The objectives of the research are to understand how natural small lipid molecules called prostaglandins (PGs) regulate normal and malignant B and T lymphocytes. The hypothesis developed by the investigator's laboratory is that prostaglandin E2 (PGE2), the major PG found in the lymphocyte milieu, is not solely immunoinhibitory, but also exhibits positive regulatory influences on B lymphocytes, shapes the class of immunoglobulin secreted and controls the types of cytokines produced by T lymphocytes. In support of this concept, this lab discovered that PGE2, which mainly signals via cAMP, is a powerful promoter of B lymphocyte immunoglobulin class switching to IgE. In contrast, 15-deoxy PGJ2, is strongly inhibitory for normal and cancerous B lymphocytes. A second key concept is that PGE2 tips the 'immunologic balance' away from a TH1 cytokine response and towards a TH2 response. The focus of this project is to study the mechanisms by which key PGs control normal and malignant B lymphocyte activation and differentiation and to ascertain how they regulate T lymphocyte development into TH1 and TH2 cells. The investigator will answer the following four questions to accomplish these goals. (1) What are the functional consequences of exposure to 15-deoxy-PGJ2 and by what mechanisms does it so profoundly inhibit normal and cancerous B lineage cell activation and growth? (2) Why do Balb/c mice generate exuberant PGE2 responses in contrast to C57BL/6 mice and is this the reason that these strains are predisposed to generate TH2 and TH1 cytokine responses, respectively? (3) Can naive T lymphocytes be preferentially driven in vitro to generate a TH1 or TH2 cytokine response by manipulation of the prostaglandin environment? (4) Can a TH1 or TH2 lymphocyte response be elicited in vivo by regulating exposure to prostaglandins? These studies will provide a basis for understanding the mechanisms whereby prostaglandins regulate the growth and differentiation of normal and malignant B- and T-lineage cells. Potential applications of this project include: targeting PG receptors on malignant B lymphoma cells to kill them, understanding how the abundance of PGs in periodontal disease contributes to disease progression, and using selected PGs or inhibitors thereof to generate polarized TH1 or TH2 responses. These applications are important in developing vaccines for cancer and infectious diseases where specific TH1 or TH2 responses are most efficacious. Immunodeficient patients such as the very young and elderly and those afflicted with cancer and AIDS might benefit from approaches to shape the immune response to vaccination at the outset.
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