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The Journal of Immunology, 1999, 162: 352-358.
Copyright © 1999 by The American Association of Immunologists

Contributions of Direct and Indirect T Cell Alloreactivity During Allograft Rejection in Mice1

Gilles Benichou*, Anna Valujskikh{dagger} and Peter S. Heeger2,{dagger}

* Immunogenetics and Transplantation Laboratory, Department of Surgery, University of California, San Francisco, CA 94114; and {dagger} Nephrology Division, Department of Medicine, Cleveland Veterans Affairs Medical Center, and Institute of Pathology, Case Western Reserve University, Cleveland, OH 44106

The immune response to transplanted allogeneic tissues is mediated by T cells that recognize donor histocompatibility Ags either via direct (donor MHC and peptides) or indirect (recipient MHC and donor-derived peptides) allorecognition pathways. The relative contribution of each of these pathways to allograft rejection remains largely unknown. To address this, we used an enzyme-linked immunospot assay to define the frequency and cytokine phenotype of T cells responding via direct and indirect pathways to alloantigens at various time points following placement of allogeneic B10.A skin grafts on BALB/c recipient mice. During acute graft rejection >90% of the anti-B10.A T cell repertoire was directed toward intact donor MHC molecules, while T cells recognizing indirectly presented, donor-derived peptides accounted for <10%. This indirect response was comprised of reactivity toward both MHC-derived and, to a lesser extent, minor Ag-derived determinants. The direct and indirect alloresponses were predominantly detected in recipient lymph nodes and were mediated by T cells displaying a mixed type 1/type 2 cytokine phenotype. Six weeks following rejection, however, the memory allospecific T cell response became predominant in the recipient spleen, with only minimal activity detectable in the draining lymph nodes. This work provides a new approach for analysis of the immunophysiology of allograft rejection and should be useful for monitoring immune responses to graft Ags in human transplant recipients.




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