Immunoregulation of Autoimmunity

在这项竞争性的更新申请中提出的研究旨在确定影响机制， (1)全身施用抗-CD 3抗体，有或没有选择的TLR接合，或（2） 产生或过继转移调节性T细胞（Tcells），以阻断糖尿病前期患者向糖尿病的进展。 糖尿病或新近发作的高血糖NOD小鼠。正在研究的假设是，这些建议 治疗有一个共同的最终作用途径。 机制研究在这个建议将使用基因芯片和蛋白质表达的新方法 在Core B中可获得，以比较在处理的小鼠中观察到的基因和蛋白质表达模式与在处理的小鼠中观察到的基因和蛋白质表达模式。 与非炎症NOD.810组织（NOD）相比，正常NOD疾病进展 先前U19合同的路线图数据），以确定治疗效果消失的机制。 以下基因和蛋白质表达模式的鉴定、分析和表征 NOD小鼠成功治疗应该提供重要的见解，如作用机制、鉴定 替代效应标志物，并可能提供额外的或替代的治疗靶点。 根据我们在以往U19资助下获得的初步数据， 在成功治疗近期高血糖NOD小鼠后;（1）免疫应答的变化 胰岛浸润性T细胞的特征导致基因和蛋白质表达模式的重组， 浸润性T细胞的结构，与抑制β-受体的自身免疫破坏同时发生， 细胞，和（2）胰腺β细胞再生（伤口愈合）作为这种变化的结果。四 已提出具体目的来检验以下假设：给予内毒素污染的 抗CD 3抗体或过继细胞疗法，使用TGF 3或局部TGF β产生，直接作用于 存在于胰岛和引流淋巴结中的自身活化淋巴细胞，或者，正如我们所认为的， 睾酮直接或间接阻断胰岛β细胞破坏，促进胰岛β细胞增殖， 再生作为伤口愈合的一种形式。 这些研究直接影响了目前治疗人类新发糖尿病的一种方法，即使用 抗CD 3抗体。尽管用抗糖尿病药物治疗最近发作的高血糖NOD小鼠非常成功， 抗CD 3抗体，在人体试验中看到的反应并不壮观。如果我们的初步调查 数据是正确的，在小鼠模型中使用的抗-CD 3抗体中的污染内毒素被 协同，使用TLR激动剂与无内毒素的抗人CDS抗体协同的概念 可以在治疗近期发病或前驱糖尿病的人类疾病中提供重大的治疗进展。

Studies proposed in this competing renewalapplication intend to identify the mechanisms of effect that allow (1) systemic administration of anti-CD3 antibody with or without selected TLR engagement or (2) the generation of, or adoptive transfer of, regulatory T cells (Tregs), to block progression to diabetes in pre- diabetic or recent onset hyperglycemic NOD mice. The hypothesis being studied is that these proposed therapies share a final common pathway ofeffect. Mechanistic studies in this proposal will use cDNA microarray and novel methods of protein expression available in Core B, to compare gene and protein expression patterns seen in treated mice to those seen in normal NOD disease progression when comparedto patterns seen in non-inflamed NOD.810 tissues (NOD Roadmap data from previous U19 contract),to identify the mechanism(s)of the observedtherapeutic effect. Identification, analysis and characterization of gene and protein expression patterns seen following successful therapy of NOD mice should provide important insights into mechanism of effect, identify surrogate markersof effect, and potentially provide additional or alternative targets for therapy. According to our preliminary data obtained under previous U19 funding, two major phenomenon occur following successful therapy of recently hyperglycemic NOD mice; (1) a change in the immune response profile of islet-infiltrating T cells leading to a reorganization of the gene and protein expression patterns and the architecture of the infiltrating T cells, co-incident with inhibition of the autoimmune destruction of beta cells, and (2) pancreatic beta cell regeneration (wound healing) as a consequence of this change. Four Specific Aims have been proposed to test the following hypothesis: administration of endotoxin contaminated anti-CD3 antibody or adoptive cellular therapy, using Tregs or local TGFp production, acting directly on autpreactive lymphocytes present in the islets and draining lymph nodes, or, as we believe, by activating Tregs, either directly, or secondarily blocks islet beta cell destruction and facilitates islet beta cell regeneration as a form of wound healing. These studies have direct impact on one current therapy of recent onset diabetes in man, the use of anti-CD3 antibodies. Despite extremely successful treatment of recent onset hyperglycemic NOD mice with anti-CD3 antibodies, responses seen in the human trials have been less than spectacular. If our preliminary data are correct, that contaminant endotoxin in the anti-CD3 antibodies used in the mouse model was synergistic, the concept of using TLR agonists in synergy with endotoxin free anti-human-CDS antibodies may provide a major therapeutic advance in the treatment of recent onset or pre-diabetic human disease.