Sensitized kidney transplant recipients experience high rates of antibody-mediated rejection due to the presence of donor-specific antibodies and immunologic memory. Here we show that transient peri-transplant treatment with the central complement component C3 inhibitor Cp40 significantly prolongs median allograft survival in a sensitized nonhuman primate model. Despite donor-specific antibody levels remaining high, fifty percent of Cp40-treated primates maintain normal kidney function beyond the last day of treatment. Interestingly, presence of antibodies of the IgM class associates with reduced median graft survival (8 vs. 40 days; p = 0.02). Cp40 does not alter lymphocyte depletion by rhesus-specific anti-thymocyte globulin, but inhibits lymphocyte activation and proliferation, resulting in reduced antibody-mediated injury and complement deposition. In summary, Cp40 prevents acute antibody-mediated rejection and prolongs graft survival in primates, and inhibits T and B cell activation and proliferation, suggesting an immunomodulatory effect beyond its direct impact on antibody-mediated injury. Donor-specific antibodies in sensitized recipients may cause kidney transplant rejection. Here the authors show that complement component C3 inhibition prolongs graft survival by inhibiting T and B cell proliferation/activation and hence tissue injury, despite antibody levels remaining unaffected.
【저자키워드】 Immunosuppression, Preclinical research, Complement cascade, Allotransplantation, 【초록키워드】 Treatment, IgM, antibody, Kidney function, complement, memory, B cell, lymphocyte, survival, inhibitor, kidney transplant, kidney transplant recipient, Injury, Allograft, proliferation, tissue injury, Activation, recipient, rejection, immunomodulatory effect, Alter, Prevent, resulting, significantly, inhibit, reduced, median, maintain, inhibiting, presence of antibody, 【제목키워드】 complement, survival, non-human primate, Allograft, renal, rejection, Prevent,