Susceptibility of genetically diverse outbred mice to acute graft vs. host disease (aGVHD)

Abstract

Mice are the primary animal of choice for modeling aGVHD. One aspect of these mouse models that may limit translation of promising therapeutic strategies to patient treatment is the use inbred mice as surrogates for genetically diverse human populations. Objective Quantify and compare tissue inflammation and injury in inbred vs. genetically diverse outbred mice using a well-characterized model of aGVHD-mediated bone marrow (BM) failure and spleen hypoplasia. Methods C57Bl6 (Bl6) CD4+ T cells (20,000 T cells/g b.w.) were injected (i.p.) into sub-lethally irradiated Bl6-H2-Ab1bm12(BM12) recipients (Bl6→BM12) or into Collaborative Cross (CC) or CD1 outbred recipients. Results Adoptive transfer of allogeneic Bl6 T cells into BM12 recipients induced marked weight loss (25%) at 20 days post T cell transfer that was associated with dramatic reductions in hematocrit as well as large and significant decreases in circulating granulocytes, platelets and erythrocytes when compared to their syngeneic controls (BM12→BM12). Total cell numbers in BM and spleen were also found to be dramatically reduced in these mice. Histopathological inspection confirmed severe hypocellularity in BM and spleen whereas no aGVHD was present in the lungs, liver, skin and colon. In contrast, adoptive transfer of Bl6 T cells into sub-lethally irradiated CC or CD1 or CC mice induced little or no weight loss at 25–30 days post T cell transfer with no significant reductions in hematocrit, circulating leukocytes, erythrocytes or platelets. BM- and spleen-associated cell numbers were not reduced when compared their CC controls. Conclusions Genetically diverse outbred mice are resistant to aGVHD-mediated BM failure and spleen hypoplasia.