T cell-mediated bone marrow and splenic hypoplasia in a mouse model of acute graft vs. host disease

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Abstract A major limitation with use of hematopoietic stem cell transplantation to treat relapsing hematological malignancies is the development of a potentially lethal, multi-organ inflammatory disorder called acute graft versus host disease (aGVHD). Acute GVHD-associated bone marrow (BM) suppression and lymphoid tissue (LT) hypoplasia creates protracted immunodeficiency that greatly increases the risk of infections, bleeding and death. Objective We wished to define the role that allogeneic CD4+ T cells play in a mouse model of aGVHD-associated BM and LT aplasia that does not require lethal myeloablative conditioning. Methods Allogeneic CD4+CD25−T cells (0.5×106 cells) obtained from Bl6-H2-Ab1bm12 (Bl6-BM12) donor mice were adoptively transferred into sub-lethally irradiated C57Bl6 (Bl6) recipients. Mice were monitored daily for clinical signs of aGVHD. Results Adoptive transfer of allogeneic but not syngeneic T cells induced a time-dependent loss of survival and remarkable reductions of cellularity in the BM and spleen. Virtually all allogeneic mice developed severe anemia at 15 days post transfer. Flow cytometric analyses revealed dramatic and significant losses of CD4+ T cells, myeloid cells and NK cells in the BM and spleen indicating BM suppression and spleen hypoplasia. Interestingly, we observed little immune cell infiltration in the lungs, liver and skin of allogeneic recipients and no evidence of disease in any tissue of syngeneic mice. These data suggest that the major target tissues in this model of aGVHD are BM and spleen. Conclusions When taken together, these data demonstrate that adoptive transfer of allogeneic CD4+ T cells into sub-lethally irradiated recipients induces aGVHD-associated immunodeficiency.