GERMINAL CENTERS, ANTIBODY PRODUCTION, AND LYMPHOMA

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In this project #2 of an IRPG request, the relationship between germinal center (GC) formation in lymphoid tissues and spontaneous lymphomas (RCS) in aging SJL mice will be explored with the aid of a few transgenic mouse models. Our recent findings show that these lymphomas express an mtv- "RCS"-LTR encoded superantigen (vSAG) and receive growth promoting help through the cytokine formation induced in the Vbeta16 T cells that this vSAG stimulates. The possibility that normal GC cells which are thought to be the precursor cells of RCS, express this same vSAG in SJL mice will be examined, making use of I-E transgenic mice that specifically express I-E in GC and not in other B cells. Three different constructs will be used to prepare mtv-RCS-LTR transgenic SJL mice, in one of these the transgene expression targeted to B cells, to determine the influence of this transgene on Vbeta16 T cell deletion, on GC formation and on paraprotein production. The effect of the bcl-2 transgene in SJL mice on GC formation and on their resistance to glucocorticosteroid-induced apoptosis will be studied in parallel with effects on antibody and paraprotein production, as well as lymphoma development. In addition, mice transgenic for an anti-TNP IgH + L chain combination (Sp6), consisting of mu-kappa, will be studied for their ability to make anti-TNP bearing GC cells. Their sensitivity to tolerance induction at the GC precursor cell level (J11D1o) in the presence and absence of the bcl-2 transgene will be evaluated. The Ig gene V regions of lymphomas arising in Sp6 transgenic mice, will be examined for somatic mutations. In all these experiments, a close collaboration will be maintained with Dr. N.M. Ponzio, who will be examining the effect of some of the transgenes on lymphoma formation and the influence of Vbeta16 T cell modulation on lymphoma growth in project #1 of this IRPG.