CROSS REGULATION OF T CELL EFFECTOR FUNCTION USING GENE THERAPY

对自身抗原耐受性的破坏是由于免疫调节的失调。 防止自身免疫的机制。 的不同子集 T细胞可以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）的抗原呈递- 编码的I类应答细胞将影响T细胞的表型， 辅助细胞 利用基因疗法，质粒DNA编码的肽 将被选择性地加载到MHC I类复合物上， 不存在II类限制性肽。 外周T细胞反应 然后通过类似地引入异位共刺激物 在同一注射部位注射。 所选的肽用于 研究是一种充分描述的细胞毒性T淋巴细胞的衍生物 先前报道的表位具有部分激动剂 或拮抗剂性质的T细胞克隆反应的原始 肽。 预先预致敏的CD 8+隔室可 建立影响CD 4+后期反应的条件 当动物用全蛋白质激发时， in vivo. 用来自未突变抗原的肽引发可能不会 影响随后的CD 4+应答的表型， 这表明，这些隔间可以协调地运作， 应答 通过改变肽配体， 与不同T细胞群体相互作用的亲合力 一个隔室在体内对另一个隔室的不同影响， 诱导。用改变的肽配体引发的效果可以 不可直接测量，且可通过变化间接检测 对后续蛋白质挑战的自然反应。 治疗 在抗原性之前或之后接受这种形式治疗的动物 已知蛋白质的挑战可以被抑制，则该模式可以 容易适应于被定义的元素被 引入免疫系统。最终的目标是开发 一种安全有效的方法， 反应

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.