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The Carlos and Marguerite Mason Transplantation Research Center and Department of Surgery, Emory University School of Medicine, Atlanta, GA 30322; and
Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
Blockade of the CD40 and CD28 costimulatory pathways significantly
prolongs allograft survival; however, certain strains of mice (i.e.,
C57BL/6) are relatively resistant to the effects of combined CD40/CD28
blockade. We have previously shown that the costimulation
blockade-resistant phenotype can be attributed to a subset of
CD8+ T cells and is independent of CD4+ T
cell-mediated help. Here we explore the role of the IL-2 pathway in
this process using mAbs against the high affinity IL-2R, CD25, and IL-2
in prolonging skin allograft survival in mice receiving combined
CD40/CD28 blockade. We have also investigated the effects of treatment
on effector function by assessment of cytotoxicity and the generation
of IFN-
-producing cells in response to allogeneic stimulators as
well as proliferation in an in vivo graft-vs-host disease model. We
find that additional blockade of either CD25 or IL-2 significantly
extends allograft survival beyond that in mice receiving costimulation
blockade alone. This correlates with diminished frequencies of
IFN--producing allospecific T cells and reduced CTL activity.
Anti-CD25 therapy also synergizes with CD40/CD28 blockade in
suppressing proliferative responses. Interestingly, depletion of
CD4+ T cells, but not CD8+ cells, prevents
prolongation in allograft survival, suggesting an IL-2-independent role
for regulation in extended survival.
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