The present proposal is designed to study T cell subsets and macrophages in the uremic experimental rat model, both phenotypically and functionally. The severely suppressed cell mediated immunity in uremia suggests that the cells involved in cellular immunity, T cells and macrophages, are defective. Indeed, our results to date indicate that this is the case as both the uremic Ia- suppressor macrophages, and defective T cells contribute to the observed immunosuppression. To better define the mechanism responsible for this suppression, the various T cell subsets and macrophages will be further studied in uremia both functionally and phenotypically. The function of uremic T cell subsets in such responses as proliferation to alloantigens, autoantigens, and antigens, and in cell mediated lympholysis, graft versus host response, natural killer cell activity, T cell dependent antibody response, and production of interleukin-2 will be examined. Such studies will provide us with information about which T cell subset is affected in uremia, and to what extent. Furthermore, it potentially will allow for the development of new therapeutic approaches. In addition, the interactions between the potent Ia- suppressor uremic macrophages and T cells will be studied with emphasis on elucidating the mechanism behind this suppressor activity. Monoclonal-hybridoma antibodies will be raised to the Ia- uremic suppressor macrophages in order that we might further study these cells and possibly provide a new therapeutic approach to the severely suppressed cell mediated immunity in uremia. Furthermore, we plan to study the suppressor serum factor(s), its biochemical characteristics, its target cell, and the mechanism by which it acts. In summary, the primary emphasis of this proposal is to study and define the T cell subsets and macrophages which are affected in uremia. We will determine how this occurs and also study the mechanism(s) responsible for the severe immunosuppression in uremia. Since a major cause of death in uremic patients is infection and since these patients have a higher incidence of malignancies, this study is of importance as it attempts to identify the mechanism(s) behind the observed immunosuppression. In turn, this knowledge may potentially be applied to the human system and will hopefully lead to new therapeutic approaches and improvement in survival rates.
