A depressed immune response appears to be responsible for the impairment in host defense following hemorrhage and trauma. We have found a multitude of functional abnormalities in post-hemorrhage T cells. Initial studies showed that certain functions of B cells are also abnormal. A 16000 Dalton polypeptide present in hemorrhagic serum was isolated, partially sequenced, and found to activate suppressor T cells. These activated suppressor T cells are responsible for most, if not all, observed abnormalities. With the long term goal of elucidating the events that lead to the impairment of host defense following hemorrhage and trauma and to assess potential clinical usefulness of the suppressor cell activating factor (SCAF), it is the objective of this proposed investigation to (1) further characterize hemorrhage-induced alterations in B cell activities and antibody response; (2) ascertain the mechanisms of action of SCAF at the subcellular and molecular levels; and (3) test our hypothesis that post-hemorrhage immunodepression and propensity for developing infection can be prevented or reversed by parental administration of anti-SCAF or anti-SCAF-receptor antibodies. Specifically, we propose to (1) determine effects of hemorrhage on serum levels of bacterial antigen specific antibodies and the number, percentages, as well as activities of antigen specific splenic plasma cells; (2) determine the effects of hemorrhage on antibody response of pulmonary mucosal plasma cells; (3) assess possible hemorrhage-induced alteration in the regulation of antibody response by determining interactions of B cells with helper T cells, suppressor T cells, and the idiotype network following hemorrhage; (4) prepare synthetic and recombinant SCAF, anti-SCAF antibodies and anti-SCAF-receptor antibodies; (5) determine effects of parental administration of anti- SCAF or anti-SCAF-receptor antibodies on hemorrhage-induced depression of immune response; (6) assess possible protective effect of anti-SCAF or anti-SCAF-receptor antibodies against experimental pneumonia in the mouse; (7) ascertain mechanisms of action of SCAF at the cellular, subcellular and molecular levels by determining its effects on the generation and release of mediators, cytoplasmic enzyme activation, nuclear ornithine decarboxylase induction, and polyamine biosynthesis. Results generated from these studies should lead to a better understanding of the impairment of host defense against infections that occurs following hemorrhage and trauma as well as permit the development of methodologies, such as the measurement of SCAF blood levels, for identifying patients with hemorrhagic, traumatic, or thermal injuries who are at particularly high risk of infections. Experimental validation of our hypotheses that post-hemorrhage immunodepression and propensity for developing infections can be prevented and/or reversed by parental administration of anti-SCAF or anti-SCAF-receptor antibodies should provide new approaches for clinical management of critically III trauma patients. Looking beyond the present proposal, the role(s) of SCAF in regulating normal immune response and in mediating immune depressions in aging, as well as its potential clinical usefulness in organ transplantation and in the treatment of auto-immune disease such as systemic lupus erythematosus (SLE) or type 1 diabetes mellitus are important areas for future investigation.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM039102-07
Application #
2179689
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Project Start
1988-02-01
Project End
1996-01-31
Budget Start
1994-02-01
Budget End
1996-01-31
Support Year
7
Fiscal Year
1994
Total Cost
Indirect Cost
Name
University of California Los Angeles
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
119132785
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Abraham, E; Jesmok, G; Tuder, R et al. (1995) Contribution of tumor necrosis factor-alpha to pulmonary cytokine expression and lung injury after hemorrhage and resuscitation. Crit Care Med 23:1319-26
Abraham, E; Bursten, S; Shenkar, R et al. (1995) Phosphatidic acid signaling mediates lung cytokine expression and lung inflammatory injury after hemorrhage in mice. J Exp Med 181:569-75
Schwartz, M D; Repine, J E; Abraham, E (1995) Xanthine oxidase-derived oxygen radicals increase lung cytokine expression in mice subjected to hemorrhagic shock. Am J Respir Cell Mol Biol 12:434-40
Shenkar, R; Abraham, E (1995) Effects of treatment with the 21-aminosteroid, U7438F, on pulmonary cytokine expression following hemorrhage and resuscitation. Crit Care Med 23:132-9
Meade, P; Shoemaker, W C; Donnelly, T J et al. (1994) Temporal patterns of hemodynamics, oxygen transport, cytokine activity, and complement activity in the development of adult respiratory distress syndrome after severe injury. J Trauma 36:651-7
Donnelly, T J; Meade, P; Jagels, M et al. (1994) Cytokine, complement, and endotoxin profiles associated with the development of the adult respiratory distress syndrome after severe injury. Crit Care Med 22:768-76
Shenkar, R; Coulson, W F; Abraham, E (1994) Anti-transforming growth factor-beta monoclonal antibodies prevent lung injury in hemorrhaged mice. Am J Respir Cell Mol Biol 11:351-7
Shenkar, R; Coulson, W F; Abraham, E (1994) Hemorrhage and resuscitation induce alterations in cytokine expression and the development of acute lung injury. Am J Respir Cell Mol Biol 10:290-7
Shenkar, R; Chang, Y H; Abraham, E (1994) Cytokine expression in Peyer's patches following hemorrhage and resuscitation. Shock 1:25-30
Abraham, E; Allbee, J (1994) Effects of therapy with interleukin-1 receptor antagonist on pulmonary cytokine expression following hemorrhage and resuscitation. Lymphokine Cytokine Res 13:343-7

Showing the most recent 10 out of 33 publications