] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
|
|
25
|
Sagmeister MS, Weiss M, Eichhorn P, Habicht A, Habersetzer R, Fischereder M, Schönermarck U. Case report: de novo ANCA-associated vasculitis after kidney transplantation treated with rituximab and plasma exchange. BMC Nephrol 2018; 19:270. [PMID: 30340563 PMCID: PMC6194699 DOI: 10.1186/s12882-018-1086-z] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2018] [Accepted: 10/09/2018] [Indexed: 01/23/2023] Open
Abstract
Background Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis causes end-stage renal failure in up to a third of cases even with treatment. The disease recurs occasionally after kidney transplantation, but new onset of ANCA-associated vasculitis after transplantation is highly unusual. The use of rituximab or plasmapheresis for de novo disease after transplantation has not previously been reported. Case presentation Routine post-transplant follow-up for a 66-year old asymptomatic woman revealed a rise in creatinine from 1.8 to 2.6 mg/dl and increased proteinuria. She had received a cadaveric kidney transplant 20 months previously for end-stage autosomal dominant polycystic kidney disease. Renal allograft biopsy unexpectedly demonstrated pauci-immune glomerulonephritis with extracapillary proliferation and interstitial inflammation. Concurrent serum tested strongly positive for ANCA specific to proteinase 3 (PR3), but stored pre- and post-transplantation serum samples tested negative. These findings established a diagnosis of de novo ANCA-associated vasculitis in the renal allograft. We started treatment with high-dose corticosteroid and rituximab. Despite this, serum creatinine continued to rise and glomerulonephritis remained active in a repeat biopsy. Escalation of the treatment with seven sessions of plasmapheresis led to a temporary improvement in creatinine. No further features of vasculitis emerged and PR3-ANCA titres declined. However, multiple infections complicated the recovery period and were associated with progressive loss of renal transplant function. Four months after the index presentation, transplant function became insufficient and dialysis was restarted. Conclusions De novo ANCA-associated vasculitis after renal transplantation is exceptionally rare. It poses a significant risk to graft survival even in the context of intensified immunosuppression. Management relies on clinical evidence from populations with native renal function, yet post-transplant patients may be at increased risk of treatment-related adverse events. Precautions against these risks are crucial in the delivery of care.
Collapse
Affiliation(s)
- Michael S Sagmeister
- Nephrology Division, Medizinische Klinik und Poliklinik IV, Klinikum der Universität München - Campus Großhadern, Munich, Germany.,Department of Renal Medicine, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | - Max Weiss
- Institute of Pathology, Ludwig-Maximilians-Universität, Munich, Germany
| | - Peter Eichhorn
- Institute of Laboratory Medicine, Ludwig-Maximilians-Universität, Munich, Germany
| | - Antje Habicht
- Centre for Transplantation, Klinikum der Universität München - Campus Großhadern, Munich, Germany
| | | | - Michael Fischereder
- Nephrology Division, Medizinische Klinik und Poliklinik IV, Klinikum der Universität München - Campus Großhadern, Munich, Germany
| | - Ulf Schönermarck
- Nephrology Division, Medizinische Klinik und Poliklinik IV, Klinikum der Universität München - Campus Großhadern, Munich, Germany.
| |
Collapse
|
|
26
|
Costello R, Kissenpfennig A, Martins PN, McDaid J. Development of transplant immunosuppressive agents - considerations in the use of animal models. Expert Opin Drug Discov 2018; 13:1041-1053. [PMID: 30332905 DOI: 10.1080/17460441.2018.1535589] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/28/2022]
Abstract
INTRODUCTION The development of all immunosuppressant agents to date has involved the experimental use of large and small animal models. Over the last half-century, immunosuppressive drugs have extended the lives of transplant patients worldwide. However, the use of animal models in the development of these drugs is not perfect, and this has brought to light a number of issues including idiosyncratic reactions that are found in animal models but not in humans. The 2006 highly publicized case of the 'elephant man' TGN 1412 drug trial highlights the importance of being cogent of the limitations of animal models. Areas covered: This review covers the utility and limitations of the use of animal models for the development of immunosuppressant agents. This includes both large and small animal models, particularly rodent models in the transplant setting. Expert opinion: The use of animal models represents a critical stage in the development of immunosuppressive drugs. Limitations include physiological differences to humans; this is especially true of immunologically naïve lab rodents with small memory cell populations. Toxic drug levels may differ widely between species. Animal models are also costly and raise ethical concerns. However, there is currently no way to recreate the complex environment of the human immune system purely in vitro.
Collapse
Affiliation(s)
- Russell Costello
- a Wellcome Wolfson Institute for Experimental Medicine , Queen's University , Belfast , UK
| | - Adrien Kissenpfennig
- a Wellcome Wolfson Institute for Experimental Medicine , Queen's University , Belfast , UK
| | - Paulo N Martins
- b Department of Surgery, Division of Transplantation, UMass Memorial Medical Center , University of Massachusetts , Worchester , MA , USA
| | - James McDaid
- c Department of Transplant Surgery , City Hospital , Belfast , UK
| |
Collapse
|
|
27
|
Khalil MAM, Khalil MAU, Khan TFT, Tan J. Drug-Induced Hematological Cytopenia in Kidney Transplantation and the Challenges It Poses for Kidney Transplant Physicians. J Transplant 2018; 2018:9429265. [PMID: 30155279 PMCID: PMC6093016 DOI: 10.1155/2018/9429265] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2017] [Revised: 06/04/2018] [Accepted: 06/25/2018] [Indexed: 12/14/2022] Open
Abstract
Drug-induced hematological cytopenia is common in kidney transplantation. Various cytopenia including leucopenia (neutropenia), thrombocytopenia, and anemia can occur in kidney transplant recipients. Persistent severe leucopenia or neutropenia can lead to opportunistic infections of various etiologies. On the contrary, reducing or stopping immunosuppressive medications in these events can provoke a rejection. Transplant clinicians are often faced with the delicate dilemma of balancing cytopenia and rejection from adjustments of immunosuppressive regimen. Differentials of drug-induced cytopenia are wide. Identification of culprit medication and subsequent modification is also challenging. In this review, we will discuss individual drug implicated in causing cytopenia and correlate it with corresponding literature evidence.
Collapse
Affiliation(s)
| | | | - Taqi F. Taufeeq Khan
- King Salman Armed Forces Hospital, Tabuk King Abdul Aziz Rd., Tabuk 47512, Saudi Arabia
| | - Jackson Tan
- RIPAS Hospital, Bandar Seri Begawan BA1710, Brunei Darussalam
| |
Collapse
|
|
28
|
Wong KY, Baron R, Seldon TA, Jones ML, Rice AM, Munster DJ. CD83 Antibody Inhibits Human B Cell Responses to Antigen as well as Dendritic Cell-Mediated CD4 T Cell Responses. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2018; 200:3383-3396. [PMID: 29643191 DOI: 10.4049/jimmunol.1700064] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/30/2017] [Accepted: 03/20/2018] [Indexed: 01/11/2023]
Abstract
Anti-CD83 Ab capable of Ab-dependent cellular cytotoxicity can deplete activated CD83+ human dendritic cells, thereby inhibiting CD4 T cell-mediated acute graft-versus-host disease. As CD83 is also expressed on the surface of activated B lymphocytes, we hypothesized that anti-CD83 would also inhibit B cell responses to stimulation. We found that anti-CD83 inhibited total IgM and IgG production in vitro by allostimulated human PBMC. Also, Ag-specific Ab responses to immunization of SCID mice xenografted with human PBMC were inhibited by anti-CD83 treatment. This inhibition occurred without depletion of all human B cells because anti-CD83 lysed activated CD83+ B cells by Ab-dependent cellular cytotoxicity and spared resting (CD83-) B cells. In cultured human PBMC, anti-CD83 inhibited tetanus toxoid-stimulated B cell proliferation and concomitant dendritic cell-mediated CD4 T cell proliferation and expression of IFN-γ and IL-17A, with minimal losses of B cells (<20%). In contrast, the anti-CD20 mAb rituximab depleted >80% of B cells but had no effect on CD4 T cell proliferation and cytokine expression. By virtue of the ability of anti-CD83 to selectively deplete activated, but not resting, B cells and dendritic cells, with the latter reducing CD4 T cell responses, anti-CD83 may be clinically useful in autoimmunity and transplantation. Advantages might include inhibited expansion of autoantigen- or alloantigen-specific B cells and CD4 T cells, thus preventing further production of pathogenic Abs and inflammatory cytokines while preserving protective memory and regulatory cells.
Collapse
Affiliation(s)
- Kuan Y Wong
- Mater Research Institute, University of Queensland, Brisbane, Queensland 4102, Australia; and
| | - Rebecca Baron
- Mater Research Institute, University of Queensland, Brisbane, Queensland 4102, Australia; and
| | - Therese A Seldon
- Mater Research Institute, University of Queensland, Brisbane, Queensland 4102, Australia; and
| | - Martina L Jones
- Australian Institute for Bioengineering and Nanotechnology, University of Queensland, Brisbane, Queensland 4072, Australia
| | - Alison M Rice
- Mater Research Institute, University of Queensland, Brisbane, Queensland 4102, Australia; and
| | - David J Munster
- Mater Research Institute, University of Queensland, Brisbane, Queensland 4102, Australia; and
| |
Collapse
|
|
29
|
Querido S, Weigert A, Adragão T, Henriques J, Birne R, Matias P, Jorge C, Nascimento C, Bruges M, Machado D. Intravenous Immunoglobulin and Rituximab in HLA Highly Sensitized Kidney Transplant Recipients. Transplant Proc 2018; 50:723-727. [PMID: 29661424 DOI: 10.1016/j.transproceed.2018.02.016] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/17/2022]
Abstract
INTRODUCTION HLA-sensitized patients are penalized both in the access to kidney transplantation (KT) and, once transplanted, in the incidence of rejections and long-term allograft survival despite aggressive induction and maintenance therapy. METHODS This study retrospectively evaluates the impact of combining T- and B-cell-depleting agents and intravenous immunoglobulin for induction therapy in 45 highly sensitized KT patients (anti-panel reactive antibodies >60%, positive flow cytometry crossmatch or donor specific antibodies at the time of transplantation). The outcome data included the occurrence of biopsy-proven acute rejection, new-onset proteinuria, development of leukopenia, incidence of poliomavirus infection (BK or JC virus), fungal or bacterial infection after KT, de novo neoplasia, graft function, graft loss, or death with functioning KT. RESULTS The average panel reactive antibody was 62.5%; 41 patients (91.1%) had ≥3 HLA mismatches with the donor and 91.1% of patients had class I or II anti-HLA antibodies. Fourteen patients (31.1%) presented pre-KT donor-specific antibodies and 6 patients (13.3%) had a positive flow cytometry cross-match at the time of transplantation. The incidence of acute rejection in the first 6 months was 24.4% and the cumulative incidence was 37.8%. Two patients were diagnosed with leukopenia in the first 6 months after KT. Two patients (4.5%) had cytomegalovirus disease, 17 patients (37.8%) were diagnosed with bacterial infections. Cutaneous neoplasms were identified in 5 patients (11.1%) and solid tumors in 4 (8.9%). The death-censored graft survival was 100% in the first 6 months and 93.5% at the last evaluation. Patient survival in the same periods was 97.8% and 93.3%, respectively. CONCLUSIONS Induction immunosuppressive therapy with intravenous immunoglobulin and rituximab is effective; outcomes demonstrate an excellent patient and allograft survival and allograft function over the follow-up period.
Collapse
Affiliation(s)
- S Querido
- Department of Nephrology, Centro Hospitalar de Lisboa Ocidental, Hospital de Santa Cruz, Carnaxide, Portugal.
| | - A Weigert
- Department of Nephrology, Centro Hospitalar de Lisboa Ocidental, Hospital de Santa Cruz, Carnaxide, Portugal
| | - T Adragão
- Department of Nephrology, Centro Hospitalar de Lisboa Ocidental, Hospital de Santa Cruz, Carnaxide, Portugal
| | - J Henriques
- Department of Pathology, Centro Hospitalar de Lisboa Ocidental, Hospital de Santa Cruz, Carnaxide, Portugal
| | - R Birne
- Department of Nephrology, Centro Hospitalar de Lisboa Ocidental, Hospital de Santa Cruz, Carnaxide, Portugal
| | - P Matias
- Department of Nephrology, Centro Hospitalar de Lisboa Ocidental, Hospital de Santa Cruz, Carnaxide, Portugal
| | - C Jorge
- Department of Nephrology, Centro Hospitalar de Lisboa Ocidental, Hospital de Santa Cruz, Carnaxide, Portugal
| | - C Nascimento
- Department of Nephrology, Centro Hospitalar de Lisboa Ocidental, Hospital de Santa Cruz, Carnaxide, Portugal
| | - M Bruges
- Department of Nephrology, Centro Hospitalar de Lisboa Ocidental, Hospital de Santa Cruz, Carnaxide, Portugal
| | - D Machado
- Department of Nephrology, Centro Hospitalar de Lisboa Ocidental, Hospital de Santa Cruz, Carnaxide, Portugal
| |
Collapse
|
|
30
|
Muller YD, Ghaleb N, Rotman S, Vionnet J, Halfon M, Catana E, Golshayan D, Venetz JP, Aubert V, Pascual M. Rituximab as monotherapy for the treatment of chronic active antibody-mediated rejection after kidney transplantation. Transpl Int 2018; 31:451-455. [DOI: 10.1111/tri.13111] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Affiliation(s)
- Yannick D. Muller
- Transplantation Center; Lausanne University Hospital; University of Lausanne; Lausanne Switzerland
| | - Nseir Ghaleb
- Transplantation Center; Lausanne University Hospital; University of Lausanne; Lausanne Switzerland
| | - Samuel Rotman
- Service of Clinical Pathology; Lausanne University Hospital; University of Lausanne; Lausanne Switzerland
| | - Julien Vionnet
- Transplantation Center; Lausanne University Hospital; University of Lausanne; Lausanne Switzerland
| | - Matthieu Halfon
- Transplantation Center; Lausanne University Hospital; University of Lausanne; Lausanne Switzerland
| | - Emmanuelle Catana
- Transplantation Center; Lausanne University Hospital; University of Lausanne; Lausanne Switzerland
| | - Déla Golshayan
- Transplantation Center; Lausanne University Hospital; University of Lausanne; Lausanne Switzerland
| | - Jean-Pierre Venetz
- Transplantation Center; Lausanne University Hospital; University of Lausanne; Lausanne Switzerland
| | - Vincent Aubert
- Service of Immunology and Allergy; Lausanne University Hospital; University of Lausanne; Lausanne Switzerland
| | - Manuel Pascual
- Transplantation Center; Lausanne University Hospital; University of Lausanne; Lausanne Switzerland
| |
Collapse
|
|
31
|
Chu Z, Zou W, Xu Y, Sun Q, Zhao Y. The regulatory roles of B cell subsets in transplantation. Expert Rev Clin Immunol 2018; 14:115-125. [PMID: 29338551 DOI: 10.1080/1744666x.2018.1426461] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Affiliation(s)
- Zhulang Chu
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
- Department of Pathology, Beijing University of Chinese Medicine, Beijing, China
| | - Weilong Zou
- Surgery of Transplant and Hepatopancrobiliary, The General Hospital of Chinese People’s Armed Police Forces, Beijing, China
| | - Yanan Xu
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
| | - Qiquan Sun
- Department of Renal Transplantation, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Yong Zhao
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
| |
Collapse
|
|
32
|
Kurata N, Onishi Y, Kamei H, Hori T, Komagome M, Kato C, Matsushita T, Ogura Y. Successful Blood Transfusion Management of a Living Donor Liver Transplant Recipient in the Presence of Anti-Jr a: A Case Report. Transplant Proc 2017; 49:1604-1607. [PMID: 28838449 DOI: 10.1016/j.transproceed.2017.06.009] [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: 03/27/2017] [Accepted: 06/16/2017] [Indexed: 11/27/2022]
Abstract
A 48-year-old Japanese woman was diagnosed with Budd-Chiari syndrome and transferred for possible living donor liver transplantation (LDLT). Examinations before LDLT revealed that the recipient had anti-Jra and preformed donor-specific anti-human leukocyte antigen (HLA) antibodies (DSA). Rituximab was administrated at 16 days prior to the patient's scheduled LDLT for the prophylaxis of antibody-mediated rejection by DSA. The clinical significance of anti-Jra has not been clearly established because of the rarity of this antibody, so we discussed blood transfusion strategy with the Department of Blood Transfusion Service and prepared for Jra-negative packed red blood cells (RBCs). Intraoperative blood salvage was used during LDLT procedures to reduce the use of packed RBCs. Although post-transplantation graft function was excellent, a total of 44 U of Jra-negative RBCs were transfused during the entire perioperative period. Because sufficient amounts of Jra-negative packed RBCs were supplied, Jra mismatched blood transfusion was avoided. The patient was discharged from our hospital on postoperative day 102 without clinical evidence of any blood transfusion-related adverse events. Although there are some controversies of blood transfusion related to anti-Jra antibodies, the current strategies of blood transfusion for liver transplantation with anti-Jra are as follows: (1) sufficient supply and transfusion of Jra-negative matched packed RBCs and (2) application of intraoperative blood salvage to reduce the total amount of rare blood type RBCs. These strategies may be changed when the mechanism of anti-Jra alloimmunization is fully understood in the future.
Collapse
Affiliation(s)
- N Kurata
- Department of Transplantation Surgery, Nagoya University Hospital, Nagoya, Aichi, Japan
| | - Y Onishi
- Department of Transplantation Surgery, Nagoya University Hospital, Nagoya, Aichi, Japan
| | - H Kamei
- Department of Transplantation Surgery, Nagoya University Hospital, Nagoya, Aichi, Japan
| | - T Hori
- Department of Transplantation Surgery, Nagoya University Hospital, Nagoya, Aichi, Japan
| | - M Komagome
- Department of Transplantation Surgery, Nagoya University Hospital, Nagoya, Aichi, Japan
| | - C Kato
- Department of Blood Transfusion Service, Nagoya University Hospital, Nagoya, Aichi, Japan
| | - T Matsushita
- Department of Blood Transfusion Service, Nagoya University Hospital, Nagoya, Aichi, Japan
| | - Y Ogura
- Department of Transplantation Surgery, Nagoya University Hospital, Nagoya, Aichi, Japan.
| |
Collapse
|
|
33
|
Okada M, Watarai Y, Iwasaki K, Murotani K, Futamura K, Yamamoto T, Hiramitsu T, Tsujita M, Goto N, Narumi S, Takeda A, Morozumi K, Uchida K, Kobayashi T. Favorable results in ABO-incompatible renal transplantation without B cell-targeted therapy: Advantages and disadvantages of rituximab pretreatment. Clin Transplant 2017; 31. [PMID: 28792635 DOI: 10.1111/ctr.13071] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/02/2017] [Indexed: 12/17/2022]
Abstract
The effectiveness of desensitization with rituximab in ABO-incompatible renal transplantation (ABO-I) has been widely reported. However, ABO-I outcomes are still worse than those of ABO-identical or ABO-compatible renal transplantation (ABO-Id/C). We retrospectively examined the outcomes in consecutive living donor ABO-Id/C (n = 412) and ABO-I (n = 205) cases to elucidate the causes of inferiority in ABO-I. ABO-I cases included recipients treated with rituximab (RIT, n = 131), splenectomy (SPX, n = 21), or neither because of low anti-A/B antibody titers (NoR/S, n = 53). Graft survival, infection, and de novo HLA antibody production were compared for ABO-I and ABO-Id/C, followed by stratification into RIT and NoR/S groups. Propensity score-based methods were employed to limit selection bias and potential confounders. Overall graft survival for ABO-I was significantly lower than that for ABO-Id/C (92.8% vs 97.2% after 5 years, P = .0037). Graft loss due to infection with ABO-I was significantly more frequent than that with ABO-Id/C, whereas acute antibody-mediated rejection (AMR) caused no graft failure in ABO-I recipients. Stratified analysis demonstrated significantly higher infection risk with RIT than with NoR/S. Safe reduction or avoidance of rituximab in desensitization protocols might contribute to further improvement of ABO-I outcome.
Collapse
Affiliation(s)
- Manabu Okada
- Department of Transplant and Endocrine Surgery, Nagoya Daini Red Cross Hospital, Nagoya, Japan.,Department of Renal Transplant Surgery, Aichi Medical University School of Medicine, Nagakute, Japan
| | - Yoshihiko Watarai
- Department of Transplant and Endocrine Surgery, Nagoya Daini Red Cross Hospital, Nagoya, Japan
| | - Kenta Iwasaki
- Department of Kidney Disease and Transplant Immunology, Aichi Medical University School of Medicine, Nagakute, Japan
| | - Kenta Murotani
- Division of Biostatistics, Clinical Research Center, Aichi Medical University Hospital, Nagakute, Japan
| | - Kenta Futamura
- Department of Transplant and Endocrine Surgery, Nagoya Daini Red Cross Hospital, Nagoya, Japan
| | - Takayuki Yamamoto
- Department of Transplant and Endocrine Surgery, Nagoya Daini Red Cross Hospital, Nagoya, Japan
| | - Takahisa Hiramitsu
- Department of Transplant and Endocrine Surgery, Nagoya Daini Red Cross Hospital, Nagoya, Japan
| | - Makoto Tsujita
- Department of Transplant and Endocrine Surgery, Nagoya Daini Red Cross Hospital, Nagoya, Japan
| | - Norihiko Goto
- Department of Transplant and Endocrine Surgery, Nagoya Daini Red Cross Hospital, Nagoya, Japan
| | - Shunji Narumi
- Department of Transplant and Endocrine Surgery, Nagoya Daini Red Cross Hospital, Nagoya, Japan
| | - Asami Takeda
- Department of Nephrology, Nagoya Daini Red Cross Hospital, Nagoya, Japan
| | - Kunio Morozumi
- Department of Nephrology, Masuko Memorial Hospital, Nagoya, Japan
| | - Kazuharu Uchida
- Department of Renal Transplant Surgery, Aichi Medical University School of Medicine, Nagakute, Japan.,Department of Kidney Disease and Transplant Immunology, Aichi Medical University School of Medicine, Nagakute, Japan
| | - Takaaki Kobayashi
- Department of Renal Transplant Surgery, Aichi Medical University School of Medicine, Nagakute, Japan
| |
Collapse
|
|
34
|
Abstract
A multidisciplinary team approach is essential for successful management of patients with solid-organ transplant. Transplant nursing encompasses care and support of transplant recipients as well as caregivers and organ donors through all phases of transplantation, from pretransplant evaluation to posttransplant recovery and maintenance. The field of solid-organ transplantation has advanced rapidly, and new treatments continue to emerge. Nurses who are responsible for the care of transplant recipients should have a knowledge base in transplant immunology and pharmacology. This review discusses mechanism of action, indication, side effects, and drug interactions of commonly used immunosuppressive medications in solid-organ transplantation. Nonoral routes of drug administration, therapeutic drug monitoring, and patient monitoring strategies are also included as practical tips for bedside nurses who are responsible for delivery of direct patient care and education of patients and their caregivers. This review focuses on the following medications: antithymocyte globulins, basiliximab, alemtuzumab, corticosteroids, tacrolimus, cyclosporine, azathioprine, mycophenolate mofetil/mycophenolate sodium, sirolimus, everolimus, belatacept, intravenous immunoglobulin, and rituximab.
Collapse
|
|
35
|
Mori DN, Shen H, Galan A, Goldstein DR. Aged B cells alter immune regulation of allografts in mice. Eur J Immunol 2016; 46:2650-2658. [PMID: 27546296 DOI: 10.1002/eji.201646353] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2016] [Revised: 07/04/2016] [Accepted: 08/17/2016] [Indexed: 11/07/2022]
Abstract
Organ transplantation in older people is increasing, but how aging impacts B-cell responses to organ transplantation is still unknown. Here, we show that the depletion of B cells with anti-CD20 antibodies has disparate effects depending on recipient age. In young murine recipients, anti-CD20 treatment impaired the ability of immune modulation to extend skin allograft survival. In contrast, anti-CD20 treatment extended allograft survival in aged recipients treated with immune modulation. Although regulatory B-cell function and the numbers of marginal and follicular B cells were similar between age groups, a subpopulation of B cells, termed age-associated B cells (ABCs), accumulated upon aging. ABCs isolated from aged mice exhibited upregulation of CD73, CD80, CD106, and TLR2 and an increased capacity to augment T-cell alloimmunity compared to ABCs from young mice. Importantly, ABCs from aged, but not young, mice impaired the ability of immune modulation to enhance allograft survival after adoptive transfer into young transplant recipients. Our study indicates that ABCs impair the immune regulation of allografts. Thus, recipient age needs to be considered when proposing B-cell-depleting immune therapy.
Collapse
Affiliation(s)
- Daniel N Mori
- Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA.,Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA
| | - Hua Shen
- Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA.,Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA
| | - Anjela Galan
- Department of Dermatology, Yale School of Medicine, New Haven, CT, USA.,Department of Pathology, Yale School of Medicine, New Haven, CT, USA
| | - Daniel R Goldstein
- Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA. .,Department of Internal Medicine, Division of Cardiology, University of Michigan, Ann Arbor, MI, USA. .,Institute of Gerontology, University of Michigan, Ann Arbor, MI, USA.
| |
Collapse
|
|
36
|
Jonker M, Wubben JAM, 't Hart BA, Haanstra KG. Lymphoid-Like Structures with Distinct B Cell Areas in Kidney Allografts are not Predictive for Graft Rejection. A Non-human Primate Study. Inflammation 2016; 38:2191-202. [PMID: 26140903 DOI: 10.1007/s10753-015-0202-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
Kidney allograft biopsies were analyzed for the presence of B cell clusters/aggregates using CD20 staining. Few B cells were found in the diffuse interstitial infiltrates, but clusters of B cells were found in nodular infiltrates. These nodular infiltrates were smaller shortly after transplantation, and their size increased over time. At the time of clinical rejection, the nodules often presented as tertiary lymphoid structures (TLS) with lymphoid-like follicles. The presence of small B cell clusters during the first 2 months after transplantation was not associated with early rejection. Even in animals that did not reject their allograft, TLS-like structures were present and could disappear over time. Although TLS were more often found in samples with interstitial fibrosis and tubular atrophy (IFTA), TLS were also present in samples without IFTA. The presence and density of clusters resembling tertiary lymphoid structures most likely reflect an ongoing immune response inside the graft and do not necessarily signify a poor graft outcome or IFTA.
Collapse
Affiliation(s)
- Margreet Jonker
- Biomedical Primate Research Centre, PO box 3306, 2280 GH, Rijswijk, The Netherlands.,Department of Immunohematology, LUMC, Leiden, The Netherlands
| | | | - Bert A 't Hart
- Biomedical Primate Research Centre, PO box 3306, 2280 GH, Rijswijk, The Netherlands.,Department of Neuroscience, University Medical Center, University of Groningen, Groningen, The Netherlands
| | - Krista G Haanstra
- Biomedical Primate Research Centre, PO box 3306, 2280 GH, Rijswijk, The Netherlands.
| |
Collapse
|
|
37
|
One-year Results of the Effects of Rituximab on Acute Antibody-Mediated Rejection in Renal Transplantation: RITUX ERAH, a Multicenter Double-blind Randomized Placebo-controlled Trial. Transplantation 2016; 100:391-9. [PMID: 26555944 DOI: 10.1097/tp.0000000000000958] [Citation(s) in RCA: 133] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
BACKGROUND Treatment of acute antibody-mediated rejection (AMR) is based on a combination of plasma exchange (PE), IVIg, corticosteroids (CS), and rituximab, but the place of rituximab is not clearly specified in the absence of randomized trials. METHODS In this phase III, multicenter, double-blind, placebo-controlled trial, we randomly assigned patients with biopsy-proven AMR to receive rituximab (375 mg/m) or placebo at day 5. All patients received PE, IVIg, and CS. The primary endpoint was a composite of graft loss or no improvement in renal function at day 12. RESULTS Among the 38 patients included, at 1 year, no deaths occurred, but 1 graft loss occurred in each group. The primary endpoint frequency was 52.6% (10/19) and 57.9% (11/19) in the rituximab and placebo groups, respectively (P = 0.744). Renal function improved in both groups, as soon as day 12 with no difference in serum creatinine level and proteinuria at 1, 3, 6, and 12 months. Supplementary administration of rituximab and total number of IVIg and PE treatments did not differ between the 2 groups. Both groups showed improved histological features of AMR and Banff scores at 1 and 6 months, with no significant difference between groups but with a trend in favor of the rituximab group. Both groups showed decreased mean fluorescence intensity of donor-specific antibodies as soon as day 12, with no significant difference between them but with a trend in favor of the rituximab group at 12 months. CONCLUSIONS After 1 year of follow-up, we observed no additional effect of rituximab in patients receiving PE, IVIg, and CS for AMR. Nevertheless, our study was underpowered and important differences between groups may have been missed. Complementary trials with long-term follow-up are needed.
Collapse
|
|
38
|
The Influence of Immunosuppressive Agents on the Risk of De Novo Donor-Specific HLA Antibody Production in Solid Organ Transplant Recipients. Transplantation 2016; 100:39-53. [PMID: 26680372 PMCID: PMC4683034 DOI: 10.1097/tp.0000000000000869] [Citation(s) in RCA: 96] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Production of de novo donor-specific antibodies (dnDSA) is a major risk factor for acute and chronic antibody-mediated rejection and graft loss after all solid organ transplantation. In this article, we review the data available on the risk of individual immunosuppressive agents and their ability to prevent dnDSA production. Induction therapy with rabbit antithymocyte globulin may achieve a short-term decrease in dnDSA production in moderately sensitized patients. Rituximab induction may be beneficial in sensitized patients, and in abrogating rebound antibody response in patients undergoing desensitization or treatment for antibody-mediated rejection. Use of bortezomib for induction therapy in at-risk patients is of interest, but the benefits are unproven. In maintenance regimens, nonadherent and previously sensitized patients are not suitable for aggressive weaning protocols, particularly early calcineurin inhibitor withdrawal without lymphocyte-depleting induction. Early conversion to mammalian target of rapamycin inhibitor monotherapy has been reported to increase the risk of dnDSA formation, but a combination of mammalian target of rapamycin inhibitor and reduced-exposure calcineurin inhibitor does not appear to alter the risk. Early steroid therapy withdrawal in standard-risk patients after induction has no known dnDSA penalty. The available data do not demonstrate a consistent effect of mycophenolic acid on dnDSA production. Risk minimization for dnDSA requires monitoring of adherence, appropriate risk stratification, risk-based immunosuppression intensity, and prospective DSA surveillance.
Collapse
|
|
39
|
Surendra M, Raju SB, Raju N, Chandragiri S, Mukku KK, Uppin MS. Rituximab in the treatment of refractory late acute antibody-mediated rejection: Our initial experience. Indian J Nephrol 2016; 26:317-321. [PMID: 27795623 PMCID: PMC5015507 DOI: 10.4103/0971-4065.177207] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Antibody-mediated rejection (AMR) is not uncommon after renal transplantation and is harder to handle compared to cell-mediated rejection. When refractory to conventional therapies, rituximab is an attractive option. This study aims to examine the effectiveness of rituximab in refractory late acute AMR. This is a retrospective study involving nine renal transplant recipients. Four doses of rituximab were administered at weekly interval for 4 weeks, at a dose of 375 mg/m2. The mean age of patients was 35.3 ± 7.38 years. The median period between transplantation and graft dysfunction was 30 ± 20 months. Mean serum creatinine at the time of discharge after transplantation and at the time of acute AMR diagnosis was 1.14 ± 0.19 mg/dl and 2.26 ± 0.57 mg/dl, respectively. After standard therapy, it was 2.68 ± 0.62 mg/dl. One patient died of Pseudomonas sepsis and three patients progressed to end-stage renal disease (ESRD). Four biopsies showed significant plasma cell infiltrations. Mean serum creatinine among non-ESRD patients at the end of 1 year progressed from 2.3 ± 0.4 to 3.8 ± 1.2 mg/dl (P value 0.04). eGFR prior to therapy and at the end of 1 year were 34.4 ± 6.18 and 20.8 ± 7.69 ml/min (P value 0.04), respectively. Only one patient showed improvement in graft function in whom donor-specific antibody (DSA) titers showed significant improvement. Rituximab may not be effective in late acute AMR unlike in early acute AMR. Monitoring of DSA has a prognostic role in these patients and plasma cell rich rejection is associated with poor prognosis.
Collapse
Affiliation(s)
- M Surendra
- Department of Nephrology, Nizam's Institute of Medical Sciences, Hyderabad, Telangana, India
| | - S B Raju
- Department of Nephrology, Nizam's Institute of Medical Sciences, Hyderabad, Telangana, India
| | - N Raju
- Department of Nephrology, Nizam's Institute of Medical Sciences, Hyderabad, Telangana, India
| | - S Chandragiri
- Department of Nephrology, Nizam's Institute of Medical Sciences, Hyderabad, Telangana, India
| | - K K Mukku
- Department of Nephrology, Nizam's Institute of Medical Sciences, Hyderabad, Telangana, India
| | - M S Uppin
- Department of Pathology, Nizam's Institute of Medical Sciences, Hyderabad, Telangana, India
| |
Collapse
|
|
40
|
Abstract
B cells play a central role in the immunopathogenesis of glomerulonephritides and transplant rejection. B cells secrete antibodies that contribute to tissue injury via multiple mechanisms. In addition, B cells contribute to disease pathogenesis in autoimmunity and alloimmunity by presenting antigens as well as providing costimulation and cytokines to T cells. B cells also play an immunomodulatory role in regulating the immune response by secreting cytokines that inhibit disease onset and/or progression. B cell-targeted approaches for treating immune diseases of the kidney and other organs have gained significant momentum. However, much remains to be understood about B-cell biology in order to determine the timing, duration, and context of optimal therapeutic response to B cell-targeted approaches. In this review, we discuss the multifaceted roles of B cells as enhancers and regulators of immunity with relevance to kidney disease and transplantation.
Collapse
Affiliation(s)
| | - Fadi G Lakkis
- Departments of Medicine (Renal-Electrolyte), Surgery, and Immunology, Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, and
| | - Geetha Chalasani
- Departments of Medicine (Renal-Electrolyte), Surgery, and Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, and Renal Section, Veterans Affairs Pittsburgh Health Care System, Pittsburgh, Pennsylvania
| |
Collapse
|
|
41
|
Cheungpasitporn W, Thongprayoon C, Edmonds PJ, Bruminhent J, Tangdhanakanond K. The effectiveness and safety of rituximab as induction therapy in ABO-compatible non-sensitized renal transplantation: a systematic review and meta-analysis of randomized controlled trials. Ren Fail 2015; 37:1522-6. [PMID: 26337918 DOI: 10.3109/0886022x.2015.1077310] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND The objective of this systematic review and meta-analysis was to evaluate the effectiveness and safety of rituximab as induction therapy in ABO-compatible, non-sensitized renal transplantation. METHODS A literature search for randomized controlled trials (RCTs) was performed from inception through February 2015. Studies that reported relative risks or hazard ratios comparing the risks of biopsy-proven acute rejection (BPAR), graft loss, leukopenia, infection or mortality in ABO-compatible, non-sensitized renal transplant recipients who received rituximab as induction therapy versus controls were included. Pooled risk ratios (RRs) and 95% confidence intervals (CIs) were calculated using a random-effect, generic inverse variance method. RESULTS Four RCTs with 480 patients were included in the meta-analysis. Pooled RR of BPAR in recipients with rituximab induction was 0.90 (95% CI 0.50-1.60). Compared to placebo, the risk of BPAR in rituximab group was 0.76 (95% CI 0.51-1.14, I(2) = 0). The risk of leukopenia was increased in rituximab group with the pooled RR of 8.22 (95% CI 2.08-32.47). There were no statistical differences in the risks of infection, graft loss and mortality at 3-6 months after transplantation with pool RRs of 1.02 (95% CI 0.85-1.21), 0.55 (95% CI 0.21-1.48) and 0.58 (95% CI 0.17-1.99), respectively. CONCLUSION This meta-analysis demonstrated insignificant reduced risks of BPAR, graft loss or mortality among in ABO-compatible, non-sensitized renal transplant recipients with rituximab induction. Although rituximab induction significantly increases risk of leukopenia, it appears to be safe with no significant risk of infection.
Collapse
Affiliation(s)
| | - Charat Thongprayoon
- a Division of Nephrology and Hypertension , Mayo Clinic , Rochester , MN , USA
| | | | - Jackrapong Bruminhent
- c Department of Medicine , Faculty of Medicine Ramathibodi Hospital, Mahidol University , Bangkok , Thailand , and
| | | |
Collapse
|
|
42
|
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.
Collapse
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
| |
Collapse
|
|
43
|
McDonald-Hyman C, Turka LA, Blazar BR. Advances and challenges in immunotherapy for solid organ and hematopoietic stem cell transplantation. Sci Transl Med 2015; 7:280rv2. [PMID: 25810312 PMCID: PMC4425354 DOI: 10.1126/scitranslmed.aaa6853] [Citation(s) in RCA: 85] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Although major advances have been made in solid organ and hematopoietic stem cell transplantation in the last 50 years, big challenges remain. This review outlines the current immunological limitations for hematopoietic stem cell and solid organ transplantation and discusses new immune-modulating therapies in preclinical development and in clinical trials that may allow these obstacles to be overcome.
Collapse
Affiliation(s)
- Cameron McDonald-Hyman
- Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota, Minneapolis, MN 55455, USA
| | - Laurence A Turka
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02115, USA.Immune Tolerance Network, Massachusetts General Hospital, Boston, MA 02114, USA. Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02115, USA.Immune Tolerance Network, Massachusetts General Hospital, Boston, MA 02114, USA.
| | - Bruce R Blazar
- Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota, Minneapolis, MN 55455, USA.
| |
Collapse
|
|
44
|
Yang Y, Yu B, Chen Y. Blood disorders typically associated with renal transplantation. Front Cell Dev Biol 2015; 3:18. [PMID: 25853131 PMCID: PMC4365751 DOI: 10.3389/fcell.2015.00018] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2014] [Accepted: 03/03/2015] [Indexed: 12/11/2022] Open
Abstract
Renal transplantation has become one of the most common surgical procedures performed to replace a diseased kidney with a healthy kidney from a donor. It can help patients with kidney failure live decades longer. However, renal transplantation also faces a risk of developing various blood disorders. The blood disorders typically associated with renal transplantation can be divided into two main categories: (1) Common disorders including post-transplant anemia (PTA), post-transplant lymphoproliferative disorder (PTLD), post-transplant erythrocytosis (PTE), and post-transplant cytopenias (PTC, leukopenia/neutropenia, thrombocytopenia, and pancytopenia); and (2) Uncommon but serious disorders including hemophagocytic syndrome (HPS), thrombotic microangiopathy (TMA), therapy-related myelodysplasia (t-MDS), and therapy-related acute myeloid leukemia (t-AML). Although many etiological factors involve the development of post-transplant blood disorders, immunosuppressive agents, and viral infections could be the two major contributors to most blood disorders and cause hematological abnormalities and immunodeficiency by suppressing hematopoietic function of bone marrow. Hematological abnormalities and immunodeficiency will result in severe clinical outcomes in renal transplant recipients. Understanding how blood disorders develop will help cure these life-threatening complications. A potential therapeutic strategy against post-transplant blood disorders should focus on tapering immunosuppression or replacing myelotoxic immunosuppressive drugs with lower toxic alternatives, recognizing and treating promptly the etiological virus, bacteria, or protozoan, restoring both hematopoietic function of bone marrow and normal blood counts, and improving kidney graft survival.
Collapse
Affiliation(s)
- Yu Yang
- Department of Urology, First Affiliated Hospital of PLA General Hospital Beijing, China
| | - Bo Yu
- Department of Urology, First Affiliated Hospital of PLA General Hospital Beijing, China
| | - Yun Chen
- BrightstarTech, Inc. Clarksburg, MD, USA
| |
Collapse
|
|
45
|
Ishida H, Furusawa M, Shimizu T, Nozaki T, Tanabe K. Influence of preoperative anti-HLA antibodies on short- and long-term graft survival in recipients with or without rituximab treatment. Transpl Int 2015; 27:371-82. [PMID: 24438437 DOI: 10.1111/tri.12267] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2013] [Revised: 08/20/2013] [Accepted: 01/13/2014] [Indexed: 01/28/2023]
Abstract
We investigated the relationship between preoperative anti-HLA antibodies (donor-specific antibody, DSA) and the graft survival rate in recipients who had or had not received rituximab (Rit) treatment. The subjects were categorized into four groups as follows: DSA+Rit-, n = 39; DSA-Rit-, n = 121; DSA+Rit+, n = 74; and DSA-Rit+, n = 47. We examined the influence of preoperative DSA on the incidence of graft rejection and the survival rate of recipients who had or who had not received rituximab before transplantation. The 6-month acute rejection rates based on graft biopsies were 39%, 19%, 15%, and 0% for the DSA+Rit-, DSA-Rit-, DSA+Rit+, and DSA-Rit+ groups. The rates of chronic antibody-mediated rejection after more than 6 months were 50%, 22%, 18%, and 0%. The 5-year graft survival rate was significantly lower in the DSA+Rit- group (84%) than in the other groups (95% for DSA-Rit-, 98% for DSA+Rit+, and 91% for DSA-Rit+). The rate of the appearance of de novo anti-HLA antibodies was higher in the groups that did not receive rituximab treatment. The rate of graft loss associated with chronic antibody-mediated rejection was also higher in the DSA+Rit- group than in the other groups (P = 0.01). The presence of DSA and the administration of rituximab had strong impacts on not only short-term graft rejection, but also long-term graft rejection and its association with the graft survival time.
Collapse
Affiliation(s)
- Hideki Ishida
- Department of Urology, Kidney Center, Tokyo Women's Medical University, Tokyo, Japan
| | | | | | | | | |
Collapse
|
|
46
|
Recent trials in immunosuppression and their consequences for current therapy. Curr Opin Organ Transplant 2015; 19:387-94. [PMID: 24905020 DOI: 10.1097/mot.0000000000000093] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
PURPOSE OF REVIEW Although the scarcity of clinical trials with de-novo immunosuppression has been typical over the last 2 years, several attempts have been made in drug conversion, dosing optimization, and bioequivalence. On the basis of recent clinical and animal studies, future directions of management and treatment are outlined. RECENT FINDINGS Studies with new tacrolimus formulations showed better bioavailability and lower doses, which might translate into less toxicity. The long-term results of studies with costimulation blockade confirmed their safety and efficacy. Calcineurin inhibitor (CNI)-free regimens based on mTOR inhibitors were shown to be associated with increased risk of the humoral response. Therefore, ongoing trials are predominantly designed to minimize calcineurin inhibitor dose only. Biologics, such as B-cell-specific agents (bortezomib and rituximab) and complement inhibitors (eculizumab) used to treat antibody-mediated rejection, recurrence of glomerulonephritis, are shifted to more preventive applications. The pretransplant quantification of alloreactive memory/effector T cell response may help to better stratify a patient's immunologic risk and allow for drug minimization. SUMMARY Despite clinical trials with innovative protocols with already established agents, tacrolimus-based and induction-based protocols have been shown to be the mainstay of immunosuppressive regimens. In the future, research aims to focus on biomarker-driven immunosuppression and cell therapy approaches.
Collapse
|
|
47
|
Solid phase-based cross-matching as solution for kidney allograft recipients pretreated with therapeutic antibodies. BIOMED RESEARCH INTERNATIONAL 2015; 2015:587158. [PMID: 25654115 PMCID: PMC4310493 DOI: 10.1155/2015/587158] [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: 06/13/2014] [Revised: 09/17/2014] [Accepted: 09/17/2014] [Indexed: 11/17/2022]
Abstract
In order to select recipients without donor-specific anti-HLA antibodies, the complement-dependent cytotoxicity crossmatch (CDC-CM) was established as the standard procedure about 40 years ago. However, the interpretability of this functional assay strongly depends on the vitality of isolated donors' lymphocytes. Since the application of therapeutic antibodies for the immunosuppressive regimen falsifies the outcome of the CDC-crossmatch as a result of these antibodies' complement-activating capacity in the recipients' sera, we looked for an alternative methodical approach. We here present 27 examples of AB0 blood group-incompatible living kidney allograft recipients who, due to their treatment with the humanized chimeric monoclonal anti-CD20 antibody Rituximab, did not present valid outcomes of CDC-based pretransplant cross-matching. Additionally, four cases of posttransplant cross-matching after living kidney allografting and consequent treatment with the therapeutic anti-CD25 antibody Basiliximab (Simulect) due to acute biopsy-proven rejection episodes are presented and compared regarding CDC- and ELISA-based crossmatch outcomes. In all cases, it became evident that the classical CDC-based crossmatch was completely unfeasible for the detection of donor-specific anti-HLA antibodies, whereas ELISA-based cross-matching not requiring vital cells was not artificially affected. We conclude that ELISA-based cross-matching is a valuable tool to methodically circumvent false positive CDC-based crossmatch results in the presence of therapeutically applied antibodies.
Collapse
|
|
48
|
Salvadori M, Bertoni E. What's new in clinical solid organ transplantation by 2013. World J Transplant 2014; 4:243-266. [PMID: 25540734 PMCID: PMC4274595 DOI: 10.5500/wjt.v4.i4.243] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2014] [Revised: 07/11/2014] [Accepted: 07/27/2014] [Indexed: 02/05/2023] Open
Abstract
Innovative and exciting advances in the clinical science in solid organ transplantation continuously realize as the results of studies, clinical trials, international conferences, consensus conferences, new technologies and discoveries. This review will address to the full spectrum of news in transplantation, that verified by 2013. The key areas covered are the transplantation activity, with particular regards to the donors, the news for solid organs such as kidney, pancreas, liver, heart and lung, the news in immunosuppressive therapies, the news in the field of tolerance and some of the main complications following transplantation as infections and cancers. The period of time covered by the study starts from the international meetings held in 2012, whose results were published in 2013, up to the 2013 meetings, conferences and consensus published in the first months of 2014. In particular for every organ, the trends in numbers and survival have been reviewed as well as the most relevant problems such as organ preservation, ischemia reperfusion injuries, and rejections with particular regards to the antibody mediated rejection that involves all solid organs. The new drugs and strategies applied in organ transplantation have been divided into new way of using old drugs or strategies and drugs new not yet on the market, but on phase Ito III of clinical studies and trials.
Collapse
|
|
49
|
Shiu KY, Dorling A. Optimising long-term graft survival: establishing the benefit of targeting B lymphocytes. Clin Med (Lond) 2014; 14 Suppl 6:s84-8. [PMID: 25468927 DOI: 10.7861/clinmedicine.14-6-s84] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
Kidney transplants do not last for the natural lifespan of most recipients. Of the reasons why transplants fail, damage by the immune system is the commonest cause. Understanding how the immune system recognises transplanted organs has increased significantly in recent years, but there is little insight into how organs are damaged, and no still no way of suppressing immune-mediated damage without exposing patients to the detrimental effects of long-term immunosuppression. In this article, we review the role of antibodies and B cells in immune-mediated damage of kidney transplants, and discuss the potential for manipulation of B cells to improve clinical outcomes.
Collapse
Affiliation(s)
- Kin Yee Shiu
- Royal Free London NHS Foundation Trust, London, UK
| | - Anthony Dorling
- MRC Centre for Transplantation, King's College London, and honorary consultant nephrologist, Guy's and St Thomas' NHS Foundation Trust, London, UK
| |
Collapse
|
|
50
|
Pankewycz O, Soliman K, Laftavi MR. The increasing clinical importance of alloantibodies in kidney transplantation. Immunol Invest 2014; 43:775-89. [DOI: 10.3109/08820139.2014.910016] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
|