MECHANISMS OF ENHANCEMENT OF INNATE IMMUNITY

请求提供支助，使候选人能够在1999年与九州大学的Tomoki Yano博士进行合作研究，并在那里停留9个月。 一次返回美国的旅行将在家乡大学协调研究。这次访问（作为休假的一部分）有双重目的：启动一项涉及免疫基本方面的合作（见下文），并使申请人具备专门知识，以利于随后的研究。 了解佐剂和免疫增强剂的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应答协调中的作用。 通过巨噬细胞活化或诱导肝脏急性期反应增强先天免疫，当在感染前实现时，可能会影响感染的结果。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计划中实现理想结果的一种手段。 该研究的长期目标包括更全面地了解肝脏急性期反应的演变（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的基因为两个积极的急性期蛋白的模式生物（虹鳟鱼），并确定这些基因的转录和翻译的动力学刺激后，不同的代理商。 目前，血浆中的急性时相蛋白被用于与组织损伤和败血症相关的诊断，但它们作为治疗剂的潜在医学用途尚未得到充分认识。 通过了解这些保护性蛋白在更原始物种（其中适应性免疫系统发育不太好）中的全部功能，我们预计在兽医物种中验证后，将导致人类医学中的这种治疗用途。

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.