Spontaneous Corneal Inflammation in gd T cell absence

描述（由申请人提供）：γ-δ T细胞在免疫应答中的作用仍在研究中。尽管这些细胞显然发挥免疫调节作用，但到目前为止，由于γ-δ T细胞受体成分的遗传失活而不能产生γ-δ T细胞的小鼠（TCR-δ敲除小鼠）似乎在很大程度上是正常的，尽管当故意诱导感染性或自身免疫性疾病时，缺陷是明显的。我们最近发现了我们认为是第一次报道的TCR-delta敲除小鼠的自发性疾病-角膜炎症，在这些小鼠中以高频率发展。角膜炎仅在有缺陷的TCR-δ基因处于C567 BL/10（B10）背景时才明显。其发病率随着年龄的增长而增加，女性比男性更常见。这种疾病发展缓慢，但即使在早期阶段，也可以看到角膜基质中的炎性浸润沿着新生血管形成。我们假设B10-TCR β基因敲除小鼠发生角膜炎症，因为它们缺乏γ-δ T细胞，使它们在自身耐受机制中有缺陷，这在B10背景下导致自发性角膜炎发病率增加。我们建议进行试点/可行性研究，以进一步调查这种疾病的起源和特点，并确定它是否可能是一个有用的模型，γ-δ T细胞的免疫作用的研究。我们的具体目标是：1.进一步定义和描述B210-TCR δ基因敲除小鼠的自发性角膜炎。这将包括进一步记录疾病的发病率和进展，以及对明显导致疾病的B 10衍生基因的初步调查。 2.探讨B10-TCR-δ基因敲除小鼠自发性角膜炎的发病机制。我们计划首先检查是否可以通过用γ-δ T细胞或特定的γ-δ T细胞亚群重建受影响的小鼠来改善或预防这种疾病。此外，我们还将进行实验，以检查这种疾病是自身免疫性的，是由细菌感染引起的，还是由肮脏的笼子垃圾释放的化学物质造成的损害引起的。

DESCRIPTION (provided by applicant): The role of gamma-delta T cells in immune responses is still being worked out. Although the cells clearly play an immunoregulatory role, up until now, mice incapable of producing gamma-delta T cells due to genetic inactivation of gamma-delta T cell receptor component (TCR-delta knockout mice) appeared to be largely normal, though defects were apparent when infectious or autoimmune disease was deliberately induced. We recently discovered what we believe to be the first reported spontaneous disease in TCR-delta knockout mice - an inflammation of the cornea that in these mice develops at a high frequency. The keratitis is only apparent when the defective TCR-delta gene is on the C567BL/10 (B10) background. Its incidence increases with age, and it is more common in females than in males. The disease develops slowly, but even in early stages, one can see inflammatory infiltrates in the corneal stroma along with neovascularization. We hypothesize that B10-TCR ( knockout mice develop corneal inflammation because their lack of gamma-delta T cells renders them defective in a mechanism of self-tolerance, which on the B10 background leads to an increased in incidence of spontaneous keratitis. We propose to carry out a pilot/feasibility study to further investigate the origin and features of this disease, and determine whether it is likely to be a useful model for the study of the immunological role of gamma-delta T cells. Our specific aims are: 1. To further define and describe the spontaneous keratitis in B210-TCR delta knockout mice. This will include further recording of the incidence and progression of the disease, as well as an initial investigation into the B 10-derived genes that apparently contribute to the disease. 2. To investigate the mechanisms that lead to the development of spontaneous keratitis in B10-TCR-delta knockout mice. We plan first to examine whether the disease can be improved or prevented by reconstituting affected mice with gamma-delta T cells, or with particular gamma-delta T cell subsets. In addition, we will carryout experiments designed to examine whether the disease is autoimmune, results from bacterial infection, or stems from damage caused by a chemical released from dirty cage litter.