Differential effects of interleukin-2 blockade on apoptosis in naïve and activated human lymphocytes.
BACKGROUND
Certain transplantation immunosuppressive strategies are primarily based on the interruption of interleukin (IL)-2 signaling by calcineurin inhibition or anti-IL-2 receptor-antibody blockade. However, recent evidence suggests that IL-2 is necessary for peripheral deletion of allograft-specific lymphocytes.


METHODS
In this study, we examined the apoptotic effects of the calcineurin inhibitor, cyclosporine A, the chimeric anti-interleukin-2 receptor monoclonal antibody, basiliximab, and the rabbit antihuman thymocyte preparation Thymoglobulin (rATG) on phytohemagglutinin-activated human lymphocyte models designed to simulate initial exposure to the graft or ongoing rejection of the graft.


RESULTS
We found that rATG increases Fas expression, decreases Bcl-2 expression, and induces early apoptosis in naïve lymphocytes. However, rATG has more of a necrotic effect on activated lymphocytes. Basiliximab and cyclosporine had little effect on apoptosis, but did alter Bcl-2 and Fas expression.


CONCLUSIONS
Compared with IL-2 pathway inhibitors, rATG increases lymphocyte apoptosis, probably via Bcl-2 pathway inhibition. Because apoptosis is required for the development of graft tolerance, induction strategies that use IL-2-independent pathways may be advantageous.
Woodside
Kenneth J
KJ
Department of Surgery, University of Texas Medical Branch, Galveston, TX, USA.
Hu
Mingdao
M
Meng
Tao
T
Hunter
Glenn C
GC
Sower
Laurie E
LE
Daller
John A
JA
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D000961:Antilymphocyte Serum / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D000077552:Basiliximab; D065095:Calcineurin Inhibitors; D002478:Cells, Cultured; D016572:Cyclosporine / Q000494:pharmacology*; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007376:Interleukin-2 / Q000037:antagonists & inhibitors*; D008213:Lymphocyte Activation / Q000502:physiology*; D008214:Lymphocytes / Q000473:pathology / Q000502:physiology*; D009336:Necrosis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors; D011817:Rabbits; D011993:Recombinant Fusion Proteins; D019014:fas Receptor / Q000378:metabolism
D000911:Antibodies, Monoclonal; D000961:Antilymphocyte Serum; D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D019253:Proto-Oncogene Proteins c-bcl-2; D011993:Recombinant Fusion Proteins; D019014:fas Receptor; D016572:Cyclosporine; D000077552:Basiliximab