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Increase in Anti-Gal IgM Level is Associated With Early Graft Failure in Intraportal Porcine Islet Xenotransplantation

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Background: Anti-Gal is a major antibody induced in non-human primates (NHPs) after xenotransplantation. To understand the mechanism of graft rejection, we investigated the association between anti-Gal responses and graft failure in NHP recipients of porcine islet transplantation (PITx). Methods: Intraportal PITx was performed in 35 diabetic NHPs, and graft function was monitored. Early graft failure (EGF) was defined as loss of graft function within a month after PITx. Seven, 19, nine NHPs received immunosuppression (IS) without CD40 pathway blockade (Group I), with anti-CD154 (Group II), and with anti-CD40 (Group III), respectively. The anti-Gal levels on day 0 and day 7 of PITx were measured by ELISA. Results: The frequency of EGF was significantly lower in Group II (26.3%) than in Group I (100%, P=0.0012) and Group III (77.8%, P=0.0166). While levels of anti-Gal IgG in Group I and anti-Gal IgM in Group III increased on day 7 compared with day 0 (P=0.0156 and 0.0273), there was no increase in either on day 7 in Group II. The ratio of anti-Gal IgM or IgG level on day 7 to that on day 0 (Ratio7/0) was significantly higher in recipients with EGF than without EGF (P=0.0009 and 0.0027). ROC curve analysis of anti-Gal IgM Ratio7/0 revealed an area under the curve of 0.789 (P=0.0003). Conclusions: IS with anti-CD154 suppressed anti-Gal responses and prevented EGF in PITx. Anti-Gal IgM Ratio7/0, being associated with EGF, is a predictive marker for EGF.

Abstract

Background: Anti-Gal is a major antibody induced in non-human primates (NHPs) after xenotransplantation. To understand the mechanism of graft rejection, we investigated the association between anti-Gal responses and graft failure in NHP recipients of porcine islet transplantation (PITx). Methods: Intraportal PITx was performed in 35 diabetic NHPs, and graft function was monitored. Early graft failure (EGF) was defined as loss of graft function within a month after PITx. Seven, 19, nine NHPs received immunosuppression (IS) without CD40 pathway blockade (Group I), with anti-CD154 (Group II), and with anti-CD40 (Group III), respectively. The anti-Gal levels on day 0 and day 7 of PITx were measured by ELISA. Results: The frequency of EGF was significantly lower in Group II (26.3%) than in Group I (100%, P=0.0012) and Group III (77.8%, P=0.0166). While levels of anti-Gal IgG in Group I and anti-Gal IgM in Group III increased on day 7 compared with day 0 (P=0.0156 and 0.0273), there was no increase in either on day 7 in Group II. The ratio of anti-Gal IgM or IgG level on day 7 to that on day 0 (Ratio7/0) was significantly higher in recipients with EGF than without EGF (P=0.0009 and 0.0027). ROC curve analysis of anti-Gal IgM Ratio7/0 revealed an area under the curve of 0.789 (P=0.0003). Conclusions: IS with anti-CD154 suppressed anti-Gal responses and prevented EGF in PITx. Anti-Gal IgM Ratio7/0, being associated with EGF, is a predictive marker for EGF.

참고문헌 (37)

  1. Shapiro AM, "Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen", N Engl J Med, 343, pp.230~238 (2000)
  2. Shapiro AM, "International trial of the Edmonton protocol for islet transplantation", N Engl J Med, 355, pp.1318~1330 (2006)
  3. Matsumoto S, "Islet cell transplantation for Type 1 diabetes", J Diabetes, 2, pp.16~22 (2010)
  4. van der Windt DJ, "Clinical islet xenotransplantation: how close are we?", Diabetes, 61, pp.3046~3055 (2012)
  5. Hering BJ, "Prolonged diabetes reversal after intraportal xenotransplantation of wild-type porcine islets in immunosuppressed nonhuman primates", Nat Med, 12, pp.301~303 (2006)
  6. Cardona K, "Long-term survival of neonatal porcine islets in nonhuman primates by targeting costimulation pathways", Nat Med, 12, pp.304~306 (2006)
  7. van der Windt DJ, "Long-term controlled normoglycemia in diabetic non-human primates after transplantation with hCD46 transgenic porcine islets", Am J Transplant, 9, pp.2716~2726 (2009)
  8. Kang HJ, "The role of the alternative complement pathway in early graft loss after intraportal porcine islet xenotransplantation", Transplantation, 97, pp.999~1008 (2014)
  9. Thompson P, "CD40-specific costimulation blockade enhances neonatal porcine islet survival in nonhuman primates", Am J Transplant, 11, pp.947~957 (2011)
  10. Kang HJ, "Dissociation between anti-porcine albumin and anti-Gal antibody responses in non-human primate recipients of intraportal porcine islet transplantation", Xenotransplantation, 22, pp.124~134 (2015)
  11. Galili U, "Anti-Gal: an abundant human natural antibody of multiple pathogeneses and clinical benefits", Immunology, 140, pp.1~11 (2013)
  12. Cramer DV, "Natural antibodies and the host immune responses to xenografts", Xenotransplantation, 7, pp.83~92 (2000)
  13. Kuwaki K, "Heart transplantation in baboons using alpha1,3-galactosyltransferase gene-knockout pigs as donors: initial experience", Nat Med, 11, pp.29~31 (2005)
  14. Chen G, "Acute rejection is associated with antibodies to non-Gal antigens in baboons using Gal-knockout pig kidneys", Nat Med, 11, pp.1295~1298 (2005)
  15. Thompson P, "Islet xenotransplantation using gal-deficient neonatal donors improves engraftment and function", Am J Transplant, 11, pp.2593~2602 (2011)
  16. van Kooten C, "CD40-CD40 ligand", J Leukoc Biol, 67, pp.2~17 (2000)
  17. Galili U., "Induced anti-non gal antibodies in human xenograft recipients", Transplantation, 93, pp.11~16 (2012)
  18. Mohiuddin MM, "Role of anti-CD40 antibody-mediated costimulation blockade on non-Gal antibody production and heterotopic cardiac xenograft survival in a GTKO.hCD46Tg pig-to-baboon model", Xenotransplantation, 21, pp.35~45 (2014)
  19. Mohiuddin MM, "Genetically engineered pigs and target-specific immunomodulation provide significant graft survival and hope for clinical cardiac xenotransplantation", J Thorac Cardiovasc Surg, 148, pp.1106~1113 (2014)
  20. Vos Q, "B-cell activation by T-cell-independent type 2 antigens as an integral part of the humoral immune response to pathogenic microorganisms", Immunol Rev, 176, pp.154~170 (2000)
  21. Alugupalli KR, "MyD88- and Bruton’s tyrosine kinase-mediated signals are essential for T cell-independent pathogen-specific IgM responses", J Immunol, 178, pp.3740~3749 (2007)
  22. Li S, "Rapidly induced, T-cell independent xenoantibody production is mediated by marginal zone B cells and requires help from NK cells", Blood, 110, pp.3926~3935 (2007)
  23. Kim HI, "Parameters for successful pig islet isolation as determined using 68 specific-pathogen-free miniature pigs", Xenotransplantation, 16, pp.11~18 (2009)
  24. Jin SM, "Islet isolation from adult designated pathogen-free pigs: use of the newer bovine nervous tissue-free enzymes and a revised donor selection strategy would improve the islet graft function", Xenotransplantation, 18, pp.369~379 (2011)
  25. Armitage RJ, "Molecular and biological characterization of a murine ligand for CD40", Nature, 357, pp.80~82 (1992)
  26. van Essen D, "CD40 ligand-transduced co-stimulation of T cells in the development of helper function", Nature, 378, pp.620~623 (1995)
  27. Noelle RJ, "A 39-kDa protein on activated helper T cells binds CD40 and transduces the signal for cognate activation of B cells", Proc Natl Acad Sci U S A, 89, pp.6550~6554 (1992)
  28. Mackey MF, "The role of CD40", CD154 interactions in the priming, differentiation, and effector function of helper and cytotoxic T cells, 1998, pp.63, 418~428
  29. Kirk AD, "Treatment with humanized monoclonal antibody against CD154 prevents acute renal allograft rejection in nonhuman primates", Nat Med, 5, pp.686~693 (1999)
  30. Boumpas DT, "A short course of BG9588 (anti-CD40 ligand antibody) improves serologic activity and decreases hematuria in patients with proliferative lupus glomerulonephritis", Arthritis Rheum, 48, pp.719~727 (2003)
  31. Kirchhof N, "Reversal of diabetes in non-immunosuppressed rhesus macaques by intraportal porcine islet xenografts precedes acute cellular rejection", Xenotransplantation, 11, pp.396~407 (2004)
  32. Snapper CM, "An in vitro model for T cell-independent induction of humoral immunity. A requirement for NK cells", J Immunol, 152, pp.4884~4892 (1994)
  33. Puga I, "B cell-helper neutrophils stimulate the diversification and production of immunoglobulin in the marginal zone of the spleen", Nat Immunol, 13, pp.170~180 (2011)
  34. Vinuesa CG, "Innate B cell helpers reveal novel types of antibody responses", Nat Immunol, 14, pp.119~126 (2013)
  35. Giovannoni L, "Enhancement of islet engraftment and achievement of long-term islet allograft survival by Toll-like receptor 4 blockade", Transplantation, 99, pp.29~35 (2015)
  36. Grewal IS, "CD40 and CD154 in cell-mediated immunity", Annu Rev Immunol, 16, pp.111~135 (1998)
  37. Sun M, "A new class of reverse signaling costimulators belongs to the TNF family", J Immunol, 179, pp.4307~4312 (2007)

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