The role of the IL-2 pathway in costimulation blockade-resistant rejection of allografts

TR Jones, J Ha, MA Williams, AB Adams… - The Journal of …, 2002 - journals.aai.org
TR Jones, J Ha, MA Williams, AB Adams, MM Durham, PA Rees, SR Cowan, TC Pearson…
The Journal of Immunology, 2002journals.aai.org
Blockade of the CD40 and CD28 costimulatory pathways significantly prolongs allograft
survival; however, certain strains of mice (ie, 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 …
Abstract
Blockade of the CD40 and CD28 costimulatory pathways significantly prolongs allograft survival; however, certain strains of mice (ie, 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-γ-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-γ-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.
journals.aai.org