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The Activating Immunoreceptor NKG2D and Its Ligands Are Involved in Allograft Transplant Rejection¹

Jim Kim^*,, Catherine K. Chang^*, Tracy Hayden^*, Feng-Chun Liu^*, Jonathan Benjamin, Jessica A. Hamerman, Lewis L. Lanier^2,, and Sang-Mo Kang^2,3,*,

^* Transplantation Research Laboratory, Division of Transplantation, Department of Surgery, Department of Microbiology and Immunology and the Cancer Research Institute, and Liver Center, University of California, San Francisco, CA 94143; and Department of Surgery, University of California San Francisco East Bay, Oakland, CA 94602

Although the linkage between innate and adaptive immunity in transplantation has been recognized, the mechanisms underlying this cooperation remain to be fully elucidated. In this study, we show that early "danger" signals associated with transplantation lead to rapid up-regulation of NKG2D ligands. A second wave of NKG2D ligand up-regulation is mediated by the adaptive immune response to allografts. Treatment with an Ab to NKG2D was highly effective in preventing CD28-independent rejection of cardiac allografts. Notably, NKG2D blockade did not deplete CD8⁺ T cells or NK1.1⁺ cells nor affect their migration to the allografts. These results establish a functional role of NKG2D and its ligands in the rejection of solid organ transplants.

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 grants from American Society of Transplant Surgeons (to C.K.C. and S.-M.K.) and National Institutes of Health Grant K08 DK61970 (to S.-M.K.). L.L.L. is an American Cancer Society Research Professor and supported by National Institutes of Health Grants R37 AI066897 and R01 CA095137. University of California San Francisco Liver Center Grant P30 DK2 6743 and the University of California San Francisco Diabetes and Endocrine Research Center Grant P30 DK063720 also supported these studies.

² L.L.L. and S.-M.K. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Sang-Mo Kang, University of California, 513 Parnassus Avenue, Box 0780, San Francisco, CA 94143. E-mail address: kangs{at}surgery.ucsf.edu

⁴ Abbreviations used in this paper: CI, confidence interval; MST, mean survival time.

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