TY - JOUR
T1 - Rapamycin Interferes With Postdepletion Regulatory T Cell Homeostasis and Enhances DSA Formation Corrected by CTLA4-Ig
AU - Oh, B.
AU - Yoon, J.
AU - Farris, A.
AU - Kirk, A.
AU - Knechtle, S.
AU - Kwun, J.
N1 - Publisher Copyright:
© Copyright 2016 The American Society of Transplantation and the American Society of Transplant Surgeons
PY - 2016/9/1
Y1 - 2016/9/1
N2 - 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.
AB - 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.
KW - T cell biology
KW - alloantibody
KW - basic (laboratory) research/science
KW - heart transplantation/cardiology
KW - immunobiology
KW - immunosuppression/immune modulation
KW - immunosuppressive regimens
KW - induction
KW - rejection: antibody-mediated (ABMR)
UR - http://www.scopus.com/inward/record.url?scp=84984607313&partnerID=8YFLogxK
U2 - 10.1111/ajt.13789
DO - 10.1111/ajt.13789
M3 - Article
C2 - 26990829
AN - SCOPUS:84984607313
SN - 1600-6135
VL - 16
SP - 2612
EP - 2623
JO - American Journal of Transplantation
JF - American Journal of Transplantation
IS - 9
ER -