MECHANISMS OF ENHANCEMENT OF INNATE IMMUNITY

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Support is requested to enable the candidate to conduct collaborative research with Dr. Tomoki Yano, Kyushu University, in 1999, remaining there for 9 months. One return trip to the U.S. will be made to coordinate research at the home university. The visit (part of a sabbatical) is for a dual purpose: initiation of a collaboration that addresses basic aspects of immunity (see below), and equipping the applicant with expertise to benefit subsequent research. Research to understand mechanisms of action of adjuvants and immuno-potentiators has contributed to our knowledge of the roles of accessory cells and cytokines in orchestration of immune responses. Potentiation of innate immunity, by means of macrophage activation or induction of the hepatic acute phase response, when achieved in advance of an infection, may influence the outcome of that infection. Indeed, rational manipulation of innate immunity prior to vaccination may prove to be a means of achieving desirable outcomes in immunization programs. The long-term objectives of the research include achievement of a fuller understanding of the evolution of the hepatic acute phase response (as reflected in altered concentrations of specific plasma proteins), and its induction. Specific aims include the cloning and sequencing of genes for two positive acute phase proteins in the model organism (rainbow trout), and determination of the kinetics of transcription and translation of these genes following stimulation by different agents. At the present, acute phase proteins in plasma are used diagnostically in relation to tissue damage and septicemia, but their potential medical utility as therapeutants is under-realized. By knowing the full functional repertoire of these protective proteins in more primitive species (in which the adaptive immune system is less well developed), we anticipate insights that will lead to such therapeutic uses in human medicine, after validation in veterinary species.