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CURRENT ISSUE ARCHIVES JASN Express ONLINE SUBMISSION


Published ahead of print on April 8, 2009
J Am Soc Nephrol 20: 1032-1040, 2009
© 2009 American Society of Nephrology
doi: 10.1681/ASN.2008070778
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BASIC RESEARCH

IL-6 and TNF-{alpha} Synergistically Inhibit Allograft Acceptance

Hua Shen and Daniel R. Goldstein

Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut

Correspondence: Dr. Daniel R. Goldstein, 333 Cedar Street, 3 FMP, P.O. Box 208017, New Haven, CT 06520-8018. Phone: 203-785-3271; Fax: 203-785-7567; E-mail: daniel.goldstein{at}yale.edu

Received for publication July 24, 2008. Accepted for publication December 18, 2008.

Previous studies suggested that activation of the innate immune system impairs the induction of transplantation tolerance, but the responsible inflammatory mediators have not been identified. In this study, we examined whether IL-6 and TNF-{alpha} promote resistance to transplantation tolerance. Using a highly immunogenic murine skin allograft model, we found that the absence of both IL-6 and TNF-{alpha} in the graft recipient synergized with co-stimulatory blockade to induce tolerance. Furthermore, IL-6 and TNF-{alpha} acted together to promote T cell alloimmune responses both in vitro and in vivo and to impair the ability of regulatory T cells to suppress effector T cell alloimmunity. In addition, deficiency of recipient IRAK-M, a negative regulator of certain innate immune pathways, augmented cellular IL-6 and TNF-{alpha} responses and impaired the ability of co-stimulatory blockade to extend allograft survival. In summary, IL-6 and TNF-{alpha} synergistically impair the efficacy of therapies that promote allograft acceptance.






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