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Requirement for Donor and Recipient CD40 Expression in Cardiac Allograft Rejection: Induction of Th1 Responses and Influence of Donor-Derived Dendritic Cells¹

Meera J. Nathan, Jeffrey E. Mold^*, Sherri C. Wood^*, Keri Csencsits^*, Guanyi Lu^*, Ernst J. Eichwald and D. Keith Bishop^2,*,

^* Section of General Surgery, Department of Surgery, and Department of Microbiology and Immunology, University of Michigan School of Medicine, Ann Arbor, MI 48109; and Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT 84132

Costimulation through the CD40-CD40 ligand (CD40L) pathway is critical to allograft rejection, in that anti-CD40L mAb therapy prolongs allograft survival. However, the majority of studies exploring CD40-CD40L interactions have targeted CD40L. Less is known about the requirement for donor- and/or host-derived CD40 during rejection. This study assessed the relative contributions of donor and recipient CD40 expression to the rejection process. As the effectiveness of costimulatory blockade may be mouse strain dependent, this study explored the requirement for donor and recipient CD40 expression in BALB/c and C57BL/6 mice. Wild-type (WT) and CD40^–/– BALB/c recipients readily rejected WT and CD40^–/– C57BL/6 allografts, and rejection was associated with a prominent Th1 response. In contrast, CD40^–/– C57BL/6 recipients failed to reject WT or CD40^–/– BALB/c allografts and did not mount Th1 or Th2 responses. However, injection of donor CD40^–/– dendritic cells induced both Th1 and Th2 responses and allograft rejection in CD40^–/– C57BL/6 recipients. Finally, WT C57BL/6 mice rejected CD40^–/– allografts, but this rejection response was associated with muted Th1 responses. These findings demonstrate that 1) CD40 expression by the recipient or the graft may impact on the immune response following transplantation; 2) the requirement for CD40 is influenced by the mouse strain; and 3) the requirement for CD40 in rejection may be bypassed by donor DC. Further, as CD40 is not required for rejection in BALB/c recipients, but anti-CD40L mAb prolongs graft survival in these mice, these results suggest that anti-CD40L therapy functions at a level beyond disruption of CD40-CD40L interactions.

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