CELLULAR MECHANISMS OF HEMORRHAGED-INDUCED SUPPRESSION

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Despite the availability of a variety of antimicrobial agents and rigorous prophylactic therapy, infections are the major cause of morbidity and mortality after traumatic injuries or burns. A depressed cell-mediated immune response appears to be primarily responsible for the impairment in host defense. We have found that unanesthetized hemorrhage in "untraumatized" animals was sufficient by itself to bring about a state of immune depression manifested by a reduced T cell proliferation in response to mitogen stimulation as well as the production of IL-2. We have found further that a serum immunosuppressive factor (SIP) with a molecular weight between 13,000 and 23,000 appears to be responsible for the alterations in lymphocyte proliferative response observed after hemorrhage. With the long term goal of elucidating the events that lead to an impairment in host defense following hemorrhage and trauma and to explore possible clinical applications of SIP, it is the objective of this proposed investigation to characterize the hemorrhage-induced alterations of immune response against specific antigens in vivo, and to test our hypotheses that (1) the hemorrhage-induced suppression of immune response is mediated by SIP and (2) SIP suppresses immune response through activation of suppressor T cells and consequently reduce the production of interleukin 2 (IL-2) by helper T cells. Specifically we propose to: (1) determine effects of hemorrhage on the development as well as the effector phase of immune response against antigens in vivo by measuring DTH, CTL, and levels of circulating antibodies in animals immunized with EL4 cells; (2) determine the subclass(s) of lymphocytes responsible for the observed alterations in immune response; (3) determine if all in vivo alterations of immune response brought about by hemorrhage can be reproduced in rats by i.v. administration of SIP alone; (4) elucidate the mechanism of action of SIP by determining its effects on mononuclear cell interactions and production of lymphokines. 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 and provide information which may permit the development of methods to identify trauma patients who are at particularly highly risk of infection as well as suggest unique therapeutic approaches to correct such conditions.