title: Rapamycin Interferes With Postdepletion Regulatory T Cell Homeostasis and Enhances DSA Formation Corrected by CTLA4-Ig.
abstract: 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.
authors.affiliation: Emory Transplant Center, Department of Surgery, Emory University School of Medicine, Atlanta, GA.
authors.forename: B
authors.initials: B
authors.lastname: Oh
authors.affiliation: Duke Transplant Center, Department of Surgery, Duke University School of Medicine, Durham, NC.
authors.forename: J
authors.initials: J
authors.lastname: Yoon
authors.affiliation: Department of Pathology, Emory University School of Medicine, Atlanta, GA.
authors.forename: A
authors.initials: A
authors.lastname: Farris
authors.affiliation: Emory Transplant Center, Department of Surgery, Emory University School of Medicine, Atlanta, GA.|Duke Transplant Center, Department of Surgery, Duke University School of Medicine, Durham, NC.
authors.forename: A
authors.initials: A
authors.lastname: Kirk
authors.affiliation: Emory Transplant Center, Department of Surgery, Emory University School of Medicine, Atlanta, GA.|Duke Transplant Center, Department of Surgery, Duke University School of Medicine, Durham, NC.
authors.forename: S
authors.initials: S
authors.lastname: Knechtle
authors.affiliation: Emory Transplant Center, Department of Surgery, Emory University School of Medicine, Atlanta, GA.|Duke Transplant Center, Department of Surgery, Duke University School of Medicine, Durham, NC.
authors.forename: J
authors.initials: J
authors.lastname: Kwun
mesh_terms: D000069594:Abatacept / Q000494:pharmacology*; D000818:Animals; D000917:Antibody Formation / Q000276:immunology*; D006084:Graft Rejection / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism; D006085:Graft Survival / Q000276:immunology; D016027:Heart Transplantation; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008212:Lymphocyte Depletion; D051379:Mice; D008810:Mice, Inbred C57BL; D020123:Sirolimus / Q000494:pharmacology*; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D014019:Tissue Donors
chemical_list: D007166:Immunosuppressive Agents; D000069594:Abatacept; D020123:Sirolimus
keywords: T cell biology; alloantibody; basic (laboratory) research/science; heart transplantation/cardiology; immunobiology; immunosuppression/immune modulation; immunosuppressive regimens; induction; rejection: antibody-mediated (ABMR)