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.
Type
Journal articleSubject
T cell biologyalloantibody
basic (laboratory) research/science
heart transplantation/cardiology
immunobiology
immunosuppression/immune modulation
immunosuppressive regimens
induction
rejection: antibody-mediated (ABMR)
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https://hdl.handle.net/10161/11778Published Version (Please cite this version)
10.1111/ajt.13789Publication Info
Oh, B; Yoon, J; Farris, A; Kirk, A; Knechtle, S; & Kwun, J (2016). Rapamycin Interferes With Postdepletion Regulatory T Cell Homeostasis and Enhances
DSA Formation Corrected by CTLA4-Ig. Am J Transplant, 16(9). pp. 2612-2623. 10.1111/ajt.13789. Retrieved from https://hdl.handle.net/10161/11778.This is constructed from limited available data and may be imprecise. To cite this
article, please review & use the official citation provided by the journal.
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Show full item recordScholars@Duke
Allan Douglas Kirk
David C. Sabiston, Jr. Distinguished Professor of Surgery
I am a surgeon with interest in immune management of transplant recipients. I am particularly
interested in therapies that influence T cell costimulation pathways and adjuvant
therapies that facilitate costimulation blockade to prevent the rejection of transplanted
organs without undue suppression of protective immunity. I am also interested in understanding
how injury, such as that occurring during trauma or in elective surgery, influences
immune responses and subsequent healing following injur
Stuart Johnston Knechtle
William R. Kenan, Jr. Distinguished Professor
During my career as an academic surgeon, I have had the privilege of leading and/or
participating in a diverse portfolio of hypothesis-driven research projects. These
projects have centered on the immunology of surgery and transplantation, including
both cellular and antibody-mediated immune responses. During my training I studied
the response of hyper-sensitized recipients to allogeneic liver transplantation, and
am currently studying means of reducing immunologic memory that might
Jean Kwun
Assistant Professor in Surgery
Research interests include humoral tolerance to organ transplants in animal model
and humans, developing a clinically relevant animal model to study the mechanisms
of antibody-mediated rejection (AMR), and establishing a conceptual basis that will
translate into therapeutic intervention of AMR.
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