MODIFICATION OF REGULATORY T-LYMHOCYTE FUNCTION

该项目的长期目标是阐明其机制

The long-term goal of this project is to elucidate the mechanisms by which autacoids (i.e. "local hormones") modulate T-lymphocyte function. We have focused our attention upon the immunoregulatory properties of adenosine (Ado). Ado is liberated from hypoxic cells and in the course of inflammatory reactions. We have previously shown that brief exposure of human T- lymphocytes to low concentrations of Ado (1 uM) causes rapid but selective alteration in the expression of T-cell surface antigens (e.g. T4, T8) and receptors (Fc) and induces the activation of a suppressor cell of T-cell dependent B-cell differentiation. These events are mediated by cell surface Ado receptors. In recent years there has been considerable progress in the characterization of Ado receptor subtypes. We hypothesize that Ado, acting via specific Ado receptors, modulates the expression of cell surface structures whose function relates directly to adenosine's ability to alter T-lymphocyte immunoregulatory behavior. To investigate this hypothesis we propose to (1) determine the Ado receptor specificity of Ado mediated immunologic events using Ado receptor specific agonists and antagonists, (2) study the distribution of Ado receptor subtypes on T-lymphocyte subsets using Ado receptor specific monoclonal antibodies as well as specific agonists and antagonists and correlate Ado receptor distribution on T-cell subsets to their immunoregulatory function and (3) identify cell surface antigens newly expressed on Ado activated suppressor cells and investigate their role in Ado- induced immunosuppression. This will be done be developing monoclonal antibodies to "adenosine activation antigens" (AAA). Based upon our preliminary observations that Ado activated suppressor cells function by limiting the availability of B-cell growth- and differentiation factors (BCGF, BCDF) we will investigate the specificity of these effects on BCGF and BCDF from various sources as well as on other lymphokines and examine the role of AAA in regulating BCGF and BCDF metabolism. We will also (4) identify the Ado receptors responsible for Ado induced alterations in phospholipid and arachidonic acid metabolism and (5) further characterize the Ado receptor specificity, target cells and role of AAA in the phenomenon of Ado enhancement of responses to allogeneic cells. The adenosine immunoregulatory system may be a physiologically important one and study of the Ado receptor specificity of these immunoregulatory events may ultimately lead to greater ability to modulate specific immunoregulatory functions using Ado receptor specific agonists and/or antagonists.