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Fully MHC-Disparate Mixed Hemopoietic Chimeras Show Specific Defects in the Control of Chronic Viral Infections¹

Brent H. Koehn^*, Matthew A. Williams^2,*, Keshawna Borom^*, Shivaprakash Gangappa^*, Thomas C. Pearson^*, Rafi Ahmed and Christian P. Larsen^3,*

^* Emory Transplant Center and Department of Surgery, and Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322

The establishment of mixed allogeneic chimerism can induce donor-specific transplantation tolerance across full MHC barriers. However, a theoretical disadvantage of this approach is the possibility that the state of mixed chimerism might negatively affect the recipient’s immune competence to control pathogens. Previous studies using murine models have not supported this hypothesis, because they indicate that acute viral infections are cleared by chimeric animals with similar kinetics to that of unmanipulated controls. However, chronic or persistent viral infections often require a more complex and sustained response with cooperation between CD4 Th cells, CTL, and B cells for effective control. The current study indicates that profound defects become manifest in the control of chronic pathogenic infections in MHC-disparate mixed allogeneic chimeric mice. Furthermore, we show that ineffective priming of the donor-restricted CTL response leads to virus persistence, as well as severe T cell exhaustion. Our results further suggest that either T cell adoptive immunotherapy or selected MHC haplotype matching partially restore immune competence. These approaches may facilitate the translation of mixed chimerism therapeutic regimens.

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 in part by Research Grants AI44644 and AI040519 from the National Institutes of Health and by the Carlos and Marguerite Mason Trust.

² Current address: Department of Immunology and Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195.

³ Address correspondence and reprint requests to Dr. Christian P. Larsen, Emory Transplant Center, 5105 WMB, 101 Woodruff Circle, Atlanta, GA 30322. E-mail address: clarsen{at}emory.edu

⁴ Abbreviations used in this paper: LCMV, lymphocytic choriomeningitis virus; NP, nuclear protein.