Apoptosis of allospecifically activated human helper T cells is blocked by calcineurin inhibition.
BACKGROUND
Classical transplantation immunosuppression relies heavily upon the interruption of interleukin-2 (IL-2) signaling by calcineurin inhibition. However, recent evidence in murine models suggests that IL-2 is necessary for activation-induced cell death (AICD) of allograft-specific lymphocytes.


METHODS
We examined the apoptotic effects of the calcineurin inhibitor cyclosporine A and mTOR inhibitor rapamycin on the apoptotic alterations that occur in allospecifically activated human lymphocytes in a one-way mixed lymphocyte culture (MLC).


RESULTS
Cyclosporine increased caspase-3 activation in MLC, which corresponded with a decrease in lymphocyte apoptosis in MLC. Cyclosporine also reduced apoptosis in the CD4+ helper T cell subset, while CD8+ cells had similar or increased apoptosis when compared to controls. In contrast, rapamycin-treated cultures had normal levels of CD4+ T cell apoptosis when compared to control MLC, with decreases seen in CD8+ T lymphocytes.


CONCLUSIONS
In humans, blockade of IL-2 receptor signal with rapamycin allows apoptosis of allospecifically activated CD4+ lymphocytes to occur, while blockade of IL-2 production with cyclosporine results in decreased apoptosis in this T cell subset. As helper T cells are integral to the immune response, these results may explain the tolerogenic effects of rapamycin.
Woodside
Kenneth J
KJ
Department of Surgery, The University of Texas Medical Branch, Galveston, TX 77555 USA.
Hu
Mingdao
M
Liu
Yan
Y
Song
Wei
W
Hunter
Glenn C
GC
Daller
John A
JA
D017209:Apoptosis / Q000187:drug effects* / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000201:enzymology / Q000276:immunology*; D019703:Calcineurin / Q000276:immunology; D065095:Calcineurin Inhibitors; D053148:Caspase 3 / Q000378:metabolism; D002478:Cells, Cultured; D018920:Coculture Techniques; D016572:Cyclosporine / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000494:pharmacology; D011494:Protein Kinases / Q000276:immunology; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases
D065095:Calcineurin Inhibitors; D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D011494:Protein Kinases; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D019703:Calcineurin; D053148:Caspase 3; D020123:Sirolimus