NZB mice are the first experimental animal model of human lupus. In previous studies we have demonstrated a characteristic hyperactive B lymphopoiesis in the early life of the NZB mice. However, this is a temporary phenomenon and declines rapidly prior to the manifestation of autoimmune phenomena and the development of autoimmune disease. Recently we have identified humoral factors which can enhance sIg-B acquisition and colony formation by sIg B precursor cells from normal strains of mice in vitro. They were first identified in the serum of very young NZB mice when they were active in B lymphopoiesis and thus termed NZB serum factors (NZB-SF). The NZB-SF activity in serum decreases with age in parallel to the decline of once hyperactive B of NZB-SF and designated as the 60 kd NZB-SF. Serological studies and analyses of biological functions of this molecule indicate that this is distinguishable from well defined cytokines. We hypothesized that in NZB mice the overproduction of NZB-SF may be, at least in part responsible for the premature hyperactive B lymphopoiesis and the dysregulation autoimmunity in later life. The long term objective of this proposal is to test this hypothesis and elucidate the roles of the 60 kd NZB-SF in relation to autoimmunity. The immediate goals are to characterize the 60 kd NZB-SF further and to define its biological functions. For that purpose, we propose 4 specific aims. They are 1) molecular characterization of 60 kd NZB-SF by cloning genes and analyzing DNA sequence and recombinant protein products of cloned cDNA coding for the 60 kd NZB-SF, 2) identification of cellular origin of the 60 kd NZB-SF utilizing ELISA, bioassays, immunocytochemical analysis, northern blot analysis, and possibly in situ hybridization technique, 3) characterization of NZB-SF present in NZB serum using immunoaffinity membrane chromatography, 4) analyses of effects of 60 kd NZB-SF on B lymphopoiesis in vivo by administration of NZB-SF to mice of non-autoimmune strains or alternatively by administration of mAb against NZB-SF to young NZB mice.
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