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1
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Alonso-Guallart P, Harle D. Role of chemokine receptors in transplant rejection and graft-versus-host disease. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2024; 388:95-123. [PMID: 39260939 DOI: 10.1016/bs.ircmb.2024.07.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/13/2024]
Abstract
Organ transplantation increases life expectancy and improves the quality of life of patients experiencing specific conditions such as terminal organ failure. Despite matching efforts between donor and recipient, immune activation can interfere with allograft survival after transplantation if immunosuppression is not used. With both innate and adaptive responses, this is a complicated immunological process. This can lead to organ rejection, or graft-versus-host disease (GVHD), depending on the origin of the immune response. Inflammatory factors, such as chemokine receptors and their ligands, are involved in a wide variety of immunological processes, including modulating transplant rejection or GVHD, therefore, chemokine biology has been a major focus of transplantation studies. These molecules attract circulating peripheral leukocytes to infiltrate into the allograft and facilitate dendritic and T cell trafficking between lymph nodes and the graft during the allogeneic response. In this chapter, we will review the most relevant chemokine receptors such as CXCR3 and CCR5, among others, and their ligands involved in the process of allograft rejection for solid organ transplantation and graft-versus-host disease in the context of hematopoietic cell transplantation.
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Affiliation(s)
| | - David Harle
- Columbia Center for Translational Immunology
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2
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Mattke J, Darden CM, Vasu S, Lawrence MC, Kirkland J, Kane RR, Naziruddin B. Inhibition of Toll-like Receptor 4 Using Small Molecule, TAK-242, Protects Islets from Innate Immune Responses. Cells 2024; 13:416. [PMID: 38474380 PMCID: PMC10931053 DOI: 10.3390/cells13050416] [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: 01/26/2024] [Revised: 02/23/2024] [Accepted: 02/24/2024] [Indexed: 03/14/2024] Open
Abstract
Islet transplantation is a therapeutic option to replace β-cell mass lost during type 1 or type 3c diabetes. Innate immune responses, particularly the instant blood-mediated inflammatory reaction and activation of monocytes, play a major role in the loss of transplanted islet tissue. In this study, we aimed to investigate the inhibition of toll-like receptor 4 (TLR4) on innate inflammatory responses. We first demonstrate a significant loss of graft function shortly after transplant through the assessment of miR-375 and miR-200c in plasma as biomarkers. Using in vitro models, we investigate how targeting TLR4 mitigates islet damage and immune cell activation during the peritransplant period. The results of this study support the application of TAK-242 as a therapeutic agent to reduce inflammatory and innate immune responses to islets immediately following transplantation into the hepatic portal vein. Therefore, TLR4 may serve as a target to improve islet transplant outcomes in the future.
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Affiliation(s)
- Jordan Mattke
- Institute of Biomedical Studies, Baylor University, Waco, TX 76706, USA; (J.M.); (R.R.K.)
| | - Carly M. Darden
- Annette C. and Harold C. Simmons Transplant Institute, Baylor University Medical Center, Dallas, TX 75204, USA; (C.M.D.); (J.K.)
| | - Srividya Vasu
- Islet Cell Laboratory, Baylor Scott and White Research Institute, Dallas, TX 75204, USA; (S.V.); (M.C.L.)
| | - Michael C. Lawrence
- Islet Cell Laboratory, Baylor Scott and White Research Institute, Dallas, TX 75204, USA; (S.V.); (M.C.L.)
| | - Jeffrey Kirkland
- Annette C. and Harold C. Simmons Transplant Institute, Baylor University Medical Center, Dallas, TX 75204, USA; (C.M.D.); (J.K.)
| | - Robert R. Kane
- Institute of Biomedical Studies, Baylor University, Waco, TX 76706, USA; (J.M.); (R.R.K.)
| | - Bashoo Naziruddin
- Annette C. and Harold C. Simmons Transplant Institute, Baylor University Medical Center, Dallas, TX 75204, USA; (C.M.D.); (J.K.)
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3
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A study of the mechanisms responsible for the action of new immunosuppressants and their effects on rat small intestinal transplantation. Transpl Immunol 2021; 70:101497. [PMID: 34785307 DOI: 10.1016/j.trim.2021.101497] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Revised: 11/08/2021] [Accepted: 11/08/2021] [Indexed: 11/20/2022]
Abstract
In a series of studies, using an identical rat intestinal transplantation model, we evaluated the effects of several drugs. FK-506 caused a significant attenuation in the proliferation of allogeneic CD4+ T cells and IFN-γ secreting effector functions. FYT720 resulted in a marked reduction in the numbers of lymphocytes, associated with a reduction of T cell recruitment, in grafts. An anti-MAdCAM antibody was next reported to significantly down-regulate CD4+ T cell infiltration in intestinal grafts by blocking the adhesion molecule, and could be useful as an induction therapy. Concerning TAK-779, this CCR5 and CXCR3 antagonist diminished the number of graft-infiltrating cells by suppressing the expression of their receptors in the graft. As a result, it reduced the total number of recipient T cells involved in graft rejection. As the next step, we focused on the participation of monocytes/ macrophages in this field. PQA-18 has been the focus of a novel immunosuppressant that attenuates not only the production of various cytokines, such as IL-2 & TNF-α, on T cells, but the differentiation of macrophages by inhibiting PAK2 as well. In this report, we summarize our previous studies not only regarding the above drugs, but on an anti-complement drug and a JAK inhibitor as well.
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McDowell RE, Ali KF, Lad S, San Martin VT, Bottino R, Walsh M, Stevens T, Wilke W, Kirwan JP, Hatipoglu B. Bioenergetics of Islet Preparations in a Pilot Clinical Trial of Peri-Transplant Hydroxychloroquine for Autologous Islet Transplantation. Cell Transplant 2021; 30:9636897211057440. [PMID: 34757864 PMCID: PMC8586172 DOI: 10.1177/09636897211057440] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
The inflammatory response is an obstacle to success in both allogeneic and autologous islet transplantation. In autologous islet transplantation (AIT), however, the recipient is also the donor, permitting pretreatment of donor/recipient for a controlled duration prior to transplantation. We sought to exploit this feature of (AIT) by pretreating donor/recipients with chronic pancreatitis undergoing total pancreatectomy and autologous islet transplantation (TPAIT) to test the hypothesis that peri-transplant treatment with the FDA-approved anti-inflammatory hydroxychloroquine (HCQ) improves graft function. In this randomized placebo-controlled pilot clinical study, patients (n = 6) were treated with oral HCQ for 30 days prior to and 90 days after TPAIT. In vivo islet function was assessed via Mixed Meal Tolerance Testing before HCQ treatment, 6- and 12-months after surgery. In vitro islet bioenergetics were assessed at the time of transplantation via extracellular flux analysis of islet preparation samples from the clinical trial cohort and six additional patients (n = 12). Our study shows that HCQ did not alter clinical endpoints, but HCQ-treated patients showed greater spare respiratory capacity (SRC) compared to samples from control patients (P=0.028). Glycolytic metabolism of islet preparations directly correlated with stimulated C-peptide secretion both before and after TPAIT (P=0.01, R2=0.489 and P=0.03, R2=0.674, respectively), and predicted in vivo islet function better than mitochondrial metabolism of islet preps or islet equivalents infused. Overnight culture of islet preparations altered bioenergetic function, significantly decreasing SRC and maximal respiration (P<0.001). In conclusion, while HCQ did not alter clinical outcomes, it was associated with significantly increased SRC in islet preparations. Bioenergetic analyses of islet preparations suggests that culture should be avoided and that glycolysis may be a more sensitive indicator of in vivo islet function than current metrics, including islet oxygen consumption and islet equivalents infused.
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Affiliation(s)
- Ruth E McDowell
- Department of Inflammation & Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.,Department of Biology, Oberlin College, Oberlin, OH, USA
| | - Khawla F Ali
- Endocrinology and Metabolism Institute, Cleveland Clinic, Cleveland, OH, USA.,Royal College of Surgeons in Ireland-Medical University of Bahrain, Muharraq, Bahrain
| | - Saloni Lad
- Cleveland Clinic Lerner College of Medicine, Cleveland, OH, USA
| | | | - Rita Bottino
- Institute for Cellular Therapeutics, Allegheny Health Network Research Institute, Pittsburgh, PA, USA.,Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, PA, USA
| | - Matthew Walsh
- Digestive Disease Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Tyler Stevens
- Digestive Disease Institute, Cleveland Clinic, Cleveland, OH, USA
| | - William Wilke
- Orthopaedic & Rheumatologic Institute, Cleveland Clinic, Cleveland, OH, USA
| | - John P Kirwan
- Department of Inflammation & Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.,Integrated Physiology and Molecular Medicine Laboratory, Pennington Biomedical Research Center, Baton Rouge, LA, USA
| | - Betul Hatipoglu
- Endocrinology and Metabolism Institute, Cleveland Clinic, Cleveland, OH, USA.,Diabetes & Obesity Center, University Hospitals Cleveland Medical Center, Cleveland, OH, USA
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5
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Wang X, Wang D, Wang X, Wang X, Sha JC, Gao Q. Mechanisms underlying the production of chemokine CXCL11 in the reaction of renal tubular epithelial cells with CD4 + and CD8 + T cells. Transpl Immunol 2020; 65:101337. [PMID: 32971208 DOI: 10.1016/j.trim.2020.101337] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2019] [Revised: 09/15/2020] [Accepted: 09/19/2020] [Indexed: 11/28/2022]
Abstract
AIM To study the release mechanism of C-X-C motif chemokine 11 (CXCL11) and other chemokines after the co-cultivation of CD4+ and CD8+ T cells with the renal tubular epithelial cells (RTEC) in the process of allograft renal transplantation rejection. METHODS The Human CD4+, CD8+ T cells were obtained from the blood of volunteers and kidney transplantation (Ktx) patients, and co-cultured with renal tubular epithelial cells (RTEC) in vitro. RT-PCR was run for detecting the mRNA transcription of CXCL11, IFN-induced protein of 10 (CXCL10), and IL-6 in cells after RTEC was stimulated with IFN-γ or co-cultured with CD4+ and CD8+ T cells. The concentration of CXCL11, CXCL10 and IL-6 in the culture medium was detected by Multiplex Assay after RTEC was stimulated with IFN-γ or co-cultured with CD4+ and CD8+ T cells. IFN-γ receptor antibody was used for interfering with the above reaction and the blocking effect was observed. Western blot was used for protein expression analysis. Finally, we applied renal biopsies from kidney transplantation patients with and without rejection to verify the results of the above experiments by using RT-PCR and Western blot. RESULTS The mRNA expression of CXCL11 and CXCL10 were significantly increased after RTEC was stimulated with IFN-γ or co-cultured with CD4+ and CD8+ T cells. Multiplex Assay showed that the concentration of CXCL11 and CXCL10 in the supernatant were significantly increased in a time-dependence fashion after stimulation RTEC by IFN-γ. Anti-IFN-γ receptor1 (anti-IFN-γR1) antibody could reduce the production of CXCL11 and CXCL10 in this situation. The concentration of CXCL11 and CXCL11 in the supernatant was significantly increased with a time-dependent effect after the co-culture of CD4+ and CD8+ T cells with RTEC. The anti-IFN-γR1 blocked this effect. Our study showed that the expression levels of CXCL11 and CXCL10 were upgraded in the biopsies of patients with renal transplant rejection comparatively to pre-transplant biopsies, both at mRNA and protein levels. CONCLUSIONS RTEC and T cells can stimulate each other during the acute rejection of allogeneic kidney transplantation and secret CXCL11，CXCL10 and other chemokines. IFN-γ plays a key role in this process.
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Affiliation(s)
- Xiaoping Wang
- Department of Nephrology, Shandong University & Jinan Central Hospital Affiliated to Shandong First Medical University, Jinan 250000, China.
| | - Dan Wang
- Department of Nephrology, Shandong University & Jinan Central Hospital Affiliated to Shandong First Medical University, Jinan 250000, China.
| | - Xiao Wang
- Department of Nephrology, Shandong University & Jinan Central Hospital Affiliated to Shandong First Medical University, Jinan 250000, China.
| | - Xiaoqi Wang
- Department of Cardiology, Shandong University & Jinan Central Hospital Affiliated to Shandong First Medical University, Jinan 250000, China.
| | - Ji-Chang Sha
- Department of Neurosurgery, Zhangqiu District People's Hospital, Jinan 250200, China.
| | - Qingzhen Gao
- Department of Nephrology, Shandong University & Jinan Central Hospital Affiliated to Shandong First Medical University, Jinan 250000, China.
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Zammit NW, Walters SN, Seeberger KL, O'Connell PJ, Korbutt GS, Grey ST. A20 as an immune tolerance factor can determine islet transplant outcomes. JCI Insight 2019; 4:131028. [PMID: 31581152 DOI: 10.1172/jci.insight.131028] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2019] [Accepted: 09/25/2019] [Indexed: 01/05/2023] Open
Abstract
Islet transplantation can restore lost glycemic control in type 1 diabetes subjects but is restricted in its clinical application by a limiting supply of islets and the need for heavy immune suppression to prevent rejection. TNFAIP3, encoding the ubiquitin editing enzyme A20, regulates the activation of immune cells by raising NF-κB signaling thresholds. Here, we show that increasing A20 expression in allogeneic islet grafts resulted in permanent survival for ~45% of recipients, and > 80% survival when combined with subtherapeutic rapamycin. Allograft survival was dependent upon Tregs and was antigen specific, and grafts showed reduced expression of inflammatory factors. Transplantation of islets with A20 containing a loss-of-function variant (I325N) resulted in increased RIPK1 ubiquitination and NF-κB signaling, graft hyperinflammation, and acute allograft rejection. Overexpression of A20 in human islets potently reduced expression of inflammatory mediators, with no impact on glucose-stimulated insulin secretion. Therapeutic administration of A20 raises inflammatory signaling thresholds to favor immune tolerance and promotes islet allogeneic survival. Clinically, this would allow for reduced immunosuppression and support the use of alternate islet sources.
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Affiliation(s)
- Nathan W Zammit
- Immunology Department, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia
| | - Stacey N Walters
- Immunology Department, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia
| | - Karen L Seeberger
- Department of Surgery, University of Alberta, Edmonton, Alberta, Canada
| | - Philip J O'Connell
- Centre for Transplant and Renal Research, Westmead Institute for Medical Research, University of Sydney at Westmead Hospital, NSW Australia
| | - Gregory S Korbutt
- Department of Surgery, University of Alberta, Edmonton, Alberta, Canada
| | - Shane T Grey
- Immunology Department, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia
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7
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Maymon E, Romero R, Bhatti G, Chaemsaithong P, Gomez-Lopez N, Panaitescu B, Chaiyasit N, Pacora P, Dong Z, Hassan SS, Erez O. Chronic inflammatory lesions of the placenta are associated with an up-regulation of amniotic fluid CXCR3: A marker of allograft rejection. J Perinat Med 2018; 46:123-137. [PMID: 28829757 PMCID: PMC5797487 DOI: 10.1515/jpm-2017-0042] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2017] [Accepted: 04/19/2017] [Indexed: 01/05/2023]
Abstract
OBJECTIVE The objective of this study is to determine whether the amniotic fluid (AF) concentration of soluble CXCR3 and its ligands CXCL9 and CXCL10 changes in patients whose placentas show evidence of chronic chorioamnionitis or other placental lesions consistent with maternal anti-fetal rejection. METHODS This retrospective case-control study included 425 women with (1) preterm delivery (n=92); (2) term in labor (n=68); and (3) term not in labor (n=265). Amniotic fluid CXCR3, CXCL9 and CXCL10 concentrations were determined by ELISA. RESULTS (1) Amniotic fluid concentrations of CXCR3 and its ligands CXCL9 and CXCL10 are higher in patients with preterm labor and maternal anti-fetal rejection lesions than in those without these lesions [CXCR3: preterm labor and delivery with maternal anti-fetal rejection placental lesions (median, 17.24 ng/mL; IQR, 6.79-26.68) vs. preterm labor and delivery without these placental lesions (median 8.79 ng/mL; IQR, 4.98-14.7; P=0.028)]; (2) patients with preterm labor and chronic chorioamnionitis had higher AF concentrations of CXCL9 and CXCL10, but not CXCR3, than those without this lesion [CXCR3: preterm labor with chronic chorioamnionitis (median, 17.02 ng/mL; IQR, 5.57-26.68) vs. preterm labor without chronic chorioamnionitis (median, 10.37 ng/mL; IQR 5.01-17.81; P=0.283)]; (3) patients with preterm labor had a significantly higher AF concentration of CXCR3 than those in labor at term regardless of the presence or absence of placental lesions. CONCLUSION Our findings support a role for maternal anti-fetal rejection in a subset of patients with preterm labor.
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Affiliation(s)
- Eli Maymon
- Perinatology Research Branch, NICHD/NIH/DHHS, Bethesda, MD, USA, and Detroit, MI, USA
- Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, USA
| | - Roberto Romero
- Perinatology Research Branch, NICHD/NIH/DHHS, Bethesda, MD, USA, and Detroit, MI, USA
- Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, MI, USA
- Department of Epidemiology and Biostatistics, Michigan State University, East Lansing, MI, USA
- Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI, USA
| | - Gaurav Bhatti
- Perinatology Research Branch, NICHD/NIH/DHHS, Bethesda, MD, USA, and Detroit, MI, USA
| | - Piya Chaemsaithong
- Perinatology Research Branch, NICHD/NIH/DHHS, Bethesda, MD, USA, and Detroit, MI, USA
- Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, USA
- Department of Obstetrics and Gynecology, Block E East Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin New Territories, Hong Kong
| | - Nardhy Gomez-Lopez
- Perinatology Research Branch, NICHD/NIH/DHHS, Bethesda, MD, USA, and Detroit, MI, USA
- Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, USA
- Department of Immunology and Microbiology, Wayne State University School of Medicine, Detroit, MI, USA
| | - Bogdan Panaitescu
- Perinatology Research Branch, NICHD/NIH/DHHS, Bethesda, MD, USA, and Detroit, MI, USA
- Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, USA
| | - Noppadol Chaiyasit
- Perinatology Research Branch, NICHD/NIH/DHHS, Bethesda, MD, USA, and Detroit, MI, USA
- Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, USA
| | - Percy Pacora
- Perinatology Research Branch, NICHD/NIH/DHHS, Bethesda, MD, USA, and Detroit, MI, USA
- Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, USA
| | - Zhong Dong
- Perinatology Research Branch, NICHD/NIH/DHHS, Bethesda, MD, USA, and Detroit, MI, USA
- Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, USA
| | - Sonia S. Hassan
- Perinatology Research Branch, NICHD/NIH/DHHS, Bethesda, MD, USA, and Detroit, MI, USA
- Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, USA
| | - Offer Erez
- Perinatology Research Branch, NICHD/NIH/DHHS, Bethesda, MD, USA, and Detroit, MI, USA
- Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, USA
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Chang CA, Akinbobuyi B, Quintana JM, Yoshimatsu G, Naziruddin B, Kane RR. Ex-vivo generation of drug-eluting islets improves transplant outcomes by inhibiting TLR4-Mediated NFkB upregulation. Biomaterials 2017; 159:13-24. [PMID: 29309990 DOI: 10.1016/j.biomaterials.2017.12.020] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2017] [Revised: 12/18/2017] [Accepted: 12/23/2017] [Indexed: 12/19/2022]
Abstract
The systemic administration of immunosuppressive and anti-inflammatory drugs is routinely employed in organ transplantation to minimize graft rejection and improve graft survival. Localized drug delivery has the potential to improve transplant outcomes by providing sustained exposure to efficacious drug concentrations while avoiding systemic immunosuppression and off-target effects. Here, we describe the synthesis of a novel prodrug and its direct covalent conjugation to pancreatic islets via a cleavable linker. Post-transplant, linker hydrolysis results in the release of a potent anti-inflammatory antagonist of TLR4, localized to the site of implantation. This covalent islet modification significantly reduces the time and the minimal effective dose of islets necessary to achieve normoglycemia in a murine transplantation model. In streptozotocin-induced diabetic C57BL/6 mice a syngeneic transplant of ∼100 modified islets achieved a 100% cure rate by the end of a 4-week monitoring period, compared to a 0% cure rate for untreated control islets. Overall, this direct prodrug conjugation to islets is well tolerated and preserves their functionality while affording significantly superior transplant outcomes. The development of drug-eluting tissues that deliver sustained and localized doses of small-molecule therapeutics represents a novel pathway for enhancing success in transplantation.
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Affiliation(s)
- Charles A Chang
- Institute of Biomedical Studies, Baylor University, Waco, TX 76798, USA
| | - Babatope Akinbobuyi
- Department of Chemistry and Biochemistry, Baylor University, Waco, TX 76798, USA
| | - Jeremy M Quintana
- Department of Chemistry and Biochemistry, Baylor University, Waco, TX 76798, USA
| | - Gumpei Yoshimatsu
- Islet Cell Laboratory, Baylor Scott & White Research Institute, Dallas, TX 75226, USA
| | - Bashoo Naziruddin
- Institute of Biomedical Studies, Baylor University, Waco, TX 76798, USA; Annette C. and Harold C. Simmons Transplant Institute, Baylor University Medical Center, Dallas, TX 75246, USA
| | - Robert R Kane
- Institute of Biomedical Studies, Baylor University, Waco, TX 76798, USA; Department of Chemistry and Biochemistry, Baylor University, Waco, TX 76798, USA.
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9
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Merani S, Truong WW, Hancock W, Anderson CC, Shapiro AMJ. Chemokines and Their Receptors in Islet Allograft Rejection and as Targets for Tolerance Induction. Cell Transplant 2017; 15:295-309. [PMID: 28863747 DOI: 10.3727/000000006783981963] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
Graft rejection is a major barrier to successful outcome of transplantation surgery. Islet transplantation introduces insulin secreting tissue into type 1 diabetes mellitus recipients, relieving patients from exogenous insulin injection. However, insulitis of grafted tissue and allograft rejection prevent long-term insulin independence. Leukocyte trafficking is necessary for the launch of successful immune responses to pathogen or allograft. Chemokines, small chemotactic cytokines, direct the migration of leukocytes through their interaction with chemokine receptors found on cell surfaces of immune cells. Unique receptor expression of leukocytes, and the specificity of chemokine secretion during various states of immune response, suggest that the extracellular chemokine milieu specifically homes certain leukocyte subsets. Thus, only those leukocytes required for the current immune task are attracted to the inflammatory site. Chemokine blockade, using antagonists and monoclonal antibodies directed against chemokine receptors, is an emerging and specific immunosuppressive strategy. Importantly, chemokine blockade may potentiate tolerance induction regimens to be used following transplantation surgery, and prevent the need for life-long immunosuppression of islet transplant recipients. Here, the role for chemokine blockade in islet transplant rejection and tolerance is reviewed.
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Affiliation(s)
- Shaheed Merani
- Department of Surgery, Faculty of Medicine and Dentistry, University of Alberta, Edmonton AB, Canada
| | - Wayne W Truong
- Department of Surgery, Faculty of Medicine and Dentistry, University of Alberta, Edmonton AB, Canada
| | - Wayne Hancock
- Department of Pathology and Laboratory Medicine, Joseph Stokes, Jr. Research Institute and Biesecker Pediatric Liver Center, Children's Hospital of Philadelphia and University of Pennsylvania, Philadelphia, PA, USA
| | - Colin C Anderson
- Department of Surgery, Faculty of Medicine and Dentistry, University of Alberta, Edmonton AB, Canada
| | - A M James Shapiro
- Department of Surgery, Faculty of Medicine and Dentistry, University of Alberta, Edmonton AB, Canada
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10
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Pham-Hua D, Padgett LE, Xue B, Anderson B, Zeiger M, Barra JM, Bethea M, Hunter CS, Kozlovskaya V, Kharlampieva E, Tse HM. Islet encapsulation with polyphenol coatings decreases pro-inflammatory chemokine synthesis and T cell trafficking. Biomaterials 2017; 128:19-32. [PMID: 28285194 DOI: 10.1016/j.biomaterials.2017.03.002] [Citation(s) in RCA: 57] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2016] [Revised: 02/28/2017] [Accepted: 03/02/2017] [Indexed: 12/27/2022]
Abstract
Type 1 Diabetes (T1D) is a chronic pro-inflammatory autoimmune disease consisting of islet-infiltrating leukocytes involved in pancreatic β-cell lysis. One promising treatment for T1D is islet transplantation; however, clinical application is constrained due to limited islet availability, adverse effects of immunosuppressants, and declining graft survival. Islet encapsulation may provide an immunoprotective barrier to preserve islet function and prevent immune-mediated rejection after transplantation. We previously demonstrated that a novel cytoprotective nanothin multilayer coating for islet encapsulation consisting of tannic acid (TA), an immunomodulatory antioxidant, and poly(N-vinylpyrrolidone) (PVPON), was efficacious in dampening in vitro immune responses involved in transplant rejection and preserving in vitro islet function. However, the ability of (PVPON/TA) to maintain islet function in vivo and reverse diabetes has not been tested. Recent evidence has demonstrated that modulation of redox status can affect pro-inflammatory immune responses. Therefore, we hypothesized that transplanted (PVPON/TA)-encapsulated islets can restore euglycemia to diabetic mice and provide an immunoprotective barrier. Our results demonstrate that (PVPON/TA) nanothin coatings can significantly decrease in vitro chemokine synthesis and diabetogenic T cell migration. Importantly, (PVPON/TA)-encapsulated islets restored euglycemia after transplantation into diabetic mice. Our results demonstrate that (PVPON/TA)-encapsulated islets may suppress immune responses and enhance islet allograft acceptance in patients with T1D.
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Affiliation(s)
- Dana Pham-Hua
- Science Technology Honors Program, University of Alabama at Birmingham, Birmingham, AL 35294-2182, USA
| | - Lindsey E Padgett
- Department of Microbiology, Comprehensive Diabetes Center, University of Alabama, Birmingham School of Medicine, Birmingham, AL 35294-2182, USA
| | - Bing Xue
- Department of Chemistry, University of Alabama at Birmingham, Birmingham, AL 35294-2182, USA
| | - Brian Anderson
- Department of Microbiology, Comprehensive Diabetes Center, University of Alabama, Birmingham School of Medicine, Birmingham, AL 35294-2182, USA
| | - Michael Zeiger
- Department of Microbiology, Comprehensive Diabetes Center, University of Alabama, Birmingham School of Medicine, Birmingham, AL 35294-2182, USA
| | - Jessie M Barra
- Department of Microbiology, Comprehensive Diabetes Center, University of Alabama, Birmingham School of Medicine, Birmingham, AL 35294-2182, USA
| | - Maigen Bethea
- Comprehensive Diabetes Center and Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Alabama at Birmingham, Birmingham, AL 35294-2182, USA
| | - Chad S Hunter
- Comprehensive Diabetes Center and Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Alabama at Birmingham, Birmingham, AL 35294-2182, USA
| | - Veronika Kozlovskaya
- Department of Chemistry, University of Alabama at Birmingham, Birmingham, AL 35294-2182, USA
| | - Eugenia Kharlampieva
- Department of Chemistry, University of Alabama at Birmingham, Birmingham, AL 35294-2182, USA; Center of Nanoscale Materials and Biointegration, University of Alabama at Birmingham, Birmingham, AL 35294-2182, USA.
| | - Hubert M Tse
- Department of Microbiology, Comprehensive Diabetes Center, University of Alabama, Birmingham School of Medicine, Birmingham, AL 35294-2182, USA.
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Bogdani M. Thinking Outside the Cell: A Key Role for Hyaluronan in the Pathogenesis of Human Type 1 Diabetes. Diabetes 2016; 65:2105-14. [PMID: 27456615 DOI: 10.2337/db15-1750] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/01/2016] [Accepted: 04/16/2016] [Indexed: 11/13/2022]
Affiliation(s)
- Marika Bogdani
- Matrix Biology Program, Benaroya Research Institute, Seattle, WA
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12
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Hårdstedt M, Lindblom S, Karlsson-Parra A, Nilsson B, Korsgren O. Characterization of Innate Immunity in an Extended Whole Blood Model of Human Islet Allotransplantation. Cell Transplant 2015; 25:503-15. [PMID: 26084381 DOI: 10.3727/096368915x688461] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
The instant blood-mediated inflammatory reaction (IBMIR) has been studied in whole blood models of human allo-islet transplantation for short periods (<6 h). Beyond this time frame the innate response to intraportally transplanted islets is less well described. A novel whole blood model was applied to study blood-islet-graft interactions up to 48 h. Heparinized polyvinyl chloride tubing was sealed into small bags containing venous blood together with allogeneic human islets and exocrine tissue, respectively. The bags were attached to a rotating wheel (37°C). Concentrated glucose and sodium hydrogen carbonate were added every 12 h to maintain physiological limits for sustained immune cell functions. Plasma was collected at repeated time points for analyses of coagulation/complement activation and chemokine/cytokine production. Immune cell infiltration was analyzed using immunohistochemistry. Coagulation and platelet activation markers, thrombin-antithrombin complex (TAT) and soluble CD40 ligand (sCD40L) showed early high concentrations (at 6-12 h). sC5b-9 steadily increased over 48 h. At 6 h neutrophils and monocytes surrounded the clotted cellular grafts with a following massive infiltration of neutrophils. High and increasing concentrations of CXCR1/2 ligands [IL-8 and growth-regulated oncogene α/β/γ (Gro-α/β/γ)] and IL-6 were produced in response to human islets and exocrine tissue. The CCR2 ligand monocyte chemoattractant protein 1 (MCP-1) exhibited increasing concentrations in response to exocrine tissue. The CXCR3 ligand interferon-inducible T cell α chemoattractant (I-TAC) was produced in response to both human islets and exocrine tissue from 6 h. Monokine induced by γ interferon (Mig) and interferon γ-induced protein 10 (IP-10) showed a later response, preferentially to exocrine tissue and with larger variations among preparations. An extended blood model of clinical islet transplantation allowed characterization of early immune activation in response to human islets and exocrine tissue. Increased production of chemokines targeting CXCR1/2, CCR2, and CXCR3 was observed, accompanied by massive intraislet neutrophil infiltration over 48 h. The model proved to be useful in exploring early blood-mediated reactions to cellular transplants and has relevance for evaluation of pharmacological interventions to prevent graft loss.
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Affiliation(s)
- Maria Hårdstedt
- Department of Immunology, Genetics and Pathology, Clinical Immunology, The Rudbeck Laboratory, Uppsala University, Uppsala, Sweden
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Alleviation of instant blood-mediated inflammatory reaction in autologous conditions through treatment of human islets with NF-κB inhibitors. Transplantation 2014; 98:578-84. [PMID: 24798306 DOI: 10.1097/tp.0000000000000107] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
BACKGROUND The instant blood-mediated inflammatory response (IBMIR) has been shown as a major factor that causes damage to transplanted islets. Withaferin A (WA), an inhibitor of nuclear factor (NF) κB, was shown to suppress the inflammatory response in islets and improve syngeneic islet graft survival in mice. We investigated how treating islets with NF-κB inhibitors affected IBMIR using an in vitro human autologous blood islet model. METHODS Human islets were pretreated with or without NF-κB inhibitors WA or CAY10512 before mixing autologous blood in a miniaturized in vitro tube model. Plasma samples were collected at multiple time points and used for the measurement of C-peptide, proinsulin, thrombin-antithrombin (TAT) complex, and a panel of proinflammatory cytokines. Infiltration of neutrophils into islets was analyzed using immunohistochemistry. RESULTS Rapid release of C-peptide and proinsulin was observed 3 hr after mixing islets and blood in the control group, but not in the NF-κB inhibitor-treated groups, whereas TAT levels were elevated in all three groups with a peak at 6 hr. Significant elevation of proinflammatory cytokines was observed in the control group after 3 hr, but not in the treatment groups. Significant inhibition of neutrophil infiltration was also observed in the WA group compared with the control (P<0.001) and CAY10512 (P<0.001) groups. CONCLUSIONS A miniaturized in vitro tube model can be useful in investigating IBMIR. The presence of NF-κB inhibitor could alleviate IBMIR, thus improving the survival of transplanted islets. Protection of islets in the peritransplant phase may improve long-term graft outcomes.
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14
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Iuamoto LR, Meyer A, Chaib E, D’Albuquerque LAC. Review of experimental attempts of islet allotransplantation in rodents: Parameters involved and viability of the procedure. World J Gastroenterol 2014; 20:13512-13520. [PMID: 25309081 PMCID: PMC4188902 DOI: 10.3748/wjg.v20.i37.13512] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2014] [Revised: 05/03/2014] [Accepted: 06/23/2014] [Indexed: 02/06/2023] Open
Abstract
The purpose of the present study was to organize the parameters involved in experimental allotransplantation in rodents to elaborate the most suitable model to supply the scarcity of islet donors. We used the PubMed database to systematically search for published articles containing the keywords “rodent islet transplantation” to review. We included studies that involved allotransplantation experiments with rodents’ islets, and we reviewed the reference lists from the eligible publications that were retrieved. We excluded articles related to isotransplantation, autotransplantation and xenotransplantation, i.e., transplantation in other species. A total of 25 studies related to allotransplantation were selected for systematic review based on their relevance and updated data. Allotransplantation in rodents is promising and continues to develop. Survival rates of allografts have increased with the discovery of new immunosuppressive drugs and the use of different graft sites. These successes suggest that islet transplantation is a promising method to overcome the scarcity of islet donors and advance the treatment options for type 1 diabetes.
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15
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Kanak MA, Takita M, Kunnathodi F, Lawrence MC, Levy MF, Naziruddin B. Inflammatory response in islet transplantation. Int J Endocrinol 2014; 2014:451035. [PMID: 24883060 PMCID: PMC4021753 DOI: 10.1155/2014/451035] [Citation(s) in RCA: 85] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2013] [Revised: 02/04/2014] [Accepted: 02/12/2014] [Indexed: 12/23/2022] Open
Abstract
Islet cell transplantation is a promising beta cell replacement therapy for patients with brittle type 1 diabetes as well as refractory chronic pancreatitis. Despite the vast advancements made in this field, challenges still remain in achieving high frequency and long-term successful transplant outcomes. Here we review recent advances in understanding the role of inflammation in islet transplantation and development of strategies to prevent damage to islets from inflammation. The inflammatory response associated with islets has been recognized as the primary cause of early damage to islets and graft loss after transplantation. Details on cell signaling pathways in islets triggered by cytokines and harmful inflammatory events during pancreas procurement, pancreas preservation, islet isolation, and islet infusion are presented. Robust control of pre- and peritransplant islet inflammation could improve posttransplant islet survival and in turn enhance the benefits of islet cell transplantation for patients who are insulin dependent. We discuss several potent anti-inflammatory strategies that show promise for improving islet engraftment. Further understanding of molecular mechanisms involved in the inflammatory response will provide the basis for developing potent therapeutic strategies for enhancing the quality and success of islet transplantation.
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Affiliation(s)
- Mazhar A. Kanak
- Institute for Biomedical Studies, Baylor University, Waco, TX 76712, USA
| | - Morihito Takita
- Islet Cell Laboratory, Baylor Research Institute, Dallas, TX 75204, USA
| | - Faisal Kunnathodi
- Islet Cell Laboratory, Baylor Research Institute, Dallas, TX 75204, USA
| | | | - Marlon F. Levy
- Baylor Annette C. and Harold C. Simmons Transplant Institute, 3410 Worth Street, Dallas, TX 75246, USA
| | - Bashoo Naziruddin
- Baylor Annette C. and Harold C. Simmons Transplant Institute, 3410 Worth Street, Dallas, TX 75246, USA
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16
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Exploring the CXCR3 Chemokine Receptor with Small-Molecule Antagonists and Agonists. TOPICS IN MEDICINAL CHEMISTRY 2014. [DOI: 10.1007/7355_2014_75] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
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Romero R, Whitten A, Korzeniewski SJ, Than NG, Chaemsaithong P, Miranda J, Dong Z, Hassan SS, Chaiworapongsa T. Maternal floor infarction/massive perivillous fibrin deposition: a manifestation of maternal antifetal rejection? Am J Reprod Immunol 2013; 70:285-98. [PMID: 23905710 DOI: 10.1111/aji.12143] [Citation(s) in RCA: 70] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2013] [Accepted: 05/07/2013] [Indexed: 01/01/2023] Open
Abstract
OBJECTIVE Massive perivillous fibrin deposition (MPFD) and maternal floor infarction (MFI) are related placental lesions often associated with fetal death and fetal growth restriction. A tendency to recur in subsequent pregnancies has been reported. This study was conducted to determine whether this complication of pregnancy could reflect maternal antifetal rejection. METHODS Pregnancies with MPFD were identified (n = 10). Controls consisted of women with uncomplicated pregnancies who delivered at term without MPFD (n = 175). Second-trimester maternal plasma was analyzed for panel-reactive anti-HLA class I and class II antibodies. The prevalence of chronic chorioamnionitis, villitis of unknown etiology, and plasma cell deciduitis was compared between cases and controls. Immunohistochemistry was performed on available umbilical vein segments from cases with MPFD (n = 4) to determine whether there was evidence of complement activation (C4d deposition). Specific maternal HLA-antibody and fetal HLA-antigen status were also determined in paired specimens (n = 6). Plasma CXCL-10 concentrations were measured in longitudinal samples of cases (n = 28 specimens) and controls (n = 749 specimens) by ELISA. Linear mixed-effects models were used to test for differences in plasma CXCL-10 concentration. RESULTS (i) The prevalence of plasma cell deciduitis in the placenta was significantly higher in cases with MPFD than in those with uncomplicated term deliveries (40% versus 8.6%, P = 0.01), (ii) patients with MPFD had a significantly higher frequency of maternal anti-HLA class I positivity during the second trimester than those with uncomplicated term deliveries (80% versus 36%, P = 0.01); (iii) strongly positive C4d deposition was observed on umbilical vein endothelium in cases of MPFD, (iv) a specific maternal antibody against fetal HLA antigen class I or II was identified in all cases of MPFD; and 5) the mean maternal plasma concentration of CXCL-10 was higher in patients with evidence of MPFD than in those without evidence of MFPD (P < 0.001). CONCLUSION A subset of patients with MPFD has evidence of maternal antifetal rejection.
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Affiliation(s)
- Roberto Romero
- Perinatology Research Branch, NICHD/NIH/DHHS, Detroit, MI, Bethesda, MD, USA
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18
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The interaction between CXCL10 and cytokines in chronic inflammatory arthritis. Autoimmun Rev 2013; 12:554-7. [DOI: 10.1016/j.autrev.2012.10.001] [Citation(s) in RCA: 62] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2012] [Accepted: 10/05/2012] [Indexed: 11/19/2022]
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Eldor R, Abel R, Sever D, Sadoun G, Peled A, Sionov R, Melloul D. Inhibition of nuclear factor-κB activation in pancreatic β-cells has a protective effect on allogeneic pancreatic islet graft survival. PLoS One 2013; 8:e56924. [PMID: 23437272 PMCID: PMC3578930 DOI: 10.1371/journal.pone.0056924] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2012] [Accepted: 01/16/2013] [Indexed: 01/22/2023] Open
Abstract
Pancreatic islet transplantation, a treatment for type 1 diabetes, has met significant challenges, as a substantial fraction of the islet mass fails to engraft, partly due to death by apoptosis in the peri- and post-transplantation periods. Previous evidence has suggested that NF-κB activation is involved in cytokine-mediated β-cell apoptosis and regulates the expression of pro-inflammatory and chemokine genes. We therefore sought to explore the effects of β-cell-specific inhibition of NF-κB activation as a means of cytoprotection in an allogeneic model of islet transplantation. To this end, we used islets isolated from the ToI-β transgenic mouse, where NF-κB signalling can specifically and conditionally be inhibited in β-cells by expressing an inducible and non-degradable form of IκBα regulated by the tet-on system. Our results show that β-cell-specific blockade of NF-κB led to a prolonged islet graft survival, with a relative higher preservation of the engrafted endocrine tissue and reduced inflammation. Importantly, a longer delay in allograft rejection was achieved when mice were systemically treated with the proteasome inhibitor, Bortezomib. Our findings emphasize the contribution of NF-κB activation in the allograft rejection process, and suggest an involvement of the CXCL10/IP-10 chemokine. Furthermore, we suggest a potential, readily available therapeutic agent that may temper this process.
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Affiliation(s)
- Roy Eldor
- Department of Endocrinology, Hadassah University Hospital, Jerusalem, Israel
| | - Roy Abel
- Department of Endocrinology, Hadassah University Hospital, Jerusalem, Israel
| | - Dror Sever
- Department of Endocrinology, Hadassah University Hospital, Jerusalem, Israel
| | - Gad Sadoun
- Department of Endocrinology, Hadassah University Hospital, Jerusalem, Israel
| | - Amnon Peled
- Goldyne Savad Institute of Gene Therapy, Hadassah University Hospital, Jerusalem, Israel
| | - Ronit Sionov
- Department of Biochemistry and Molecular Biology, IMRIC, Hebrew University-Hadassah Medical School, Jerusalem, Israel
| | - Danielle Melloul
- Department of Endocrinology, Hadassah University Hospital, Jerusalem, Israel
- * E-mail:
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20
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Herzig DS, Guo Y, Fang G, Toliver-Kinsky TE, Sherwood ER. Therapeutic efficacy of CXCR3 blockade in an experimental model of severe sepsis. CRITICAL CARE : THE OFFICIAL JOURNAL OF THE CRITICAL CARE FORUM 2012; 16:R168. [PMID: 22992408 PMCID: PMC3682267 DOI: 10.1186/cc11642] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/24/2012] [Accepted: 09/14/2012] [Indexed: 01/21/2023]
Abstract
Introduction In our previous studies we demonstrated that CXC chemokine receptor 3 (CXCR3) participates in the regulation of lymphocyte trafficking during cecal ligation and puncture (CLP)-induced sepsis. In this study, we evaluated the effects of treatment with anti-CXCR3 immunoglobulin (IgG) and antibiotics on outcome during septic shock caused by CLP. Methods C57BL/6J mice were treated with neutralizing IgG against CXCR3 plus Primaxin either 24 hours prior to, 2 hours after or 6 hours after CLP. Control mice received nonspecific IgG plus Primaxin in the same regimen. Survival, core body temperature, bacterial clearance and systemic cytokine production were evaluated. Results Our results show that treatment with anti-CXCR3 IgG plus Primaxin significantly improved survival when administered 24 hours prior to CLP (50% vs. 10%), 2 hours after CLP (55% vs. 10%) or 6 hours after CLP (55% vs. 25%) compared with mice receiving nonspecific IgG plus Primaxin. Treatment with anti-CXCR3 plus Primaxin 24 hours prior to CLP attenuated hypothermia and IL-6 and macrophage inflammatory protein 2 (MIP-2) production but did not alter bacterial clearance. Treatment with anti-CXCR3 IgG and Primaxin 2 hours after CLP did not improve bacterial clearance and systemic cytokine production compared with mice treated with IgG and Primaxin, whereas 6 hours after CLP the bacterial clearance and IL-6 and MIP-2 concentrations, both in plasma and peritoneal lavage fluid, were significantly improved in mice receiving anti-CXCR3 IgG and Primaxin compared with mice that only received nonspecific IgG and Primaxin. Conclusion The results from this study indicate that neutralization of CXCR3 prior to, 2 hours after or 6 hours after the initiation of CLP-induced septic shock improves survival and attenuates CLP-induced inflammation and physiologic dysfunction.
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Wijtmans M, de Esch IJP, Leurs R. Therapeutic Targeting of the CXCR3 Receptor. METHODS AND PRINCIPLES IN MEDICINAL CHEMISTRY 2011. [DOI: 10.1002/9783527631995.ch13] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/08/2022]
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22
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Nakajima T, Palchevsky V, Perkins DL, Belperio JA, Finn PW. Lung transplantation: infection, inflammation, and the microbiome. Semin Immunopathol 2011; 33:135-56. [DOI: 10.1007/s00281-011-0249-9] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2010] [Accepted: 01/12/2011] [Indexed: 12/29/2022]
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Vaithilingam V, Oberholzer J, Guillemin GJ, Tuch BE. The humanized NOD/SCID mouse as a preclinical model to study the fate of encapsulated human islets. Rev Diabet Stud 2010; 7:62-73. [PMID: 20703439 DOI: 10.1900/rds.2010.7.62] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/24/2023] Open
Abstract
Despite encouraging results in animal models, the transplantation of microencapsulated islets into humans has not yet reached the therapeutic level. Recent clinical trials using microencapsulated human islets in barium alginate showed the presence of dense fibrotic overgrowth around the microcapsules with no viable islets. The major reason for this is limited understanding of what occurs when encapsulated human islets are allografted. This warrants the need for a suitable small animal model. In this study, we investigated the usefulness of NOD/SCID mice reconstituted with human PBMCs (called humanized NOD/SCID mice) as a preclinical model. In this model, human T cell engraftment could be achieved, and CD45+ cells were observed in the spleen and peripheral blood. Though the engrafted T cells caused a small fibrotic overgrowth around the microencapsulated human islets, this failed to stop the encapsulated islets from functioning in the diabetic recipient mice. The ability of encapsulated islets to survive in this mouse model might partly be attributed to the presence of Th2 cytokines IL-4 and IL-10, which are known to induce graft tolerance. In conclusion, this study showed that the hu-NOD/SCID mouse is not a suitable preclinical model to study the allograft rejection mechanisms of encapsulated human islets. As another result, the maintained viability of transplanted islets on the NOD/SCID background emphasized a critical role of protective mechanisms in autoimmune diabetes transplanted subjects due to specific immunoregulatory effects provided by IL-4 and IL-10.
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Affiliation(s)
- Vijayaganapathy Vaithilingam
- Diabetes Transplant Unit, Prince of Wales Hospital and University of New South Wales, and Australian Foundation for Diabetes Research, Sydney, Australia
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Li B, Xu W, Xu L, Jiang Z, Wen Z, Li K, Xiong S. I-TAC is a dominant chemokine in controlling skin intragraft inflammation via recruiting CXCR3+ cells into the graft. Cell Immunol 2010; 260:83-91. [PMID: 19875106 DOI: 10.1016/j.cellimm.2009.09.004] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2009] [Revised: 08/16/2009] [Accepted: 09/04/2009] [Indexed: 02/05/2023]
Abstract
Chemokines play a critical role in the acute transplant rejection. In order to provide an overview of the chemokine expression during the course of acute allograft rejection, the intragraft expression profile of 11 chemokines representative of all four chemokine subfamilies was analyzed in a murine skin transplantation model of acute rejection. It was found that RANTES/CCL5, TARC/CCL17 and FKN/CX(3)CL1 were expressed at equivalent levels in iso- and allografts. However, the other eight chemokines expression was up-regulated to some extent in allograft compared with that in isograft. The levels of MIP-1alpha/CCL3, MIP-3alpha/CCL20 and CTACK/CCL27 were progressively increased from early stage (day 3 post-transplantation) to late stage (day 11). Mig/CXCL9, IP-10/CXCL10, I-TAC/CXCL11, CXCL16 and LTN/XCL1 expression was elevated at middle stage (day 7), and peaked at late stage. Among the up-regulated chemokines, I-TAC was the most obviously elevated chemokine. Therefore, the effect of I-TAC on the skin acute allograft rejection was evaluated. Block of I-TAC by the intradermal injection of anti-I-TAC monoclonal antibody (mAb) reduced the number of CXCR3(+) cells in skin allograft and significantly prolonged the skin allograft survival. The mAb treatment did not influence the proliferation of the intragraft infiltrating cells in response to the allogeneic antigens, but significantly decreased the number of the infiltrating cells and consequently lowered the secretion of IFN-gamma and TNF-alpha. These data indicate I-TAC might be a dominant chemokine involved in the intradermal infiltration and I-TAC-targeted intervening strategies would have potential application for the alleviation of acute transplant rejection.
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Affiliation(s)
- Baohua Li
- Department of Immunology, Institute for Immunobiology, Shanghai Medical College of Fudan University, Shanghai 200032, PR China
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Roep BO, Kleijwegt FS, van Halteren AGS, Bonato V, Boggi U, Vendrame F, Marchetti P, Dotta F. Islet inflammation and CXCL10 in recent-onset type 1 diabetes. Clin Exp Immunol 2010; 159:338-43. [PMID: 20059481 DOI: 10.1111/j.1365-2249.2009.04087.x] [Citation(s) in RCA: 146] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023] Open
Abstract
Type 1 diabetes results from a T cell-mediated destruction of insulin-producing pancreatic beta cells. Little is known on local factors contributing to migration of T cells to pancreatic tissue. We recently demonstrated evidence of viral infection in beta cells in several recent-onset type 1 diabetes patients. Islet inflammation was analysed in a series of new- or recent-onset type 1 diabetic patients and non-diabetic control subjects. Autoimmune T cell reactivity was studied in lymphocytes derived from pancreas-draining lymph nodes of one recent-onset type 1 diabetes patient in partial clinical remission. Insulitic lesions were characterized by presence of beta cells, elevated levels of the chemokine CXCL10 and infiltration of lymphocytes expressing the corresponding chemokine receptor CXCR3 in all pancreatic lesions of type 1 diabetes patients, regardless of enterovirus infection of beta cells. CXCR3 and CXCL10 were undetectable in pancreata of non-diabetic control subjects. T cells isolated from draining lymph nodes of a recent-onset patient with virally infected beta cells and in clinical remission reacted with multiple islet autoantigens and displayed a mixed interferon (IFN)-gamma/interleukin (IL)-10 cytokine pattern. Our data point to CXCL10 as an important cytokine in distressed islets that may contribute to inflammation leading to insulitis and beta cell destruction, regardless of local viral infection. We demonstrate further pro- and anti-inflammatory islet autoreactivity, indicating that different adaptive and innate immune responses may contribute to insulitis and beta cell destruction.
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Affiliation(s)
- B O Roep
- Department of Immunohaematology and Blood Transfusion, Leiden University Medical Center, Leiden, the Netherlands
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Byrne FR, Winters A, Brankow D, Hu S, Juan T, Steavenson S, Doellgast G, Kuchimanchi K, Brown H, Anderson S, Smelt S, Sullivan T, Alcorn D, Tocker J, Dean C, Macmaster J, Kirchner J, Buys J, Manoukian R, Jiao E, Zou X, Campanella GS, Siu G. An antibody to IP-10 is a potent antagonist of cell migration in vitro and in vivo and does not affect disease in several animal models of inflammation. Autoimmunity 2009; 42:171-82. [PMID: 19301198 DOI: 10.1080/08916930802629547] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
IP-10 secretion is induced by pro-inflammatory cytokines and mediates the migration of CXCR3+ cells. Its elevation in clinical samples has been associated with multiple inflammatory diseases and its antagonism has been reported to be effective in several animal models of inflammatory disease. We generated a mouse anti-mouse IP-10 monoclonal antibody (mAb; Clone 20A9) that specifically bound murine IP-10 with high affinity and inhibited in vitro IP-10 induced BaF3/mCXCR3 cell migration with an IC(50) of approximately 4 nM. The 20A9 mAb was completely absorbed in vivo and had dose proportional pharmacokinetic exposure with a serum half life of 2.4-6 days. The 20A9 mAb inhibited IP-10 mediated T-cell recruitment to the airways, indicating that it is effective in vivo. However, administration of the 20A9 mAb had no significant effect on disease in mouse models of delayed type hypersensitivity, collagen induced arthritis, cardiac allograft transplantation tolerance, EAE or CD4+ CD45RBHi T-cell transfer-induced IBD. These data suggest that the 20A9 mAb can antagonize IP-10 mediated chemotaxis in vitro and in vivo and that this is insufficient to cause a therapeutic benefit in multiple mouse models of inflammatory disease.
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Feferman T, Aricha R, Mizrachi K, Geron E, Alon R, Souroujon MC, Fuchs S. Suppression of experimental autoimmune myasthenia gravis by inhibiting the signaling between IFN-γ inducible protein 10 (IP-10) and its receptor CXCR3. J Neuroimmunol 2009; 209:87-95. [DOI: 10.1016/j.jneuroim.2009.01.021] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2008] [Revised: 01/20/2009] [Accepted: 01/22/2009] [Indexed: 12/14/2022]
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CXCR3 antagonism impairs the development of donor-reactive, IFN-gamma-producing effectors and prolongs allograft survival. Transplantation 2009; 87:360-9. [PMID: 19202440 DOI: 10.1097/tp.0b013e31819574e9] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
BACKGROUND Current immunosuppression regimens are toxic to transplant recipients and, in many cases, acute rejection episodes occur because of escape of donor-reactive lymphocytes from the immunosuppression. T cells are the mediators of acute, cell-mediated graft damage and are hypothesized to use the CXCR3 chemokine axis for migration into the allograft. This study investigates the effect of CXCR3 blockade using a nonpeptide, small molecule inhibitor, AMG1237845, in murine cardiac allograft survival. METHODS C57BL/6 (H-2) mice received vascularized cardiac allografts from A/J (H-2) donors and were treated with the CXCR3 antagonist. Histologic and flow cytometric analyses were used to measure infiltration of leukocytes, and quantitative reverse-transcriptase polymerase chain reaction and interferon-gamma ELISPOT assays were used to measure donor-specific reactivity. RESULTS CXCR3 antagonism modestly prolonged allograft survival compared with vehicle treatment, but at time-matched intervals posttransplant, neutrophil, CD8, and CD4 T cell infiltration was indistinguishable. Although proliferation of donor-reactive naïve T cells was unaffected by CXCR3 antagonism, the frequency of interferon-gamma-producing cells in the recipient spleen was significantly reduced by AMG1237845 treatment. CXCR3 blockade for 30 days synergized with short-term, low-dose anti-CD154 monoclonal antibodies to prolong survival past 50 days in 75% of grafts and past 80 days in 25% of the cases. CONCLUSIONS These results indicate that in synergy with co-stimulation blockade, CXCR3 is a viable therapeutic target to prevent acute graft rejection.
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Lai Y, Chen C, Linn T. Innate immunity and heat shock response in islet transplantation. Clin Exp Immunol 2009; 157:1-8. [PMID: 19302242 DOI: 10.1111/j.1365-2249.2009.03899.x] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Islet transplantation is an extremely effective therapy for patients with type I diabetes, providing tight control of blood glucose and persistent insulin release. Islet grafts struggle with various stress responses and immunity attacks, which contribute to loss of islet grafts in the long term. In this review we focus upon the innate immunity and heat shock responses, which are closely relevant to the outcome of islet grafts. Potential strategies provided by more comprehensive interventions to control innate immunity and by selective induction of heat shock proteins may ameliorate the outcome of islet transplantation.
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Affiliation(s)
- Y Lai
- Department of Molecular Microbiology and Immunology, University of Missouri-Columbia, USA
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31
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Effects of Blocking the Chemokine Receptors, CCR5 and CXCR3, With TAK-779 in a Rat Small Intestinal Transplantation Model. Transplantation 2008; 86:1810-7. [DOI: 10.1097/tp.0b013e31818fe7fe] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
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Abstract
Transplant vasculopathy (TV) remains the leading cause of late death among heart transplant recipients. Transplant vasculopathy is characterized by progressive neointimal proliferation, leading to ischemic failure of the allograft. Multiple experimental and clinical studies have shown that injury to the graft at various stages of transplantation can be a risk factor for development of transplant vasculopathy. The hallmark of cardiac allograft injury is the infiltration of leukocytes. Recruitment of leukocytes requires intercellular communication between infiltrating cells, endothelium, parenchymal cells, and components of extracellular matrix. These events are mediated via the generation of adhesion molecules, cytokines, and chemokines. The chemokines, by virtue of their specific cell receptor expression, can selectively mediate the local recruitment/activation of distinct leukocytes/cells, allowing for migration across the endothelium and beyond the vascular compartment. This report provides a comprehensive review of the chemokines that participate in the development of transplant vasculopathy.
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Affiliation(s)
- John A Belperio
- Division of Pulmonary and Critical Care Medicine, David Geffen School of Medicine, University of California, Los Angele, CA 90095, USA
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33
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Prolongation of cardiac and islet allograft survival by a blocking hamster anti-mouse CXCR3 monoclonal antibody. Transplantation 2008; 86:137-47. [PMID: 18622291 DOI: 10.1097/tp.0b013e31817b8e4b] [Citation(s) in RCA: 64] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
BACKGROUND Acute allograft rejection requires a multifaceted immune response involving trafficking of immune cells into the transplant and expression of effector cell functions leading to graft destruction. The chemokine receptor CXCR3 and its ligands, CXCL9, CXCL10 and CXCL11, constitute an important pathway for effector cell recruitment posttransplant. However, analysis of CXCR3 expression and function has been hampered by a general lack of availability of a neutralizing anti-CXCR3 monoclonal antibody (mAb) for use in experimental models. METHODS We report the generation, characterization, and use of CXCR3-173, a new hamster mAb specific for mouse CXCR3 that recognizes CXCR3 on cells from wild-type but not CXCR3-/- mice. RESULTS Using CXCR3-173 mAb, we demonstrate CXCR3 expression on primary memory phenotype CD4+ and CD8+ T cells, naturally occurring CD4+CD25+ Foxp3+ regulatory T cells, natural killer T cells, and approximately 25% of NK cells. CXCR3-173 blocked chemotaxis in vitro in response to CXCL10 or CXCL11 but not CXCL9. When injected into mice, this mAb significantly prolonged both cardiac and islet allograft survival. When combined with a subtherapeutic regimen of rapamycin, CXCR3-173 mAb induced long-term (>100 day) survival of cardiac and islet allografts. The in vivo effects of CXCR3-173 mAb were not associated with effector lymphocyte depletion. CONCLUSION These data highlight the utility of CXCR3-173 mAb in developing immunotherapeutic approaches to inhibit transplant rejection and potentially other immune-mediated diseases in murine models.
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Kwun J, Hazinedaroglu SM, Schadde E, Kayaoglu HA, Fechner J, Hu HZ, Roenneburg D, Torrealba J, Shiao L, Hong X, Peng R, Szewczyk JW, Sullivan KA, DeMartino J, Knechtle SJ. Unaltered graft survival and intragraft lymphocytes infiltration in the cardiac allograft of Cxcr3-/- mouse recipients. Am J Transplant 2008; 8:1593-603. [PMID: 18476975 DOI: 10.1111/j.1600-6143.2008.02250.x] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
Previous studies showed that absence of chemokine receptor Cxcr3 or its blockade prolong mouse cardiac allograft survival. We evaluated the effect of the CXCR3 receptor antagonist MRL-957 on cardiac allograft survival, and also examined the impact of anti-CXCR3 mAb in human CXCR3 knock-in mice. We found only a moderate increase in graft survival (10.5 and 16.6 days, p < 0.05) using either the antagonist or the antibody, respectively, compared to control (8.7 days). We re-evaluated cardiac allograft survival with two different lines of Cxcr3(-/-) mice. Interestingly, in our hands, neither of the independently derived Cxcr3(-/-) lines showed remarkable prolongation, with mean graft survival of 9.5 and 10.8 days, respectively. There was no difference in the number of infiltrating mononuclear cells, expansion of splenic T cells or IFN-gamma production of alloreactive T cells. Mechanistically, an increased other chemokine receptor fraction in the graft infiltrating CD8 T cells in Cxcr3(-/-) recipients compared to wild-type recipients suggested compensatory T-cell trafficking in the absence of Cxcr3. We conclude Cxcr3 may contribute to, but does not govern, leukocyte trafficking in this transplant model.
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Affiliation(s)
- J Kwun
- Division of Transplantation, Department of Surgery, University of Wisconsin-Madison, Madison, WI, USA
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Wijtmans M, Verzijl D, Leurs R, de Esch IJ, Smit M. Towards Small-Molecule CXCR3 Ligands with Clinical Potential. ChemMedChem 2008; 3:861-72. [DOI: 10.1002/cmdc.200700365] [Citation(s) in RCA: 67] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
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36
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Abstract
The chemokine system coordinates leukocyte migration in immunity and inflammation and is implicated in the pathogenesis of many human diseases. Although several successful strategies have been identified to develop drugs targeting chemokines and their receptors, this has not yet resulted in many new therapeutics. This is likely due to a complexity of the chemokine system, which was not initially appreciated, that is characterized by redundancy, pleiotropy, and differences among species. Nevertheless, our understanding of chemokine biology is continuing to grow and several promising drugs are currently being tested in late-stage clinical trials. In this review, we examine the role of chemokines in health and diseases and discuss strategies to target the chemokine system.
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Affiliation(s)
- Antonella Viola
- Istituto Clinico Humanitas IRCCS, 20089 Rozzano, Milan, Italy.
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37
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Du X, Chen X, Mihalic JT, Deignan J, Duquette J, Li AR, Lemon B, Ma J, Miao S, Ebsworth K, Sullivan TJ, Tonn G, Collins TL, Medina JC. Design and optimization of imidazole derivatives as potent CXCR3 antagonists. Bioorg Med Chem Lett 2008; 18:608-13. [DOI: 10.1016/j.bmcl.2007.11.072] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2007] [Revised: 11/16/2007] [Accepted: 11/19/2007] [Indexed: 10/22/2022]
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Knight RL, Allen DR, Birch HL, Chapman GA, Galvin FC, Jopling LA, Lock CJ, Meissner JW, Owen DA, Raphy G, Watson RJ, Williams SC. Development of CXCR3 antagonists. Part 4: Discovery of 2-amino-(4-tropinyl)quinolines. Bioorg Med Chem Lett 2008; 18:629-33. [DOI: 10.1016/j.bmcl.2007.11.075] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2007] [Revised: 11/19/2007] [Accepted: 11/19/2007] [Indexed: 11/25/2022]
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Development of CXCR3 antagonists. Part 2: Identification of 2-amino(4-piperidinyl)azoles as potent CXCR3 antagonists. Bioorg Med Chem Lett 2007; 17:6806-10. [DOI: 10.1016/j.bmcl.2007.10.029] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2007] [Revised: 10/08/2007] [Accepted: 10/10/2007] [Indexed: 01/20/2023]
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40
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Haskova Z, Izawa A, Contreras AG, Flynn E, Boulday G, Briscoe DM. Organ-Specific Differences in the Function of MCP-1 and CXCR3 During Cardiac and Skin Allograft Rejection. Transplantation 2007; 83:1595-601. [PMID: 17589343 DOI: 10.1097/01.tp.0000266892.69117.9a] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
BACKGROUND Chemokines are well-established to function in the recruitment of leukocytes into allografts in the course of rejection. Moreover, some studies have indicated that there are organ-specific differences in chemokine function, but the mechanism accounting for this difference is not known. METHODS Fully major histocompatibility complex-mismatched vascularized cardiac transplants or skin transplants were performed using BALB/c (H-2d), C57BL/6 (H-2b), MCP-1-/- (H-2b) and CXCR3-/- (H-2b) mice as donors or recipients. Also, skin grafts (H-2b) were placed onto SCID mice (H-2d) that received BALB/c splenocytes (H-2d) by adoptive transfer either at the time of transplantation, or after a period of 28 days. RESULTS Cardiac allografts in MCP-1-/- recipients survived significantly longer (P<0.0005) than wild-type (WT) controls. However, there was no prolongation of survival when MCP-1-/- grafts were used a donors in WT mice. In contrast, the absence of donor but not recipient MCP-1 prolonged skin allograft survival. WT donor cardiac grafts in CXCR3-/- recipients had a modest prolongation of survival (P<0.0005), whereas CXCR3-/- donor cardiac grafts in WT recipients were rejected similar to controls. Also, while recipient CXCR3 had no effect on the rejection of skin, CXCR3-/- donor skin grafts survived significantly longer than WT controls. This survival advantage was lost when vascularized CXCR3-/- skin grafts were used as donors in the SCID model of rejection. CONCLUSION Recipient derived MCP-1 and CXCR3 are functional in the rejection of vascularized, but not nonvascularized, allografts. In contrast, donor-derived MCP-1 and CXCR3 are functional in nonvascularized, but not vascularized grafts.
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Affiliation(s)
- Zdenka Haskova
- Transplantation Research Center and the Division of Nephrology, Children's Hospital Boston, and the Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA
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Schnickel GT, Hsieh GR, Garcia C, Shefizadeh A, Fishbein MC, Ardehali A. Role of CXCR3 and CCR5 in allograft rejection. Transplant Proc 2007; 38:3221-4. [PMID: 17175228 DOI: 10.1016/j.transproceed.2006.10.164] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2006] [Indexed: 10/23/2022]
Abstract
UNLABELLED Chemokines are known to participate in allograft rejection by mediating leukocyte trafficking. Despite redundancy in chemokine family, several chemokine-chemokine receptor interactions have proven critical in alloimmune responses. We sought to determine the effect of combined blockade of CXCR3 and CCR5, two critical chemokine receptors, in acute rejection. METHODS Heterotopic heart transplantation was performed using BALB/c to B6/129 mice deficient in CCR5. Following transplantation these mice were treated with goat anti-CXCR3 serum every other day. In the control group, BALB/c hearts were transplanted in wild type B6/129 recipients and treated with goat serum alone. No immunosuppression was given to either group. Recipient mice were then assessed daily for allograft function by abdominal palpation, and graft survival was confirmed by laparotomy. RESULTS The donor hearts in the control group were rejected at 6 +/- 1 days posttransplantation. Combined blockade of CXCR3 and CCR5 prolonged allograft survival versus control; all allografts survived to 24 days. In addition, there was a decrease in graft infiltrating CD4 and CD8 lymphocytes in the experimental group at 24 days. CONCLUSION Combined CXCR3 and CCR5 blockade is effective in prolonging allograft survival in a fully MHC mismatched murine model. Combined chemokine blockade holds promise in control of acute rejection in organ transplantation.
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Affiliation(s)
- G T Schnickel
- Division of Cardiac Surgery, Department of Surgery, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, California 90095, USA
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42
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Overbergh L, Gysemans C, Mathieu C. Quantification of chemokines by real-time reverse transcriptase PCR: applications in type 1 diabetes. Expert Rev Mol Diagn 2007; 6:51-64. [PMID: 16359267 DOI: 10.1586/14737159.6.1.51] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Type 1 diabetes is a T-cell mediated autoimmune disease, characterized by the destruction of insulin-producing pancreatic beta-cells. This review will discuss the role of chemokines in the recruitment of immune cells leading to the pathology of this disease. There will be a focus on the quantification of chemokines and chemokine receptors by the recently developed real-time reverse transcriptase PCR technique. Today, this technique is in widespread use for analysis of chemokines in cells, tissues and tissue biopsies. The minute amount of tissue needed for analysis, as well as the very high sensitivity of this method, make it the method of choice for analysis of chemokines, which are often expressed at very low levels in target tissues. However, validation and optimization of the technique is of crucial importance for obtaining reliable results.
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Affiliation(s)
- Lut Overbergh
- Laboratory for Experimental Medicine & Endocrinology (LEGENDO), University Hospital Gasthuisberg, Catholic University of Leuven, Leuven, Belgium.
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43
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Johnson M, Li AR, Liu J, Fu Z, Zhu L, Miao S, Wang X, Xu Q, Huang A, Marcus A, Xu F, Ebsworth K, Sablan E, Danao J, Kumer J, Dairaghi D, Lawrence C, Sullivan T, Tonn G, Schall T, Collins T, Medina J. Discovery and optimization of a series of quinazolinone-derived antagonists of CXCR3. Bioorg Med Chem Lett 2007; 17:3339-43. [PMID: 17448658 DOI: 10.1016/j.bmcl.2007.03.106] [Citation(s) in RCA: 83] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2007] [Revised: 03/30/2007] [Accepted: 03/30/2007] [Indexed: 12/11/2022]
Abstract
A series of quinazolinone-derived inhibitors of the CXCR3 receptor have been synthesized and their affinity for the receptor evaluated. Compounds were evaluated in a (125)I-IP10 displacement assay and in in vitro cell migration assays to IP10, ITAC, and MIG using human peripheral blood mononuclear cells.
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Affiliation(s)
- Michael Johnson
- Amgen Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA
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Chakravarty SD, Xu J, Lu B, Gerard C, Flynn J, Chan J. The chemokine receptor CXCR3 attenuates the control of chronic Mycobacterium tuberculosis infection in BALB/c mice. THE JOURNAL OF IMMUNOLOGY 2007; 178:1723-35. [PMID: 17237422 DOI: 10.4049/jimmunol.178.3.1723] [Citation(s) in RCA: 48] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
The chemokine receptor CXCR3 plays a significant role in regulating the migration of Th1 cells. Given the importance of Th1 immunity in the control of tuberculous infection, the results of the present study demonstrating that CXCR3-deficient BALB/c mice are more resistant to Mycobacterium tuberculosis, compared with wild-type mice, is surprising. This enhanced resistance manifests in the chronic but not the acute phase of infection. Remarkable differences in the cellular composition of the pulmonic granuloma of the CXCR3(-/-) and wild-type mice were found, the most striking being the increase in the number of CD4(+) T cells in the knockout strain. In the chronic phase of infection, the number of CD69-expressing CD4(+) T lymphocytes in the lungs of CXCR3(-/-) mice was higher than in wild-type mice. Additionally, at 1 mo postinfection, the number of IFN-gamma-producing CD4(+) T cells in the lungs and mediastinal lymph nodes of the CXCR3-deficient strain was elevated compared with wild-type mice. Pulmonic expression of IFN-gamma, IL-12, TNF-alpha, or NO synthase 2, the principal antimycobacterial factors, were equivalent in the two mouse strains. These results indicate that: 1) CXCR3 plays a role in modulating the cellular composition of tuberculous granuloma; 2) CXCR3 impairs antimycobacterial activity in chronic tuberculosis; and 3) in the absence of CXCR3, mice exhibit a heightened state of CD4(+) T lymphocyte activation in the chronic phase of infection that is associated with enhanced CD4(+) T cell priming. Therefore, CXCR3 can attenuate the host immune response to M. tuberculosis by adversely affecting T cell priming.
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Affiliation(s)
- Soumya D Chakravarty
- Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA
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45
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Allen DR, Bolt A, Chapman GA, Knight RL, Meissner JWG, Owen DA, Watson RJ. Identification and structure-activity relationships of 1-aryl-3-piperidin-4-yl-urea derivatives as CXCR3 receptor antagonists. Bioorg Med Chem Lett 2006; 17:697-701. [PMID: 17097877 DOI: 10.1016/j.bmcl.2006.10.088] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2006] [Revised: 10/26/2006] [Accepted: 10/27/2006] [Indexed: 11/25/2022]
Abstract
The synthesis and biological evaluation of a series of 1-aryl-3-piperidin-4-yl-urea derivatives as small-molecule CXCR3 antagonists is described. SAR studies resulted in significant improvement of potency and physicochemical properties and established the key pharmacophore of the series, and led to the identification of 9t, which exhibits an IC50 of 16 nM in the GTPgammaS35 functional assay.
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Affiliation(s)
- Daniel R Allen
- UCB, Inflammation Discovery, Granta Park, Great Abington, Cambridge CB21 6GS, UK
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46
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Manes TD, Pober JS, Kluger MS. Endothelial Cell-T Lymphocyte Interactions: iP-10 Stimulates Rapid Transendothelial Migration of Human Effector but not Central Memory CD4+ T Cells. Requirements for Shear Stress and Adhesion Molecules. Transplantation 2006; 82:S9-14. [PMID: 16829798 DOI: 10.1097/01.tp.0000231356.57576.82] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
The chemokine interferon (IFN)-gamma-inducible protein of 10 kDa (IP-10; CXCL10) has been implicated in recruitment of T cells into rejecting allografts yet appears ineffective at stimulating human peripheral blood CD4 T cells to transmigrate across tumor necrosis factor (TNF)-treated human endothelial cell (EC) monolayers in vitro. The same cells rapidly (within 15 min) transmigrate across TNF-treated EC monolayers overlaid with stromal cell-derived factor-1 alpha (SDF-1 alpha) and subjected to shear stress. The effector memory subset within the CD4 T cell population, defined as CD45RO, CD62L and CCR7, which constitutes less than 10% of total CD4 T cells, does respond to IP-10 but requires enrichment to be observed in this model. Central memory T cells do not respond to IP-10. Transendothelial migration of effector memory CD4 T cells requires TNF-pretreatment of the EC monolayer and application of venular shear force during the assay. TNF treatment of ECs may be effectively replaced by transduction of vascular cell adhesion molecule-1 or intercellular adhesion molecule-1 but not E-selectin.
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Affiliation(s)
- Thomas D Manes
- Interdepartmental Program in Vascular Biology and Transplantation, Yale University School of Medicine, New Haven, CT, USA
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47
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Hasegawa H, Inoue A, Kohno M, Muraoka M, Miyazaki T, Terada M, Nakayama T, Yoshie O, Nose M, Yasukawa M. Antagonist of interferon-inducible protein 10/CXCL10 ameliorates the progression of autoimmune sialadenitis in MRL/lpr mice. ACTA ACUST UNITED AC 2006; 54:1174-83. [PMID: 16575871 DOI: 10.1002/art.21745] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
OBJECTIVE Mononuclear cell infiltration of the salivary glands is a major feature of Sjögren's syndrome (SS) and its animal model. Local generation of chemokines and the presence of chemokine receptors on the infiltrating cells may be involved in this process. We undertook the present study to investigate the expression of chemokines during the development of autoimmune sialadenitis in MRL/lpr mice and the therapeutic effect of chemokine antagonists on sialadenitis. METHODS NH2-terminal-truncated interferon-inducible protein 10 (IP-10)/CXCL10 analogs were transfected into a nonmetastatic fibroblastoid cell line, MRL/N-1, and injected subcutaneously into MRL/lpr mice, and the effects on sialadenitis were monitored. RESULTS IP-10 analogs truncated by 5 or more amino acid residues from the N-terminal failed to induce chemotaxis and calcium influx by CXCR3-expressing cells. Of these, the most potent antagonist (AT) (IP-10-AT) was a molecule with methionine added after removal of the 5 N-terminal amino acid residues. Significantly increased expression of the Th1-associated chemokines IP-10, monokine induced by interferon-gamma/CXCL9, and interferon-inducible T cell chemoattractant/CXCL11 was induced in the ductal epithelium by interferon-gamma produced in the salivary glands, whereas expression of the Th2-associated chemokines thymus and activation-regulated chemokine (TARC)/CCL17 and monocyte-derived chemokine/CCL22 was almost undetectable during sialadenitis. Inoculation of IP-10-AT into MRL/lpr mice during the early stage of sialadenitis significantly reduced periductal mononuclear cell infiltration and parenchymal destruction compared with these features in control and TARC-AT-bearing mice. This was due to a significant reduction in infiltration of CXCR3+ T cells, predominantly Th1 cells, resulting in decreased interferon-gamma production. CONCLUSION We prepared a novel potent IP-10 antagonist and demonstrated its ability to ameliorate the progression of autoimmune sialadenitis. This agent may provide a new therapeutic approach to SS.
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Affiliation(s)
- Hitoshi Hasegawa
- First Department of Internal Medicine, Ehime University School of Medicine, Ehime, Japan.
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48
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Dagan-Berger M, Feniger-Barish R, Avniel S, Wald H, Galun E, Grabovsky V, Alon R, Nagler A, Ben-Baruch A, Peled A. Role of CXCR3 carboxyl terminus and third intracellular loop in receptor-mediated migration, adhesion and internalization in response to CXCL11. Blood 2005; 107:3821-31. [PMID: 16368892 DOI: 10.1182/blood-2004-01-0214] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023] Open
Abstract
The chemokine receptor CXCR3 is predominantly expressed on activated T and natural killer (NK) cells. CXCR3 and its ligands, CXCL11, CXCL10, and CXCL9, play a major role in T-helper 1 (Th1)-dependent inflammatory responses. CXCL11 is the most dominant physiological inducer of adhesion, migration, and internalization of CXCR3. To study the role of CXCR3 carboxyl-terminus and the third intracellular (3i) loop in chemokine-mediated migration, adhesion, and CXCR3 internalization, we generated CXCR3 receptors mutated in their distal (Ser-Thr domain) or proximal (trileucine domain) membrane carboxyl terminus, and/or the third intracellular loop. We found that migration of CXCR3-expressing HEK 293 cells toward CXCL11 was pertussis toxin-dependent and required the membrane proximal carboxyl terminus of CXCR3. Internalization induced by CXCL11 and protein kinase C (PKC) activation was also regulated by the membrane proximal carboxyl terminus; however, only CXCL11-induced internalization required the LLL motif of this region. Internalization and Ca(2+) flux induced by CXCL11 were independent of the 3i loop S245, whereas migration at high CXCL11 concentrations, integrin-dependent adhesion, and actin polymerization were S245 dependent. Our findings indicate that CXCL11-dependent CXCR3 internalization and cell migration are regulated by the CXCR3 membrane proximal carboxyl terminus, whereas adhesion is regulated by the 3i loop S245. Thus, distinct conformational changes induced by a given CXCR3 ligand trigger different downstream effectors of adhesion, motility, and CXCR3 desensitization.
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Affiliation(s)
- Michal Dagan-Berger
- Gene Therapy Institute, Hadassah University Hospital, PO Box 12000, Jerusalem, Israel
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Wang L, Han R, Lee I, Hancock AS, Xiong G, Gunn MD, Hancock WW. Permanent Survival of Fully MHC-Mismatched Islet Allografts by Targeting a Single Chemokine Receptor Pathway. THE JOURNAL OF IMMUNOLOGY 2005; 175:6311-8. [PMID: 16272282 DOI: 10.4049/jimmunol.175.10.6311] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Chemokine receptor blockade can diminish the recruitment of host effector cells and prolong allograft survival, but little is known of the role of chemokine receptors in promoting host sensitization. We engrafted fully allogeneic islets into streptozotocin-treated normal mice or mice with the autosomal recessive paucity of lymph node T cell (plt) mutation; the latter lack secondary lymphoid expression of the CCR7 ligands, secondary lymphoid organ chemokine (CCL21) and EBV-induced molecule-1 ligand chemokine (CCL19). plt mice showed permanent survival of islets engrafted under the kidney capsule, whereas controls rejected islet allografts in 12 days (p < 0.001), and consistent with this, plt mice had normal allogeneic T cell responses, but deficient migration of donor dendritic cell to draining lymph nodes. Peritransplant i.v. injection of donor splenocytes caused plt recipients to reject their allografts by 12 days, and sensitization at 60 days posttransplant of plt mice with well-functioning allografts restored acute rejection. Finally, islet allografts transplanted intrahepatically in plt mice were rejected approximately 12 days posttransplant, like controls, as were primarily revascularized cardiac allografts. These data show that the chemokine-directed homing of donor dendritic cell to secondary lymphoid tissues is essential for host sensitization and allograft rejection. Interruption of such homing can prevent T cell priming and islet allograft rejection despite normal T and B cell functions of the recipient, with potential clinical implications.
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Affiliation(s)
- Liqing Wang
- Division of Transplantation Immunology, Department of Pathology and Laboratory Medicine, Joseph Stokes Jr. Research Institute and Biesecker Pediatric Liver Center, Philadelphia, PA 19104, USA
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50
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Hårdstedt M, Finnegan CP, Kirchhof N, Hyland KA, Wijkstrom M, Murtaugh MP, Hering BJ. Post-transplant upregulation of chemokine messenger RNA in non-human primate recipients of intraportal pig islet xenografts. Xenotransplantation 2005; 12:293-302. [PMID: 15943778 DOI: 10.1111/j.1399-3089.2005.00228.x] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
BACKGROUND We have previously shown that pig-to-primate intraportal islet xenografts reverse diabetes, escape hyperacute rejection, and undergo acute cellular rejection in non-immunosuppressed recipients. To gain a better understanding of mechanisms contributing to xenoislet rejection in non-human primates we examined gene expression in livers bearing islet xenografts in the first 72 h after transplantation. METHODS Liver specimens were collected at sacrifice from seven non-immunosuppressed rhesus macaques at 12, 24, 48 and 72 h after intraportal porcine islet transplantation. Following total RNA extraction, mRNA was quantified using SYBR green real-time reverse transcription polymerase chain reaction (RT-PCR) for species-specific immune response genes. Data were analyzed using comparative cycle threshold (Ct) analysis, adjusted for specific primer-efficiencies and normalized to cyclophilin expression. RESULTS Porcine insulin mRNA was detected in all liver samples. Cluster analysis revealed differential gene expression patterns at 12 and 24 h (early) compared with at 48 and 72 h (late) post-transplant. Gene expression patterns were associated with histological findings of predominantly neutrophils and only a few lymphocytes at 12 and 24 h and an increasing number of lymphocytes and macrophages at 48 and 72 h. Transcript levels of CXCR3 and its ligands, interferon-inducible protein 10 (IP-10) and monokine induced by IFN-gamma (Mig), significantly increased between early and late time points together with expression of MIP-1alpha, regulated on activation normal T expressed and secreted protein (RANTES) and MCP-1. CCR5 showed only a marginal, non-significant increase. Fas ligand, perforin and granzyme B transcripts were all elevated at 48 and 72 h post-transplant. CONCLUSIONS Our data suggest that CXCR3, with ligands IP-10 and Mig, is involved in T cell recruitment in acute islet xenograft rejection in non-human primates. Upregulation of RANTES and MIP-1alpha transcripts in the absence of a significant CCR5 increase suggests a possible involvement of other chemokine receptors. MCP-1 expression is associated with T cell and macrophage infiltration. Elevated cytotoxic effector molecule expression (Fas ligand, perforin, granzyme B) indicates T-cell mediated graft destruction by cytotoxic and cytolytic mechanisms within 48 to 72 h after transplantation. These results identify the CXCR3-mediated chemoattractant pathway as an immunosuppressive target in pig-to-primate islet xenotransplantation.
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Affiliation(s)
- Maria Hårdstedt
- Diabetes Institute for Immunology and Transplantation, Department of Surgery, University of Minnesota, Minneapolis MN, USA.
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