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

Thomas R. Jones, Jongwon Ha, Matthew A. Williams, Andrew B. Adams, Megan M. Durham, Phyllis A. Rees, Shannon R. Cowan, Thomas C. Pearson, Christian P. Larsen

Research output: Contribution to journalArticlepeer-review

46 Scopus citations

Abstract

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-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.

Original languageEnglish (US)
Pages (from-to)1123-1130
Number of pages8
JournalJournal of Immunology
Volume168
Issue number3
DOIs
StatePublished - Feb 1 2002
Externally publishedYes

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