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-Dependent Mechanism1
* Division of Bone Marrow Transplant, University of Minnesota Cancer Center and Department of Pediatrics, Minneapolis, MN 55455;
Wyeth Research, Cambridge, MA 02140;
Department of Medical Chemistry, Graduate School of Medicine, Kyoto University, Kyoto, Japan;
Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan; and
¶ Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138
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-
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- production and suggest a novel therapeutic target for inhibiting GVHD lethality.
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