Blockade of programmed death-1 engagement accelerates graft-versus-host disease lethality by an IFN-γ-dependent mechanism

Bruce R Blazar, Beatriz M. Carreno, Angela Panoskaltsis-Mortari, Laura Carter, Yoshiko Iwai, Hideo Yagita, Hiroyuki Nishimura, Patricia A. Taylor

Research output: Contribution to journalArticlepeer-review

226 Scopus citations

Abstract

Acute graft-vs-host disease (GVHD) is influenced by pathways that can enhance or reduce lethality by providing positive or negative signals to donor T cells. To date, the only reported pathway to inhibit GVHD is the CTLA-4: B7 pathway. Because absence of the programmed death-1 (PD-1) pathway has been implicated in a predisposition to autoimmunity and hence a lack of negative signals, the effect of PD-1 pathway blockade on GVHD was explored using several distinct approaches. In each, GVHD lethality was markedly accelerated. Coblockade of CTLA-4 and PD-1 was additive in augmenting GVHD, indicating that these pathways are not fully redundant. Although neither perforin nor Fas ligand expression was required for GVHD enhancement, donor IFN-γ production was required for optimal GVHD acceleration in the absence of PD-1 ligation. These data indicate that PD-1 ligation down-regulates GVHD through modulation of IFN-γ production and suggest a novel therapeutic target for inhibiting GVHD lethality.

Original languageEnglish (US)
Pages (from-to)1272-1277
Number of pages6
JournalJournal of Immunology
Volume171
Issue number3
DOIs
StatePublished - Aug 1 2003

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