The Superdominant Minor Histocompatibility Antigen (MHAg) H60 Recognized by CD8 T Cells Fails to Elicit Lethal Graft Versus Host Disease (GVHD) Regardless of Its Tissue Expression Pattern (102.26)

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Abstract Studies both in mice and humans have argued that immunodominant MHAg eliciting CD8 T cells cause increased risk for GVHD. We have shown that the H60 MHAg is remarkably immunodominant in that an overwhelmingly predominant CD8 T cell response developed after the transfer of T cells and bone marrow (BM) into MHAg-mismatched lethally irradiated recipients is directed against H60. Here we address whether H60 is a barrier to lethal (L) GVHD. Matching of donor cells and recipients for H60 while remaining disparate for all other MHAg failed to result in improved survival, indicating that H60 is not a barrier for LGVHD. Expression of H60 is normally limited to hematopoietic tissues, possibly explaining H60’s inertness in LGVHD. To broaden its expression, we produced transgenic mice expressing H60 driven by a tissue-ubiquitous cassette. We then evaluated whether H60 expressed broadly in recipients resulted in GVHD. Naïve B6 T cells transferred into B6-H60 transgenic or congenic mice failed to show any evidence of GVHD regardless of a robust anti-H60 CD8 T cell response. Augmentation of the response to H60 by preimmunization, resulting on over 50% of the CD8 T cell compartment being H60-specific in GVHD target organs, an failed to result in LGVHD. The overall results are inconsistent with a recent report (B. Kappel, et al. Blood, 2006.107:2045) and clearly indicate that potent CD8 T cell responses to MHAg are remarkably inert in GVHD.