EVIDENCE AGAINST A KEY ROLE FOR TRANSFORMING GROWTH-FACTOR-BETA-1 IN CYTOMEGALOVIRUS-INDUCED BONE-MARROW APLASIA

During immunodeficiency after sublethal haemato-ablative treatment, cy tomegalovirus (CMV) infection interferes with haematopoietic reconstit ution and can cause lethal bone marrow (BM) aplasia, The in vivo model of murine CMV infection has identified the BM stroma as the principal target site of CMV in the haematopoietic cord, The infected cell type is the reticular stromal cell which forms the stromal network and pro duces essential haemopoietins, such as stem-cell factor (SCF), The exp ression of SCF was found to be reduced in the infected stroma, but the stromal network was not disrupted and the number of infected stromal cells was too low to explain the functional deficiency, These facts ca ll for a negatively regulating cytokine that is induced by the infecti on and that potentiates the direct effect of infection by down-regulat ing haemopoietins in uninfected bystander cells, Recent work has sugge sted that transforming growth factor (TGF)-beta 1 might be the cytokin e involved in CMV-induced BM aplasia, We show here that murine CMV ind irectly induces the accumulation of mature TGF-beta 1 in uninfected re nal tubular epithelial cells and TGF-beta 1 transcription in BM stroma l cells, whereas infected renal glomerular and interstitial cells, hep atocytes and BM stromal cells do not coexpress mature TGF-beta 1, Anti viral CD8 T-cell therapy prevented BM aplasia and also prevented the d own-regulation of stromal SCF and interleukin-6 gene expression, Inter estingly, however, the CD8 T cells did not preclude the up-regulation of mature TGF-beta 1, but proved to be inducers of TGF-beta 1 gene exp ression in BM stroma, These findings suggest that TGF-beta 1 is not th e mediator of BM aplasia.