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Altered Distribution of H60 Minor H Antigen-Specific CD8 T Cells and Attenuated Chronic Vasculopathy in Minor Histocompatibility Antigen Mismatched Heart Transplantation in Cxcr3^–/– Mouse Recipients

Jean Kwun^*, Huaizhong Hu^*, Erik Schadde^*, Drew Roenneburg^*, Kathleen A. Sullivan, Julie DeMartino, William J. Burlingham^* and Stuart J. Knechtle^1,*

^* Department of Surgery, Division of Transplantation, University of Wisconsin, Madison, WI 53792-7375; and Merck Research Laboratories, Rahway, NJ 07065

Chemokine-chemokine receptor interactions and the subsequent recruitment of T lymphocytes to the graft are believed to be among the initial events in the development of acute and chronic rejection of heart transplants. We sought to determine the role of chemokine receptor Cxcr3 on the development of acute and chronic rejection in a multiple minor Ag mismatched mouse heart transplant model. The frequencies and kinetics of immunodominant H60 (LTFNYRNL) miHA-specific CD8 T cells in wild-type or Cxcr3^–/– C57BL/6 recipients were monitored using MHC class I tetramer after BALB/b donor hearts were transplanted. Acceptance of grafts, severity of rejection, and infiltration of T cells were not altered in Cxcr3^–/– recipients. However, graft survival was moderately prolonged in Cxcr3^–/– recipient mice undergoing acute rejection. Analyses of splenocytes, PBLs, and graft-infiltrating cells revealed increased alloreactive T cells (H60-specific CD8 T cells) in the peripheral blood and spleen but not in the graft. Adoptively transferred Cxcr3^–/– CD8 T cells in the BALB/b heart-bearing B6 scid mice showed retention of alloreactive CD8 T cells in the blood but less infiltration into the graft. Cxcr3^–/– recipients with long-term graft survival also showed a marked decrease of CD8⁺ T cell infiltration and reduced neo-intimal hyperplasia. These data indicate that Cxcr3 plays a critical role in the trafficking as well as activation of alloreactive T cells. This role is most eminent in a transplant model when a less complex inflammatory milieu is involved such as a well-matched graft and chronic rejection.

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 Address correspondence and reprint requests to Dr. Stuart J. Knechtle, Department of Surgery, Division of Transplantation, University of Wisconsin-Madison, 600 Highland Avenue, CSC H4/766, Madison, WI 53792-7375. E-mail address: STUART{at}surgery.wisc.edu

² Abbreviations used in this paper: I/R, ischemia/reperfusion; Mig, monokine induced by IFN-; IP-10, IFN-inducible protein 10; I-TAC, IFN-inducible T cell chemoattractant; miHA, minor H Ag; POD, posttransplantation on day; MST, mean survival time.

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