Immune-mediated bone marrow failure in C57BL/6 mice

We established a model of immune-mediated bone marrow (BM) failure in C57BL16 (B6) mice with 6.5 G total-body irradiation followed by the infusion of 4-10 x 10(6) lymph node (LN) cells/recipient from Friend leukemia virus BIN (FVB) donors. Forty-three percent of animals succumbed, with surviving animals showing marked declines in blood neutrophils, red blood cells, platelets and total BM cells at 8 to 14 days following LN cell infusion. Lowering the total-body irradiation dose to 5 G or altering the LN source from FVB to BALB/cBy donors failed to produce BM destruction. Affected animals showed significant expansion and activation of CD8 T lymphocytes in both the blood and BM; cytotoxic T cells had elevated Fas ligand expression and were oligoclonal, mainly displaying V beta 7 and V beta 17 T cell receptors. There were significant increases in blood plasma interferon gamma and tissue necrosis factor cc in affected animals. Chemokine ligands CCL3, CCL4, CCL5, CCL20, CXCL2, and CXCL5 and hematopoietic growth factors G-CSF, M-CSF, GM-CSF, VEGF were also elevated. In B6 mice carrying a Fas gene mutation, BM failure was attenuated when they were infused with FVB LN cells. Our model establishes a useful platform to define the roles of individual genes and their products in immune-mediated BM failure. Published by Elsevier Inc. on behalf of ISEH - International Society for Experimental Hematology.