title: Programmed death-1 targeting can promote allograft survival.
abstract: The recently identified CD28 homolog and costimulatory molecule programmed death-1 (PD-1) and its ligands, PD-L1 and PD-L2, which are homologs of B7, constitute an inhibitory regulatory pathway of potential therapeutic use in immune-mediated diseases. We examined the expression and functions of PD-1 and its ligands in experimental cardiac allograft rejection. In initial studies, we found that most normal tissues and cardiac isografts had minimal expression of PD-1, PD-L1, or PD-L2, but intragraft induction of all three molecules occurred during development of cardiac allograft rejection. Intragraft expression of all three genes was maintained despite therapy with cyclosporin A or rapamycin, but was prevented in the early posttransplant period by costimulation blockade using CD154 or anti-inducible costimulator mAb. We prepared PD-L1.Ig and PD-L2.Ig fusion proteins and showed that each bound to activated PD-1(+) T cells and inhibited T cell functions in vitro, thereby allowing us to test the effects of PD-1 targeting on allograft survival in vivo. Neither agent alone modulated allograft rejection in wild-type recipients. However, use of PD-L1.Ig administration in CD28(-/-) recipients, or in conjunction with immunosuppression in fully MHC-disparate combinations, markedly prolonged cardiac allograft survival, in some cases causing permanent engraftment, and was accompanied by reduced intragraft expression of IFN-gamma and IFN-gamma-induced chemokines. PD-L1.Ig use also prevented development of transplant arteriosclerosis post-CD154 mAb therapy. These data show that when combined with limited immunosuppression, or in the context of submaximal TCR or costimulatory signals, targeting of PD-1 can block allograft rejection and modulate T and B cell-dependent pathologic immune responses in vivo.
authors.affiliation: Millennium Pharmaceuticals, Cambridge, MA 02139, USA.
authors.forename: Engin
authors.initials: E
authors.lastname: Ozkaynak
authors.forename: Liqing
authors.initials: L
authors.lastname: Wang
authors.forename: Andrew
authors.initials: A
authors.lastname: Goodearl
authors.forename: Kevin
authors.initials: K
authors.lastname: McDonald
authors.forename: Shixin
authors.initials: S
authors.lastname: Qin
authors.forename: Theresa
authors.initials: T
authors.lastname: O'Keefe
authors.forename: Thao
authors.initials: T
authors.lastname: Duong
authors.forename: Tammy
authors.initials: T
authors.lastname: Smith
authors.forename: Jose-Carlos
authors.initials: JC
authors.lastname: Gutierrez-Ramos
authors.forename: James B
authors.initials: JB
authors.lastname: Rottman
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Coyle
authors.forename: Wayne W
authors.initials: WW
authors.lastname: Hancock
mesh_terms: D000818:Animals; D000954:Antigens, Surface / Q000235:genetics / Q000276:immunology*; D051017:Apoptosis Regulatory Proteins; D018122:B7-1 Antigen; D060890:B7-H1 Antigen; D001483:Base Sequence; D001798:Blood Proteins / Q000235:genetics / Q000276:immunology / Q000494:pharmacology; D018106:CD28 Antigens / Q000235:genetics / Q000378:metabolism; D016572:Cyclosporine / Q000494:pharmacology; D018076:DNA, Complementary / Q000235:genetics; D015870:Gene Expression; D006084:Graft Rejection / Q000276:immunology / Q000517:prevention & control; D006085:Graft Survival / Q000276:immunology*; D016027:Heart Transplantation / Q000276:immunology / Q000473:pathology; D007166:Immunosuppressive Agents / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D008562:Membrane Glycoproteins; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010455:Peptides / Q000235:genetics / Q000276:immunology / Q000494:pharmacology; D061027:Programmed Cell Death 1 Ligand 2 Protein; D061026:Programmed Cell Death 1 Receptor; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D020123:Sirolimus / Q000494:pharmacology; D014018:Tissue Distribution; D014184:Transplantation, Homologous; D014185:Transplantation, Isogeneic
chemical_list: D000954:Antigens, Surface; D051017:Apoptosis Regulatory Proteins; D018122:B7-1 Antigen; D060890:B7-H1 Antigen; D001798:Blood Proteins; D018106:CD28 Antigens; C498919:Cd274 protein, mouse; D018076:DNA, Complementary; D007166:Immunosuppressive Agents; D008562:Membrane Glycoproteins; C491383:Pdcd1 protein, mouse; C556978:Pdcd1lg2 protein, mouse; D010455:Peptides; D061027:Programmed Cell Death 1 Ligand 2 Protein; D061026:Programmed Cell Death 1 Receptor; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D016572:Cyclosporine; D020123:Sirolimus