The long-term objective of the studies described in this proposal is to understand how the expression of a major cross reactive idiotype (CRI) in distinct B cell subpopulations ultimately affects the production of CRI+ antibody in vivo. As a model system we are examining the CRI associated with the anti-p-azophenylarsonate antibody response of A strain mice. We have recently shown that this idiotype is expressed in distinct B cell subpopulations. CRI+ antibodies are derived from a single VH structural gene. The proposed research will examine: (1) the induction requirements for CRI production in distinct B cell sets, as well as the sensitivity of distinct B cell sets to suppression; (2) the interactions between distinct B cell sets and T cells that lead to the generation of idiotye specific T regulatory cells; and (3) the process of antibody diversification in distinct B cell subpopulations. Induction requirements will be established for distinct B cell sets by in vitro techniques using cloned carrier-specific T cells, in combination with idiotype-specific T helper populations. Suppression will be assessed in vitro and by adoptive transfer using allotypically defined B and allelically distinct T cell populations. Antibody diversification will be examined in homogeneous populations by examining the product of hybridomas from distinct B cell subpopulations by analysis of CRI+ antibody using: protein sequencing, affinity determinations, and idiotope analysis. Hybridomas will also be analyzed by molecular biological techniques to determine the structural gene used, and nucleic acid sequence of the mRNA for CRI+ antibody. Diversification will be examined in heterogeneous populations by examining: affinity maturation, isoelectric focusing patterns combined with idiotype analysis using monoclonal anti-CRI antibodies, and by radioimmunoassays that detect specific idiotype loss. Defining the interactions of distinct B cell sets with T regulatory cells should provide information useful for determining the prognosis, or for establishing treatments for various B cell malignancies.
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