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.
Showing the most recent 10 out of 33 publications
