CROSS REGULATION OF T CELL EFFECTOR FUNCTION USING GENE THERAPY

对自身抗原耐受性的破坏是由于 保护自身免疫的机制。的不同子集 T细胞可能通过相互交叉调节来促进这种平衡。 在这个项目中，我们建议检查是否操纵 主要组织相容性复合体(MHC)的抗原提呈 编码的I类反应细胞将影响T细胞的表型 辅助细胞。利用基因治疗，由质粒DNA编码的多肽 将被选择性地加载到MHC I类复合体中 没有第II类限制性多肽。外周T细胞反应 然后通过类似地引入异位共刺激分子来启动 在同一注射部位的分子。所选的多肽 研究是一种众所周知的细胞毒性T淋巴细胞的来源 先前已报道的具有部分激动剂的表位 或拮抗对原始T细胞克隆起反应的特性 多肽。优先预启动CD8+隔室可以 建立影响CD4+细胞后期反应的条件 当动物被用全蛋白挑战时的隔间 在活体内。用来自未突变抗原的多肽启动可能不会 影响随后的CD4+反应的表型，这将 建议这些舱室可以协调地运行在他们的 回应。通过改变多肽配体和可能的 不同T细胞群相互作用的亲和力A谱 体内一个隔室对另一个隔室的不同影响可能是 诱导性。用改变的多肽配体启动的效果可能 不可直接测量，并可通过变化间接检测 在对后续蛋白质挑战的自然反应中。治疗 在抗原之前或之后使用这种形式的治疗的动物 可以抑制对已知蛋白质的挑战，然后该方案可以 容易适应定义的元素正在被 进入免疫系统。最终目的是要发展 一种安全有效的流产有害自身免疫的方法 回应。

A breach in tolerance of self antigens results from a dysregulation of mechanisms that protect against autoimmunity. Different subsets of T cells may contribute to this balance by crossregulating each other. In this project we propose to examine whether manipulation of antigen presentation of major histocompatibility complex (MHC)- encoded class I responsive cells will influence the phenotype of T helper cells. Using gene therapy, peptides encoded by plasmid DNA will be selectively loaded onto MHC class I complexes in the absence of class II-restricted peptides. A peripheral T cell response will then be initiated by similarly introducing ectopic costimulator molecules at the same site of injection. The peptides selected for study are derivations of a well described cytotoxic T lymphocyte epitope that have been previously reported as having partial agonist or antagonist properties to T cell clones reactive to the original peptide. Preferentially prepriming the CD8+ compartment may establish conditions that influence the later response of the CD4+ compartment when the animals are challenged with the whole protein in vivo. Priming with a peptide from an unmutated antigen may not effect the phenotype of the subsequent CD4+ response, which would suggest that these compartments can operate concordantly in their responses. By changing the peptide ligand and presumably the avidity of the interaction with different T cell populations a spectrum of different effects of one compartment on the other in vivo could be induced. The effect of priming with an altered peptide ligand may not be directly measurable and be indirectly detectable by a change in the natural response to a subsequent protein challenge. Treatment of animals with this form of therapy before or after antigenic challenge of a known protein can be suppressed then this schema can be readily adapted to situations where a defined element is being introduced into the immune system. The ultimate goal is to develop a safe and effective means of aborting a deleterious autoimmune response.