I propose to test the idea that normal immunoglobulin production is controlled by specific cellular interactions. Consistent with this hypothesis is the evidence recently obtained that genetically unexpected (latent) variable region allotypes and allotypic internal images can be routinely induced by immunizing rabbits or mice with anti-allotype antibody. In the studies described here, I intend to define the mechanism(s) for induction of unexpected allotypes and to determine the molecular basis for latent allotypes and allotypic internal images. I will assess the ability of anti-immunoglobulin antibodies to cause shifts in allotype-specific and isotype-specific regulatory influences that operate during chronic allotype suppression, normal immunoglobulin production, and antigen-induced antibody responses. The major experimental systems and methods to be employed are in vivo immunizations, in vitro culturing of cells from allotype-defined and MHC-matched rabbits, and monoclonal antibodies that display rabbit allotypic images. The information obtained should help clarify our understanding of immune system homeostasis and be of relevance for the biological modification of human immunodeficiency states such as AIDS and the immunotherapy of cancer.
