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IFN- Production Is Specifically Regulated by IL-10 in Mice Made Tolerant with Anti-CD40 Ligand Antibody and Intact Active Bone

Dengping Yin^1,*, Nadav Dujovny^*, Lianli Ma^1,*, Anncy Varghese^*, JiKun Shen^1,*, D. Keith Bishop and Anita S. Chong^1,2,*,

Departments of ^* General Surgery and Immunology/Microbiology, Rush Presbyterian-St. Luke’s Medical Center, Chicago, IL 60612; and Departments of Surgery, and Microbiology and Immunology, University of Michigan School of Medicine, Ann Arbor, MI 48109

We have developed a strategy to induce tolerance to allografts, involving cotransplantation of allogeneic intact active bone and transient anti-CD40 ligand mAb therapy. Tolerance induced by this approach in C57BL/6 mice receiving BALB/c hearts is not mediated by deletional mechanisms, but by peripheral regulatory mechanisms. Tolerance is associated with diminished ex vivo IFN- production that is donor specific, and a reduction in the frequency of IFN--producing cells. Splenocytes from mice tolerant to BALB/c grafts, but sensitized to third-party C3H skin grafts, demonstrated normally primed ex vivo IFN- responses to C3H stimulators. Neutralizing anti-IL-10 and anti-IL-10R, but not anti-TGF-, anti-IL-4, or anti-CTLA-4, Abs restored the ex vivo IFN- response to BALB/c stimulators. There was no significant difference in IL-2 or IL-4 production between tolerant and rejecting mice, and anti-IL-10 mAbs had no effect on IL-2 or IL-4 production. The Cincinnati cytokine capture assay was used to test whether suppression of IFN- production in vivo was also a marker of tolerance. In naive mice, we observed a dramatic increase in serum IFN- levels following challenge with allogeneic BALB/c splenocytes or hearts. Tolerant mice challenged with allogeneic BALB/c splenocytes or hearts made significantly less or undetectable amounts of IFN-. No IL-4 or IL-10 production was detected in tolerant or rejecting mice. Collectively, our studies suggest that active suppression of IFN- production by IL-10 is correlated with, and may contribute to, tolerance induced with intact active bone and anti-CD40 ligand mAbs.

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