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Clinical and Developmental Immunology
Volume 2013 (2013), Article ID 986859, 9 pages
http://dx.doi.org/10.1155/2013/986859
Research Article

Glucocorticoid-Induced TNFR-Related Protein Stimulation Reverses Cardiac Allograft Acceptance Induced by CD40-CD40L Blockade

1Program in Cellular and Molecular Biology, University of Michigan, Medical School, Ann Arbor, MI 48109, USA
2Department of Pathology and Laboratory Medicine, University of Texas Medical School at Houston, Houston, TX 77030, USA
3Section of Transplantation Surgery, Department of Surgery, University of Michigan, Medical School, Ann Arbor, MI 48109, USA
4Graduate Program in Immunology, University of Michigan, Medical School, Ann Arbor, MI 48109, USA

Received 1 February 2013; Accepted 14 March 2013

Academic Editor: Stanislav Vukmanovic

Copyright © 2013 Kenneth T. Krill et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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 ( ) 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.