期刊
AMERICAN JOURNAL OF TRANSPLANTATION
卷 16, 期 9, 页码 2612-2623出版社
WILEY-BLACKWELL
DOI: 10.1111/ajt.13789
关键词
basic (laboratory) research; science; immunosuppression; immune modulation; immunobiology; heart transplantation; cardiology; alloantibody; immunosuppressive regimens; induction; rejection: antibody-mediated (ABMR); T cell biology
资金
- Children's Hospital of Atlanta (CHOA) Cardiovascular Biology Pilot grant
- American Heart Association (AHA)/Enduring Hearts Foundation Research Award [15SDG25710165]
- CHOA Pediatric Liver Transplant Research Program
Previously, we demonstrated that alemtuzumab induction with rapamycin as sole maintenance therapy is associated with an increased incidence of humoral rejection in human kidney transplant patients. To investigate the role of rapamycin in posttransplant humoral responses after T cell depletion, fully MHC mismatched hearts were transplanted into hCD52Tg mice, followed by alemtuzumab treatment with or without a short course of rapamycin. While untreated hCD52Tg recipients acutely rejected B6 hearts (n = 12), hCD52Tg recipients treated with alemtuzumab alone or in conjunction with rapamycin showed a lack of acute rejection (MST > 100). However, additional rapamycin showed a reduced beating quality over time and increased incidence of vasculopathy. Furthermore, rapamycin supplementation showed an increased serum donor-specific antibodies (DSA) level compared to alemtuzumab alone at postoperation days 50 and 100. Surprisingly, additional rapamycin treatment significantly reduced CD4(+)CD25(+)FoxP3(+) T reg cell numbers during treatment. On the contrary, ICOS+PD-1(+)CD4 follicular helper T cells in the lymph nodes were significantly increased. Interestingly, CTLA4-Ig supplementation in conjunction with rapamycin corrected rapamycin-induced accelerated posttransplant humoral response by directly modulating Tfh cells but not Treg cells. This suggests that rapamycin after T cell depletion could affect Treg cells leading to an increase of Tfh cells and DSA production that can be reversed by CTLA4-Ig. This study demonstrates that rapamycin treatment enhances de novo donor-specific antibody production in a T cell depletion-mediated chronic antibody-mediated rejection model, while the addition of CTLA4-Ig suppresses antibody production by regulating follicular helper T cells.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据