期刊
AMERICAN JOURNAL OF TRANSPLANTATION
卷 20, 期 10, 页码 2728-2739出版社
WILEY
DOI: 10.1111/ajt.15878
关键词
alloantibodies; basic (laboratory) research; science; immunobiology; immunosuppression; immune modulation; islet transplantation; lymphocyte biology; trafficking; sensitization; tolerance
资金
- National Institute of Allergy and Infectious Diseases
- National Institutes of Health [P01 AI112522, R01 EB009910]
- Chinese Scholarship Council
- Northwestern University Transplant Surgery Scientist Training Program [T32]
Allosensitization constitutes a major barrier in transplantation. Preexisting donor-reactive memory T and B cells and preformed donor-specific antibodies (DSAs) have all been implicated in accelerated allograft rejection in sensitized recipients. Here, we employ a sensitized murine model of islet transplantation to test strategies that promote long-term immunosuppression-free allograft survival. We demonstrate that donor-specific memory T and B cells can be effectively inhibited by peritransplant infusions of donor apoptotic cells in combination with anti-CD40L and rapamycin, and this treatment leads to significant prolongation of islet allograft survival in allosensitized recipients. We further demonstrate that late graft rejection in recipients treated with this regimen is associated with a breakthrough of B cells and their aggressive graft infiltration. Consequently, additional posttransplant B cell depletion effectively prevents late rejection and promotes permanent acceptance of islet allografts. In contrast, persistent low levels of DSAs do not seem to impair graft outcome in these recipients. We propose that B cells contribute to late rejection as antigen-presenting cells for intragraft memory T cell expansion but not to alloantibody production and that a therapeutic strategy combining donor apoptotic cells, anti-CD40L, and rapamycin effectively inhibits proinflammatory B cells and promotes long-term islet allograft survival in such recipients.
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