MECHANISMS OF ENHANCEMENT OF INNATE IMMUNITY

要求提供支助，以使候选人能够在1999年与九州大学的矢野智树博士进行合作研究，并在那里停留9个月。将有一次返回美国的行程，以协调国内大学的研究。这次访问(休假的一部分)有两个目的：启动一项涉及豁免基本方面的合作(见下文)，并为申请人提供专业知识，以利于后续研究。对佐剂和免疫增强剂作用机制的研究有助于我们了解辅助细胞和细胞因子在免疫反应中的协调作用。通过巨噬细胞激活或诱导肝脏急性时相反应来增强先天免疫，当在感染之前实现时，可能会影响感染的结局。事实上，在接种疫苗之前合理地操纵先天免疫可能被证明是在免疫规划中实现理想结果的一种手段。这项研究的长期目标包括更全面地了解肝脏急性时相反应的演变(反映在特定血浆蛋白浓度的变化中)及其诱导。具体目标包括克隆和测序模式生物(彩虹鲑鱼)中两个阳性急性时相蛋白的基因，以及确定这些基因在不同刺激因素刺激下的转录和翻译动力学。目前，血浆中的急性时相蛋白被用于组织损伤和败血症的诊断，但其作为治疗突变剂的潜在医疗价值尚未被充分认识。通过了解这些保护蛋白在更原始的物种(适应性免疫系统不太发达)中的完整功能谱，我们预计在兽医物种中验证后，将有洞察力导致此类治疗用途在人类医学中的应用。

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.