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Rapamycin Interferes With Postdepletion Regulatory T Cell Homeostasis and Enhances DSA Formation Corrected by CTLA4-Ig.

dc.contributor.author Farris, A
dc.contributor.author Kirk, Allan D
dc.contributor.author Knechtle, Stuart J
dc.contributor.author Kwun, J
dc.contributor.author Oh, B
dc.contributor.author Yoon, J
dc.coverage.spatial United States
dc.date.accessioned 2016-04-01T13:08:38Z
dc.date.issued 2016-09
dc.identifier http://www.ncbi.nlm.nih.gov/pubmed/26990829
dc.identifier.uri http://hdl.handle.net/10161/11778
dc.description.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.
dc.language eng
dc.relation.ispartof Am J Transplant
dc.relation.isversionof 10.1111/ajt.13789
dc.subject T cell biology
dc.subject alloantibody
dc.subject basic (laboratory) research/science
dc.subject heart transplantation/cardiology
dc.subject immunobiology
dc.subject immunosuppression/immune modulation
dc.subject immunosuppressive regimens
dc.subject induction
dc.subject rejection: antibody-mediated (ABMR)
dc.title Rapamycin Interferes With Postdepletion Regulatory T Cell Homeostasis and Enhances DSA Formation Corrected by CTLA4-Ig.
dc.type Journal article
pubs.author-url http://www.ncbi.nlm.nih.gov/pubmed/26990829
pubs.begin-page 2612
pubs.end-page 2623
pubs.issue 9
pubs.organisational-group Clinical Science Departments
pubs.organisational-group Duke
pubs.organisational-group School of Medicine
pubs.organisational-group Surgery
pubs.organisational-group Surgery, Abdominal Transplant Surgery
pubs.publication-status Published
pubs.volume 16
dc.identifier.eissn 1600-6143


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