The objectives of the research are to delineate the mechanisms underlying thermal injury-associated immunosuppression and to develop therapeutic modalities efficacious in preventing or attenuating this hyporesponsive immunologic state. Data suggest that changes in endocrine status, especially concentrations of corticosteroid hormones, contribute greatly to burn-associated immunosuppression by inducing sequestration of helper T-cells in inappropriate lymphoid compartments such as the bone marrow. Direct and/or syngeristic inhibitory effects of corticosteroids prostaglandins and catecholamines also are considered as contributing factors in devlopment of depressed immunologic function following thermal injury. Specifically, the proposed research will evaluate in mice the relationship between burn injury, hormonal activity sand immune function by: 1) correlating thermal injury-induced changes in plasma corticosteroid concentrations with both changes in functional immunologic activity and lymphocyte distribution patterns; 2) manipulating plasma corticosteroid levels in unburned mice to determine if functional and distributional immunologic changes occur in a manner similar to that observed in burned mice; 3) developing a therapeutic means of modulating adrenal activity in mice and evaluating immune function and lymphocyte distribution in thermally injured mice undergoing such therapy; 4) assessing the in vitro ability of lymphocytes from thermally-injured mice and humans to proliferate with and without the exogenous addition of corticosteroids and other immunomodulatory hormones known to be affected by thermal injury; 5) evaluating the effect of thermal injury on levels of lymphocyte cyclic nucleotides and identifying differential effects of hormones on cyclic nucleotide levels in lymphocytes from burned versus normal subjects. Corticosteroids will be quantified by RIA. Changes in lymphocyte distribution will be evaluated by two methods. First, cells from various lymphoid organs will be phenotyped by fluorescence flow cytometry. Second, migration of 51Cr-labeled T-cells will be assessed. This will be accomplished both by injection of labeled cells from burned mice into normal mice and injection of labeled cells from normal mice into burned mice. Proliferation will be assessed by mitogen stimulation and the autologous/syngeneic mixed lymphocyte reaction. Cyclic nucleotides will be extracted from lymphocytes, column purified, and quantified by RIA.
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