The research described is a natural extension to studies conducted during the previous period of funding. During that period, we advanced our understanding of immunoglobulin (Ig) variable region gene (V gene) expression in B cell chronic lymphocytic leukemia (CLL), the most common adult leukemia in Western societies. We identified the molecular bases for the frequent expression of autoantibody-associated cross reactive idiotypes (CRIs) in B cell CLL, generated and/or characterized mAbs reactive with additional CRIs that frequently are expressed in this disease, examined the relationship between leukemia B cells and normal B cell subsets with respect to CRI and Ig V gene expression, and initiated a limited phase I clinical trial for patients with this disease, testing the safety of synthetic peptide vaccines that correspond to Ig variable region determinants expressed by leukemia B cells. Through these studies we discerned an apparent skewing of the Ig V gene repertoire expressed by CLL B cells compared to that expressed by normal B lymphocytes. This skewing is evident when comparing the Ig heavy chain variable region third complementarity determining regions (CDR3) expressed - in CLL with that of normal B cells that use homologous Ig VH gene segments. To explore the significance of this observation, we developed a novel PCR-based assay to examine whether this skewing associates exclusively with the leukemia-cell state or merely reflects the cytogenesis of this CD5 B cell leukemia. In addition, we developed recombinant Ig expression vectors to examine whether amino-acid residues encoded by nontemplated DNA codons contribute substantially to the polyreactive autoantibody activity that frequently is associated with the Ig expressed in this disease. Finally, to enhance the potential effectiveness of vaccines for active immunotherapy of this disease, we examined for means to increase the antigen presenting capacity of CLL B cells. We discovered that crosslinking CD40 induces leukemia B cells to express B7/BB1 and other accessory molecules that are crucial for stimulatory T-B cell interactions. As a consequence, leukemia B cells become significantly more efficient at alloantigen presentation. Accordingly, we intend to examine whether strategies that incorporate CD40 cross-linking may enhance the ability of leukemia B cells to present either self- or exogenous antigens to autologous T cells in vitro. Through these studies we may appreciate whether expressed Ig contributes to this leukemia's etiopathogenesis and discover means with which to make active immunotherapy effective for this disease.
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