Cross-species graft-versus-host-disease is accompanied by a donor-derived cellular immune response

Acute graft-versus-host-disease is classically described as reactivity of donor lymphocytes to recipient alloantigens. To date there is debate as to whether GVHD can be induced across a species barrier. We recently reported the induction of stable xenogeneic chimerism (rat-->mouse) and donor-specific transplantation tolerance using the transplantation of untreated rat bone marrow cells into B10 mouse recipients. Survival of chimeras was excellent, and there was no evidence of GVHD. We now describe the induction of xenogeneic GVHD by transplanting large numbers of donor rat spleen cells with the bone marrow inoculum. All chimeras that received bone marrow and untreated spleen cells developed an external appearance compatible with GVHD and had a median survival time of 14 days. Mice that received equivalent numbers of untreated rat bone marrow alone appeared healthy, had no evidence for GVHD, and survived > 90 days. The usual epithelial target tissues for allogeneic GVHD in those mice that received xenogeneic bone marrow and spleen cells showed the presence of tissue injury and histologic features compatible with GVHD. Donor rat MHC class I and class II positive cells were prominent cell types present in the tongues of mice that developed features of GVHD, and this was accompanied by a significant inflammatory tissue response with loss of the dermal-epidermal architecture. In contrast, fully xenogeneic chimeras without GVHD had no evidence for tissue injury or pathologic cellular infiltrates when examined by immunohistochemical analysis. These data suggest that although fully xenogeneic chimeras resist GVHD, GVHD can be induced across a species barrier if sufficient numbers of donor rat spleen cells are added to the bone marrow inoculum. Further comparisons of these models may provide an approach to study the mechanisms responsible for xenoreactivity in vivo.