title: Critical role of OX40 in CD28 and CD154-independent rejection.
abstract: Blocking both CD28 and CD154 costimulatory pathways can induce transplant tolerance in some, but not all, transplant models. Under stringent conditions, however, this protocol often completely fails to block allograft rejection. The precise nature of such CD28/CD154 blockade-resistant rejection is largely unknown. In the present study we developed a new model in which both CD28 and CD154, two conventional T cell costimulatory molecules, are genetically knocked out (i.e., CD28/CD154 double-knockout (DKO) mice) and used this model to examine the role of novel costimulatory molecule-inducible costimulator (ICOS), OX40, 4-1BB, and CD27 in mediating CD28/CD154-independent rejection. We found that CD28/CD154 DKO mice vigorously rejected fully MHC-mismatched DBA/2 skin allografts (mean survival time, 12 days; n = 6) compared with the wild-type controls (mean survival time, 8 days; n = 7). OX40 costimulation is critically important in skin allograft rejection in this model, as blocking the OX40/OX40 ligand pathway, but not the ICOS/ICOS ligand, 4-1BB/4-1BBL, or CD27/CD70 pathway, markedly prolonged skin allograft survival in CD28/CD154 DKO mice. The critical role of OX40 costimulation in CD28/CD154-independent rejection is further confirmed in wild-type C57BL/6 mice, as blocking the OX40/OX40 ligand pathway in combination with CD28/CD154 blockade induced long term skin allograft survival (>100 days; n = 5). Our study revealed a key cellular mechanism of rejection and identified OX40 as a critical alternative costimulatory molecule in CD28/CD154-independent rejection.
authors.affiliation: Department of Medicine, Harvard Medical School, and Division of Immunology, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.
authors.forename: Gülçin
authors.initials: G
authors.lastname: Demirci
authors.forename: Farhana
authors.initials: F
authors.lastname: Amanullah
authors.forename: Reshma
authors.initials: R
authors.lastname: Kewalaramani
authors.forename: Hideo
authors.initials: H
authors.lastname: Yagita
authors.forename: Terry B
authors.initials: TB
authors.lastname: Strom
authors.forename: Mohamed H
authors.initials: MH
authors.lastname: Sayegh
authors.forename: Xian Chang
authors.initials: XC
authors.lastname: Li
mesh_terms: D000818:Animals; D019138:Antibodies, Blocking / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D018106:CD28 Antigens / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D023201:CD40 Ligand / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D006084:Graft Rejection / Q000235:genetics / Q000276:immunology*; D008213:Lymphocyte Activation / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D053262:Receptors, OX40; D018124:Receptors, Tumor Necrosis Factor / Q000096:biosynthesis / Q000276:immunology / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D016038:Skin Transplantation / Q000276:immunology*; D014184:Transplantation, Homologous
chemical_list: D019138:Antibodies, Blocking; D000911:Antibodies, Monoclonal; D018106:CD28 Antigens; D053262:Receptors, OX40; D018124:Receptors, Tumor Necrosis Factor; C505717:Tnfrsf4 protein, mouse; D023201:CD40 Ligand