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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM034021-02
Application #
3284398
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Project Start
1985-04-01
Project End
1988-03-31
Budget Start
1986-04-01
Budget End
1987-03-31
Support Year
2
Fiscal Year
1986
Total Cost
Indirect Cost
Name
Weill Medical College of Cornell University
Department
Type
Schools of Medicine
DUNS #
201373169
City
New York
State
NY
Country
United States
Zip Code
10065
Hawes, A S; Richardson, R P; Antonacci, A C et al. (1995) Chronic pathophysiologic elevation of corticosterone after thermal injury or thermal injury and burn wound infection adversely affects body mass, lymphocyte numbers, and outcome. J Burn Care Rehabil 16:1-15
Calvano, S E; Barber, A E; Hawes, A S et al. (1992) Effect of combined cortisol-endotoxin administration on peripheral blood leukocyte counts and phenotype in normal humans. Arch Surg 127:181-6
Silen, M L; Hesse, D G; Felsen, D et al. (1989) Cachectin/tumor necrosis factor production by fetal and newborn rat hepatic macrophages. J Pediatr Surg 24:34-8;Discussion 38
Organ, B C; Antonacci, A C; Chiao, J et al. (1989) Changes in lymphocyte number and phenotype in seven lymphoid compartments after thermal injury. Ann Surg 210:78-89
Richardson, R P; Rhyne, C D; Fong, Y et al. (1989) Peripheral blood leukocyte kinetics following in vivo lipopolysaccharide (LPS) administration to normal human subjects. Influence of elicited hormones and cytokines. Ann Surg 210:239-45
Calvano, S E; deRiesthal, H F; Marano, M A et al. (1988) The decrease in peripheral blood CD4+ T cells following thermal injury in humans can be accounted for by a concomitant decrease in suppressor-inducer CD4+ T cells as assessed using anti-CD45R. Clin Immunol Immunopathol 47:164-73
Warren, R S; Starnes Jr, H F; Alcock, N et al. (1988) Hormonal and metabolic response to recombinant human tumor necrosis factor in rat: in vitro and in vivo. Am J Physiol 255:E206-12
Inturrisi, C E; Branch, A D; Robertson, H D et al. (1988) Glucocorticoid regulation of enkephalins in cultured rat adrenal medulla. Mol Endocrinol 2:633-40
Inturrisi, C; Franklin, S; Shapiro, J et al. (1988) Adrenal enkephalin biosynthesis regulated by glucocorticoid. NIDA Res Monogr 81:129-35
Calvano, S E; Greenlee, P G; Reid, A M et al. (1988) Granulocyte contamination of Ficoll-Hypaque preparations of mononuclear cells following thermal injury may lead to substantial overestimation of lymphocyte recovery. J Trauma 28:353-61

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