This proposal is designed to purify the murine lymphokine called BMF (for B cell Maturation Factor), and to determine its roles in normal and neoplastic B lymphocyte development and function. Model systems for further molecular and cellular studies may also be identified. BMF is released from T cell - macrophage immune reactions, and has been partially purified and shown to have different molecular properties from other previously recognized lymphokines. The defining activity of BMF is to induce, in normal resting B lymphocytes and certain B cell tumor lines, all of the biochemical changes involved in going from resting B cell to Ig-secreting plasma cell. B cells responding to BMF also rapidly die. BMF may thus be a centrally important molecule in the humoral immune response, both driving B cells to differentiate and controlling their lifespan. It may also affect the generation of B cells from their pre-B precursors. If BMF is important in limiting the lifespan of normal B cells and their progeny, loss of responsiveness to this molecule could favor the generation of B cell neoplasia. Conversely, B cell tumors which remain susceptible to BMF toxicity might be diagnosable or treatable via this means. The three specific goals of this proposal are to purify BMF (including making a monoclonal antibody to it), to determine which normal B cell populations it acts on, and to explore its effects on various B cell tumor lines. Purification of BMF will utilize standard protein purification methods and two BMF-responsive B cell lines as assay systems. To determine which normal B cell populations are responsive to BMF, B cells from normal and mutant mice will be examined for these parameters: cell surface BMF receptors, intermediate biochemical changes (both pre- and post-translational) leading to Ig secretion, active Ig secretion itself, and cell death. Cell populations will be isolated by physical characteristics, age of the animal used, and quantity of these cell surface antigens: IgM, IgD, 'C' Receptors, Ia, and Lyb-3 and -5. A wide variety of B cell tumors will also be typed for these antigens and tested for BMF responsiveness.
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