The longterm objective of this research project is to understand the maturation of resting immunocompetent B lymphocytes into actively immunoglobulin-secreting plasma cells at the cellular, biochemical, molecular and genetic levels. Currently, attention is focussed on the identity, mechanisms of action, and biological relevance of several distinct protein molecules termed B cell Maturation Factors (BMFs). BMFs are derived from several cell types in the immune system, and are able to induce, in cultured normal or tumor B cells, all of the changes thought to be part of the resting B cell to plasma cell transition. The identity of these BMFs is being pursued both by classical protein purification and by recombinant DNA cloning. Their mechanisms of action (cell surface receptors, intracellular signals, changes in Ig metabolism and cell growth, etc.) are being investigated by a combination of molecular biological, biochemical, immunological, and genetic techniques. The relevance of BMFs is being approached by studying the effects of endogenously produced or exogenously administered BMFs on both normal and BMF-unresponsive mouse strains and tumor cells in vitro and in vivo. The information gained in these studies may have medical significance for several reasons. First, a detailed understanding of the maturation of B lymphocytes to active Ig secretion, the central process of humoral immunity may lead to more specific and efficient manipulation of the immune system in normal individuals and patients with heightened (autoimmune) or depressed (immunodeficient) immune capabilities. Second, since WEHI-279 tumor B cells are an important component of this project, these studies directly address the growth and differentiation of certain B cell tumors and how these may be modified. Finally, by identifying and cloning lymphokine (BMF) structural genes in the mouse, probes will be obtained which should allow isolation of the equivalent genes and molecules in man, for eventual diagnostic or therapeutic use.
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