A XENOPUS LAEVIS RESEARCH RESOURCE FOR IMMUNOBIOLOGY

描述(由申请人提供)：非洲爪哇长期以来一直被成功地用作研究复杂免疫系统系统发育的外温脊椎动物物种。此外，莱维氏X.laevis已被证明是回答基本免疫学问题的极好的模式系统，这些问题在系统发育上不限于给定的分类单元。这在一定程度上是因为非洲爪哇免疫系统的发育有两个不同的时间：一次是在幼虫的生活中，另一次是在从具有免疫能力的幼虫到具有免疫能力的成虫的变态转变过程中。由于幼虫是自由游动的，可以接受各种手术和非手术干预，因此可以获得从哺乳动物宫内研究中无法获得的有价值的信息(例如，对成体特定抗原的自我耐受性的发展，第二个T细胞库的获得，以及自然环境中T细胞亚群的个体发育)。 此外，变态是由激素驱动的，这使得可以在发育中的免疫系统中检查与免疫相关的神经内分泌-免疫系统的相互作用。非洲爪哇免疫学的另一个关键方面使其成为一个重要的模型是有充分证据证明在变态幼虫前期缺乏经典和非经典的MHC-I类表达。最后，表达或缺乏MHC I和II类分子的可移植肿瘤细胞系也有助于非洲爪哇作为自然产生的“基因敲除”物种的使用。这项建议的主要目标是通过以下方式进一步发展非洲爪哇作为非哺乳动物免疫生物学模型：(1)确保非洲爪哇不同克隆、品系和物种的系统繁育和饲养；(2)组织科学界随时可用的信息和现有研究材料(如细胞系、DNA文库、单抗、动物)的中央储存库；以及(3)产生免疫学研究的新工具(如新的单抗、cDNA文库、细胞系、转基因青蛙)。许多现有的和新的研究领域应该会从实现这些目标中受益。我们展望了莱氏X.laevis的进一步发展：(1)肿瘤免疫；(2)个体发育过程中的自我耐受和自身免疫；(3)宿主-病原体相互作用；(4)基因组进化和基因组调控；(5)免疫毒理学(如内分泌干扰物)；(6)热休克蛋白在免疫中的作用；(7)非经典MHC I类抗原的功能；以及(8)Toll样受体(结构和功能)在免疫中的进化。

DESCRIPTION (provided by applicant): Xenopus laevis has long been used successfully as the ectothermic vertebrate species of choice for studying the phylogeny of the complex immune system. In addition, X. laevis has proved to be an excellent model system for answering fundamental immunological questions that are not phylogenetically restricted to a given taxon. In part, this is because development of the Xenopus immune system occurs at two distinct times: once during larval life, and then again during the metamorphic transition from immunocompetent larva to immunocompetent adult. Since the larval form is free-swimming and amenable to a variety of surgical and nonsurgical interventions, valuable information can be obtained that is not possible to obtain from in utero studies of mammals (e.g., development of self-tolerance to adult specific antigens, acquisition of a second T-cell repertoire, and ontogeny of T-cell subsets in a natural setting). Moreover, metamorphosis is hormonally driven which permits examination of immunologically relevant neuroendocrine-immune system interactions in a developing immune system. Another critical aspect of Xenopus immunology that makes it important as a model is the well-documented absence of classical and non-classical MHC class I expression during the pre-metamophic larval period. Finally, transplantable tumor cell lines that either express or lack MHC class I and II molecules also contribute to the use of Xenopus as a naturally-occurring "knockout" species. The broad objectives of this proposal are to further develop Xenopus laevis as a non-mammalian immunobiologically-focused model by: (1) assuring the systematic breeding and husbandry of different clones, strains, and species of Xenopus; (2) organizing a central repository of information and existing research materials (e.g., cell lines, DNA libraries, mAbs, animals) readily available to the scientific community; and (3) generating new tools for immunological research (e.g., new mAbs, cDNA libraries, cells lines, transgenics frogs). Many areas of existing and new research should benefit from satisfying these aims. We envision: further development of X. laevis as: a nonmammalian model for studying: (1) tumor immunity; (2) self-tolerance and autoimmunity during ontogeny; (3) host-pathogen interactions; (4) genome evolution and genomic regulation; (5) immunotoxicology (e.g. endocrine disruptors); (6) the role of heat shock proteins in immunity; (7) the function of nonclassical MHC class I antigens; and (8) the evolution of toll-like receptors (structure and function) in immunity.