title: Glucocorticoid-induced TNFR-related protein stimulation reverses cardiac allograft acceptance induced by CD40-CD40L blockade.
abstract: CD40-CD40L blockade has potent immunosuppressive effects in cardiac allograft rejection but is less effective in the presence of inflammatory signals. To better understand the factors that mediate CD40-CD40L blockade-resistant rejection, we studied the effects of stimulation through glucocorticoid-induced TNFR-related protein (GITR), a costimulatory protein expressed by regulatory and effector T cells. Stimulation of CD40-/- or wild-type recipient mice treated with anti-CD40L mAb (WT+anti-CD40L) and with agonistic anti-GITR mAb resulted in cardiac allograft rejection. GITR stimulation did not induce rejection once long-term graft acceptance was established. In vitro, GITR stimulation increased proliferation of effector T cells and decreased regulatory T cell (Treg) differentiation in both treatment groups. GITR-stimulated CD40-/- recipients rejected their allografts more rapidly compared to GITR-stimulated WT+anti-CD40L recipients, and this rejection, characterized by a robust Th2 response and significant eosinophilic infiltrate, could be mediated by CD4+ T cells alone. In contrast, both CD4+ and CD8+ T cells were required to induce rejection in GITR-stimulated WT+anti-CD40L-treated recipients, and the pathology of rejection was less severe. Hence, early GITR stimulation could initiate graft rejection despite CD40 deficiency or anti-CD40L mAb treatment, though the recipient response was dependent on the mechanism of CD40-CD40L disruption.
authors.affiliation: Program in Cellular and Molecular Biology, University of Michigan, Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Kenneth T
authors.initials: KT
authors.lastname: Krill
authors.forename: Keri
authors.initials: K
authors.lastname: Csencsits-Smith
authors.forename: Sherri C
authors.initials: SC
authors.lastname: Wood
authors.forename: Susan
authors.initials: S
authors.lastname: Faust
authors.forename: Guanyi
authors.initials: G
authors.lastname: Lu
authors.forename: D Keith
authors.initials: DK
authors.lastname: Bishop
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D019013:CD40 Antigens / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D023201:CD40 Ligand / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D002454:Cell Differentiation; D049109:Cell Proliferation; D053450:Glucocorticoid-Induced TNFR-Related Protein / Q000819:agonists / Q000235:genetics / Q000276:immunology*; D006084:Graft Rejection / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D006085:Graft Survival / Q000276:immunology; D016027:Heart Transplantation; D051379:Mice; D018345:Mice, Knockout; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000473:pathology; D018418:Th2 Cells / Q000276:immunology / Q000473:pathology; D014184:Transplantation, Homologous
chemical_list: D000911:Antibodies, Monoclonal; D019013:CD40 Antigens; D053450:Glucocorticoid-Induced TNFR-Related Protein; C106544:Tnfrsf18 protein, mouse; D023201:CD40 Ligand