title: New insights in CD28-independent allograft rejection.
abstract: CD28 costimulatory blockade induces tolerance in most murine transplant models but fails to do so in stringent transplant models, such as skin transplantation. The precise immunological mechanisms of CD28-independent rejection remain to be fully defined. Using two novel mouse strains in which both CD28 and either CD4 or CD8 are knocked out (CD4(-/-)CD28(-/-) or CD8(-/-)CD28(-/-) mice), we examined mechanisms of CD28-independent CD4(+) or CD8(+) T-cell-mediated allograft rejection. CD4(-/-)CD28(-/-) and CD8(-/-)CD28(-/) deficient mice rejected fully allogeneic skin allografts at a tempo comparable with that in wild-type mice. Rejection proceeded despite significant reduction in alloreactive T-cell clone sizes suggesting the presence of a subset of T cells harnessing alternate CD28-independent costimulatory pathways. Blockade of CD40-CD154 and CD134-CD134L, but not ICOS-B7h pathways in combination significantly prolonged allograft survival in CD8(-/-)CD28(-/-) recipients and to a lesser extent in CD4(-/-)CD28(-/-) recipients. Prolongation in allograft survival was associated with reduced effector-memory T-cell generation, decreased allospecific Th1 cytokine generation and diminished alloreactive T-cell proliferation in vivo. In aggregate, the data identify these two pathways as critical mediators of CD28-independent rejection by CD4(+) and to a lesser extent CD8(+) T cells, and provide novel mechanistic insights into functions of novel T-cell co-stimulatory pathways in vivo.
authors.affiliation: Transplantation Research Center, Renal Division, Brigham & Women's Hospital and Children's Hospital Boston, Harvard Medical School, Boston, MA, USA.
authors.forename: A
authors.initials: A
authors.lastname: Habicht
authors.forename: N
authors.initials: N
authors.lastname: Najafian
authors.forename: H
authors.initials: H
authors.lastname: Yagita
authors.forename: M H
authors.initials: MH
authors.lastname: Sayegh
authors.forename: M R
authors.initials: MR
authors.lastname: Clarkson
mesh_terms: D000818:Animals; D017209:Apoptosis; D018106:CD28 Antigens / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D023201:CD40 Ligand / Q000037:antagonists & inhibitors; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation; D004195:Disease Models, Animal; D006084:Graft Rejection / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D006085:Graft Survival / Q000276:immunology; D007111:Immunity, Cellular; D007371:Interferon-gamma / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D053278:OX40 Ligand / Q000037:antagonists & inhibitors; D011379:Prognosis; D016038:Skin Transplantation / Q000276:immunology* / Q000473:pathology; D014184:Transplantation, Homologous
chemical_list: D018106:CD28 Antigens; D053278:OX40 Ligand; D023201:CD40 Ligand; D015847:Interleukin-4; D007371:Interferon-gamma