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Prevention of Allograft Tolerance by Bacterial Infection with Listeria monocytogenes¹

Tongmin Wang^*, Luqiu Chen, Emily Ahmed^*, Lianli Ma^*, Dengping Yin^*, Ping Zhou, Jikun Shen^*, Honglin Xu, Chyung-Ru Wang, Maria-Luisa Alegre^2, and Anita S. Chong^2,3,*

^* Section of Transplantation, Department of Surgery, Section of Rheumatology, Department of Medicine, and Department of Pathology, University of Chicago, Chicago, IL 60637

Exposure to certain viruses and parasites has been shown to prevent the induction of transplantation tolerance in mice via the generation of cross-reactive memory T cell responses or the induction of bystander activation. Bacterial infections are common in the perioperative period of solid organ allograft recipients in the clinic, and correlations between bacterial infections and acute allograft rejection have been reported. However, whether bacterial infections at the time of transplantation have any effect on the generation of transplantation tolerance remains to be established. We used the Gram-positive intracellular bacterium Listeria monocytogenes (LM) as a model pathogen because its effects on immune responses are well described. Perioperative LM infection prevented cardiac and skin allograft acceptance induced by anti-CD154 and donor-specific transfusion in mice. LM-mediated rejection was not due to the generation of cross-reactive T cells and was largely independent of signaling via MyD88, an adaptor for most TLRs, IL-1, and IL-18. Instead, transplant rejection following LM infection was dependent on the expression of the phagosome-lysing pore former listeriolysin O and on type I IFN receptor signaling. Our results indicate that bacterial exposure at the time of transplantation can antagonize tolerogenic regimens by enhancing alloantigen-specific immune responses independently of the generation of cross-reactive memory T cells.

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 is supported by American Heart Association Fellowship Grant 0620026Z (to L.C.), National Institutes of Health Grants R01 AI052352 (to M.-L.A.) and R01 AI072630, Roche Organ Transplantation Research Foundation Grant 280559271 (to A.S.C.), and an American Society of Transplantation Branch-Out Faculty Grant (to A.S.C. and C.-R.W.).

² M.-L.A. and A.S.C. are co-senior authors.

³ Address correspondence and reprint requests to Dr. Anita Chong, Department of Surgery, 5841 South Maryland Avenue, Room AMB-J542, Chicago, IL 60637. E-mail address: achong{at}surgery.bsd.uchicago.edu

⁴ Abbreviations used in this paper: LM, Listeria monocytogenes; ActA, actin assembly-inducing protein; B/c, BALB/c mice; B6, C57BL/6 mice; DC, dendritic cell; DST, donor-specific transfusion; LLO, listeriolysin O; Tip, TNF-- and inducible NO synthase-producing; Treg, regulatory T cell; WT, wild type.