title: The role of the IL-2 pathway in costimulation blockade-resistant rejection of allografts.
abstract: Blockade of the CD40 and CD28 costimulatory pathways significantly prolongs allograft survival; however, certain strains of mice (i.e., C57BL/6) are relatively resistant to the effects of combined CD40/CD28 blockade. We have previously shown that the costimulation blockade-resistant phenotype can be attributed to a subset of CD8+ T cells and is independent of CD4+ T cell-mediated help. Here we explore the role of the IL-2 pathway in this process using mAbs against the high affinity IL-2R, CD25, and IL-2 in prolonging skin allograft survival in mice receiving combined CD40/CD28 blockade. We have also investigated the effects of treatment on effector function by assessment of cytotoxicity and the generation of IFN-gamma-producing cells in response to allogeneic stimulators as well as proliferation in an in vivo graft-vs-host disease model. We find that additional blockade of either CD25 or IL-2 significantly extends allograft survival beyond that in mice receiving costimulation blockade alone. This correlates with diminished frequencies of IFN-gamma-producing allospecific T cells and reduced CTL activity. Anti-CD25 therapy also synergizes with CD40/CD28 blockade in suppressing proliferative responses. Interestingly, depletion of CD4+ T cells, but not CD8+ cells, prevents prolongation in allograft survival, suggesting an IL-2-independent role for regulation in extended survival.
authors.affiliation: The Carlos and Marguerite Mason Transplantation Research Center, Emory University School of Medicine, 1639 Pierce Drive, Atlanta, GA 30322, USA.
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Jones
authors.forename: Jongwon
authors.initials: J
authors.lastname: Ha
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Williams
authors.forename: Andrew B
authors.initials: AB
authors.lastname: Adams
authors.forename: Megan M
authors.initials: MM
authors.lastname: Durham
authors.forename: Phyllis A
authors.initials: PA
authors.lastname: Rees
authors.forename: Shannon R
authors.initials: SR
authors.lastname: Cowan
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Pearson
authors.forename: Christian P
authors.initials: CP
authors.lastname: Larsen
mesh_terms: D000069594:Abatacept; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000494:pharmacology; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000008:administration & dosage; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D023201:CD40 Ligand / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D060908:CTLA-4 Antigen; D003601:Cytotoxicity Tests, Immunologic; D015536:Down-Regulation / Q000276:immunology; D004357:Drug Synergism; D006084:Graft Rejection / Q000276:immunology* / Q000517:prevention & control*; D006085:Graft Survival / Q000276:immunology; D006086:Graft vs Host Disease / Q000276:immunology; D007106:Immune Sera / Q000008:administration & dosage; D018796:Immunoconjugates; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007274:Injections, Intraperitoneal; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D007376:Interleukin-2 / Q000037:antagonists & inhibitors / Q000276:immunology / Q000502:physiology*; D008213:Lymphocyte Activation / Q000276:immunology*; D007959:Lymphocyte Culture Test, Mixed; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D015375:Receptors, Interleukin-2 / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology*; D016038:Skin Transplantation / Q000276:immunology; D014184:Transplantation, Homologous / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D007106:Immune Sera; D018796:Immunoconjugates; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D015375:Receptors, Interleukin-2; D023201:CD40 Ligand; D000069594:Abatacept; D007371:Interferon-gamma