EFECTS OF STRESS IN IMMUNOCOMPROMISED HOSTS

University Of Rochester, Rochester NY

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Abstract

DESCRIPTION: A large literature unequivocally reveals that exposure of humans and experimental animals to psychological and physical stressors can be immunomodulatory. Very few studies, however, support the popular notion that this immunomodulation typically and causally relates to a clinically significant increase in the incidence and/or severity of infectious disease. We hypothesize that although the immune system in healthy individuals may be modulated by stressor exposure, the resulting changes in immune function may not be of sufficient magnitude or duration to render that individual clinically immunodeficient in terms of the ability to effectively combat opportunistic pathogens. Further, if the immune system is compromised either naturally or artificially (e.g., by immunosuppressive drug therapy), this lower "immune system set point" now puts the organism at a greater relative health risk when exposed to an immunomodulatory stressor. Many pharmacologically immunosuppressed transplant and other patients perceive significant levels of stress, and become ill with potentially lethal opportunistic viral infections. As for the fate of a transplant, however, we hypothesize that immunosuppression induced by stressors should interact with drug treatment to increase allograft survival. The overall goal of our proposed research is to understand the impact of a stressor in an organism whose immune response capacity has already been lowered by deliberate pharmacological immunosuppression. We are particularly interested in understanding whether stressors in mice subjected to immunosuppressive regimens can result in increased graft survival. We are also interested in determining if stress and drug-induced immunosuppression interact to adversely affect the number of, and/or recovery from, opportunistic infections. Initial studies will be performed with the broadly immunosuppressive reagent cyclophosphamide (CY) to test our hypothesis. Later studies will employ the targeted reagent cyclosporin A (CsA), to establish the principle or generality of the finding and to begin to determine mechanisms. The administration of a stressor to an immunocompromised animal will increase the magnitude of immunosuppression. In turn, this will result in prolonged allograft survival. In contrast, the immunocompromised animal will have poorer immune responses to an opportunistic pathogen (HSV-1).