CYTOMEGALOVIRUS INHIBITS THE ENGRAFTMENT OF DONOR BONE-MARROW CELLS BY DOWN-REGULATION OF HEMOPOIETIN GENE-EXPRESSION IN RECIPIENT STROMA

Cytomegalovirus (CMV) disease after bone marrow (BM) transplantation i s often associated with BM graft failure. There are two possible reaso ns for such a correlation. First, a poor hematopoietic reconstitution of unrelated etiology could promote the progression of CMV infection b y the lack of immune control, Alternatively, CMV infection could inter fere with the engraftment of donor BR I cells in recipient BM stroma. Evidence for a causative role of CMV in BR I aplasia came from studies in long-term BM cultures and from the murine in vivo model of CMV-ind uced aplastic anemia. A deficiency in the expression of essential stro mal hemopoietins, such as stem cell factor (SCF), has indicated a func tional insufficiency of the stromal microenvironment, It remained open to question whether CMV mediates a negative regulation of hemopoietin gene expression (the downregulation model) or whether it causes the d efault of a positive regulator (the lack-of-induction model). Further, even though implicitly assumed, it has never been formally documented that CMV directly interferes with the engraftment of a BM cell transp lant. We addressed these problems in a murine model of CMV infection a fter experimental male-into-female BM transplantation. The data indica te that the downregulation model applies. Quantitation of the male-sex -determining gene tdy demonstrated an impaired engraftment of donor BM cells in the BM stroma of the female recipients. This graft failure w as reflected by a diminished population of SCF-receptor-expressing hem atopoietic progenitor cells and correlated with a reduced level of str omal SCF gene expression. Interestingly, high doses of BM cells protec ted against stromal insufficiency by a mechanism unrelated to control of infection.