Our general goal is to understand the relationship of Ii to the expression, cycling, and function of Ia on normal and transformed cells. Several model systems of leukemic, virus-transformed or activated normal lymphoid cells demonstrate Ii hyperexpression and can be used to define mechanisms regulating Ii synthesis, processing, and influence on Ia function. These models include cells of a unique subset of patients with hairy cell leukemia, P3HR-1 Epstein-Barr virus (EBV) superinfected Raji cells, butyrate-treated P3HR-1 lymphoblastoid cells, and polyclonally-activated B and T lymphocytes. Variations in structure and rates of processing of Ii and Ia in these systems will be quantitated, including definition of post-translational modifications and kinetic analysis of mRNA structure and amounts in these cells as a function of transformation or activation. Structural epitopes on Ii will be defined with monoclonal antibodies and related to external and internal domains to sites of interaction with Ia and to expression of function. Hypotheses to test the function of Ii will include: (1) the view that Ii is a transporter of Ia to membranal-coated pits where it remains as a potential receptosome anchor protein (an entity postulated by Pastan et al.); (2) that Ii directs, further, the cycling of Ia which has been expressed on the cell surface into receptosomes within the cell; (3) that a small but identifiable subpopulation of li molecules operates as a transducer of Ia function; and (4) that Ii interacts with membrane molecules in addition to Ia and could be an oncogene product or induced by oncogene function. While this project should well define structure of Ii in terms of chemistry, kinetics, and immunogenic domains, we expect to relate these basic findings to the function of Ii. In particular, we seek to explain why Ii is so prominently expressed on some B-lineage human leukemias, on EBV-superinfected cells (as a principal, host cell gene-coded, EBV-induced protein), and (apparently, transiently) on activated normal lymphocytes. Understanding such processes leads to a better understanding of the immunobiology of these cell populations and could contribute to developing options to therapeutically alter that biology. (AG)

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National Cancer Institute (NCI)
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Immunobiology Study Section (IMB)
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University of Massachusetts Medical School Worcester
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