The proliferation and differentiation of hematopoietic cells is under the control of hematopoietic growth factors. A variety of cell types are capable of producing these growth factors including endothelial cells, fibroblasts, stromal cells, monocytes and lymphocytes. Growth factors stimulate both proliferation and/or differentiation of hematopoietic cells. There is substantial redundancy in the spectra of activity of hematopoietic growth factors in that several individual factors may act on mature and immature cells of several lineages and there are several factors that have overlapping spectra of activity. Our goal has been to devise strategies to determine the in vivo role of particular factors in both hematopoietic and lymphoid cell differentiation. We have devised an expression vector that results in production of antisense RNA complimentary to the sequences of interleukin-3 (IL-3) mRNA. Transgenic mouse strains have been developed using this vector in an effort to inhibit production of IL-3 in vivo. Expression of the antisense sequences has been documented in lymphoid tissues and brain. Some transgenic mice exhibit a syndrome of neurological dysfunction characterized by gait abnormalities suggesting that IL-3 or an IL-3 related protein may have a role in neurological function. A second syndrome observed in two independent transgenic strains is the development of a highly proliferative, rapidly fatal lymphoma composed of primitive B cells that express B220 and RAG-1, an enzyme involved in gene rearrangement. However, the immunoglobulin genes are not rearranged placing these neoplastic cells at the pro-B cell stage of lymphoid differentiation. IL-3 production by T-lymphocytes is reduced to 20-30 percent of control in transgenic strains that develop lymphomas. These data suggest that IL-3 may have a critical, physiological role in controlling the growth of early, undifferentiated B-cells.
