Blockade of programmed death-1 engagement accelerates graft-versus-host disease lethality by an IFN-gamma-dependent mechanism.
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-gamma 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-gamma production and suggest a novel therapeutic target for inhibiting GVHD lethality.
Blazar
Bruce R
BR
University of Minnesota Cancer Center and Department of Pediatrics, Minneapolis, MN 55455, USA. blaza001@tc.umn.edu
Carreno
Beatriz M
BM
Panoskaltsis-Mortari
Angela
A
Carter
Laura
L
Iwai
Yoshiko
Y
Yagita
Hideo
H
Nishimura
Hiroyuki
H
Taylor
Patricia A
PA
D000208:Acute Disease; D000818:Animals; D019138:Antibodies, Blocking / Q000008:administration & dosage*; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000502:physiology; D000954:Antigens, Surface / Q000276:immunology* / Q000378:metabolism* / Q000502:physiology; D051017:Apoptosis Regulatory Proteins; D018122:B7-1 Antigen / Q000502:physiology; D060890:B7-H1 Antigen; D001798:Blood Proteins / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism / Q000502:physiology; D016026:Bone Marrow Transplantation / Q000276:immunology / Q000473:pathology; D060908:CTLA-4 Antigen; D015536:Down-Regulation / Q000276:immunology; D053222:Fas Ligand Protein; D006086:Graft vs Host Disease / Q000276:immunology* / Q000401:mortality* / Q000517:prevention & control; D007371:Interferon-gamma / Q000096:biosynthesis / Q000502:physiology*; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010455:Peptides / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism / Q000502:physiology; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D061026:Programmed Cell Death 1 Receptor; D015398:Signal Transduction / Q000276:immunology*; D019014:fas Receptor / Q000502:physiology
D019138:Antibodies, Blocking; D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000943:Antigens, Differentiation; D000954:Antigens, Surface; D051017:Apoptosis Regulatory Proteins; D018122:B7-1 Antigen; D060890:B7-H1 Antigen; D001798:Blood Proteins; D060908:CTLA-4 Antigen; C498919:Cd274 protein, mouse; C556707:Ctla4 protein, mouse; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins; C491383:Pdcd1 protein, mouse; D010455:Peptides; D052899:Pore Forming Cytotoxic Proteins; D061026:Programmed Cell Death 1 Receptor; D019014:fas Receptor; D054353:Perforin; D007371:Interferon-gamma