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PMID: 17511761 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Contrasting effects of cyclosporine and rapamycin in de novo generation of alloantigen-specific regulatory T cells.

American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons ·Vol. 7 ·No. 7 ·2007-07-00 ·Pages 1722-32

Gao W, Lu Y, El Essawy B, Oukka M, Kuchroo VK, Strom TB

Abstract

The outcome of T-cell-mediated responses, immunity or tolerance, critically depends on the balance of cytopathic versus regulatory T (T(reg)) cells. In the creation of stable tolerance to MHC incompatible allografts, reducing the unusually large mass of donor-reactive cytopathic T effector (T(eff)) cells via apoptosis is often required. Cyclosporine (CsA) blocks activation-induced cell death (AICD) of T(eff) cells, and is detrimental to tolerance induction by costimulation blockade, whereas Rapamycin (RPM) preserves AICD, and augments the potential of costimulation blockade to create tolerance. While differences between CsA and RPM in influencing apoptosis of activated graft-destructive T(eff) cells are apparent, their effects on graft-protective T(reg) cells remain enigmatic. Moreover, it is unclear whether tolerizing regimens foster conversion of naïve peripheral T cells into alloantigen-specific T(reg) cells for graft protection. Here we show, using reporter mice for T(reg) marker Foxp3, that RPM promotes de novo conversion of alloantigen-specific T(reg) cells, whereas CsA completely inhibits this process. Upon transfer, in vivo converted T(reg) cells potently suppress the rejection of donor but not third party skin grafts. Thus, the differential effects of RPM and CsA on T(eff) and T(reg) cells favor the use of RPM in shifting the balance of aggressive to protective type alloimmunity.

MeSH Terms
Animals Cyclosporine Forkhead Transcription Factors/immunology Genetic Markers Immunosuppressive Agents/pharmacology Isoantigens/immunology Mice Mice, Inbred C57BL Mice, Transgenic Sirolimus T-Lymphocytes, Regulatory/drug effects,immunology
Chemicals
Forkhead Transcription Factors Foxp3 protein, mouse Genetic Markers Immunosuppressive Agents Isoantigens Cyclosporine Sirolimus
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Gao W
Department of Medicine, Division of Transplant Immunology and Transplant Research Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA. wgao@bidmc.harvard.edu
Lu Y
El Essawy B
Oukka M
Kuchroo V K
Strom T B
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Article Info
Journal
American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons
Abbr.
Am J Transplant
ISSN
1600-6135
DOI
10.1111/j.1600-6143.2007.01842.x
Email
wgao@bidmc.harvard.edu
Published
2007-07-00
Epub
2007-00-19
Pages
1722-32
Language
English
Region
United States
NLM ID
100968638
PMCID
PMC3831357
Subset
IM
Grants
NINDS NIH HHS · R01 NS030843 · United States
NIAID NIH HHS · AI41521-08 · United States
NINDS NIH HHS · NS 30843 · United States
NIAID NIH HHS · P01 AI041521 · United States
NINDS NIH HHS · R37 NS030843 · United States
NINDS NIH HHS · R29 NS030843 · United States
External Links
PubMed source DOI: 10.1111/j.1600-6143.2007.01842.x PMC Full Text View journal details
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