Kinetics of in vitro immune responses of T and B cells during tolerance induction by sirolimus.
OBJECTIVE
The purpose of the study presented herein was to examine immune performances of rat heart allograft recipients immunosuppressed with sirolimus (SRL, rapamycin; Rapamune, Wyeth-Ayerst, Princeton, NJ).


METHODS
The immune performances of lymphocytes harvested from SRL-treated Wistar Furth (WF; RT1u) recipients of Buffalo (BUF; RT1b) heart allografts were examined on days 7, 14, and 90 postgrafting.


RESULTS
Whether derived from normal WF rats, SRL-treated WF heart recipients, or SRL-untreated WF heart recipients, pan-T cell population purified from the lymph nodes or spleens on day 7 or 14 displayed similar responses to phytohemaglutinin, anti-T cell receptor R73 monoclonal antibody, donor-type BUF, or third-party Brown Norway alloantigenic stimulators. There was no in vitro evidence of suppressor T cells in SRL-treated recipients. The frequencies of anti-BUF-specific cytotoxic T cells, as shown by limiting dilution analysis, were similar in the short- (days 7 or 14) and in the long- (day 90) term surviving recipients. SRL treatment did not affect the expression of interleukin-2 (IL-2) messenger RNA (mRNA) by T helper 1 (Th1) or of IL-4 and IL-10 mRNA by Th2 cells on days 7 and 14 postgrafting, but did induce selective activation of Th2 cells on day 60 postgrafting. Administration of SRL induced the production of non-complement (C')-fixing IgG2c BUF-specific alloantibodies that appeared in the sera of unresponsive recipients on day 14 postgrafting and reached a peak concentration on day 120 postgrafting. In contrast to untreated recipients that rejected BUF heart allografts, all SRL-treated WF recipients failed to produce C'-fixing BUF-specific alloantibodies.


CONCLUSIONS
SRL promotes long-term selective activation of Th2 cells and the production of non-C'-fixing IgG2c blocking antibodies.
Ghobrial
R
R
Department of Surgery, University of Texas Medical School-Houston, USA.
Karczewski
M
M
Ferraresso
M
M
Tian
L
L
Stepkowski
S M
SM
Kahan
B D
BD
D000818:Animals; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D016207:Cytokines / Q000235:genetics; D016027:Heart Transplantation / Q000276:immunology*; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007700:Kinetics; D008213:Lymphocyte Activation; D016133:Polymerase Chain Reaction; D051381:Rats; D011912:Rats, Inbred ACI; D011914:Rats, Inbred BN; D011915:Rats, Inbred BUF; D011920:Rats, Inbred WF; D011948:Receptors, Antigen, T-Cell / Q000187:drug effects / Q000502:physiology; D020123:Sirolimus / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D014158:Transcription, Genetic / Q000187:drug effects
D016207:Cytokines; D007166:Immunosuppressive Agents; D011948:Receptors, Antigen, T-Cell; D020123:Sirolimus