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OX40 Costimulation Prevents Allograft Acceptance Induced by CD40-CD40L Blockade¹

Bryna E. Burrell^*,, Guanyi Lu^*, Xian C. Li and D. Keith Bishop^2,*,

^* Section of General Surgery and Graduate Program in Immunology, University of Michigan School of Medicine, Ann Arbor, MI 48109; and Department of Medicine, Harvard Medical School, Boston, MA 02215

Disrupting the CD40-CD40L costimulation pathway promotes allograft acceptance in many settings. Herein, we demonstrate that stimulating OX40 overrides cardiac allograft acceptance induced by disrupting CD40-CD40L interactions. This effect of OX40 stimulation was dependent on CD4⁺ T cells, which in turn provided help for CD8⁺ T cells and B cells. Allograft rejection was associated with donor-reactive Th1 and Th2 responses and an unconventional granulocytic infiltrate and thrombosis of the arteries. Interestingly, OX40 stimulation induced a donor-reactive IgG class switch in the absence of CD40-CD40L interactions, and the timing of OX40 stimulation relative to transplantation affected the isotype of donor-reactive Ab produced. Inductive OX40 stimulation induced acute graft rejection, which correlated with both IgG1 and IgG2a deposition within the graft. Once graft acceptance was established following CD40-CD40L blockade, delayed OX40 stimulation did not induce acute allograft rejection despite priming of graft-reactive Th1 and Th2. Rather, chronic rejection was induced, which was characterized by IgG1 but not IgG2a deposition within the graft. These studies reveal both redundancy and key differences in function among costimulatory molecules that manifest in distinct pathologies of allograft rejection. These findings may help guide development of therapeutics aimed at promoting graft acceptance in transplant recipients.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grants R01 AI061469 (to D.K.B.), R01 HL070613 (to D.K.B.), and R01 AI070315 (to X.C.L.), and The Herman and Dorothy Miller Fund Award for Innovative Immunology Research (to B.E.B.).

² Address correspondence and reprint requests to Dr. D. Keith Bishop, Transplant Immunology Research Laboratory, Section of General Surgery, A560 MSRB II, Box 0654, University of Michigan Medical Center, Ann Arbor, MI 48109. E-mail address: kbishop{at}umich.edu

³ Abbreviations used in this paper: OX40L, OX40 ligand; AP, alkaline phosphatase; CD40^–/–, CD40 deficient; CD40L^–/–, CD40L deficient; GIC, graft-infiltrating cell; WT, wild type.