Spontaneous Keratitis in T-Cell Deficient Female Mice

描述（由申请人提供）：多种机制有助于眼睛中的“免疫赦免”。不能充分抑制眼部免疫应答通常导致疾病，包括自身免疫性角膜炎，其可以作为患有现有自身免疫性疾病的个体的继发症状，作为先前感染或损伤的结果，或自发地自身发展。自身免疫性角膜炎的小鼠模型将有助于更好地理解角膜中的炎症过程，并设计治疗该疾病的潜在方法。在本研究中，我们介绍了两种新的自身免疫性角膜炎小鼠模型：B10.TCR？-/-和B10.TCR？-/-雌性老鼠，哪些缺乏？然后呢？T细胞，分别。这些小鼠自发地以非常高的速率发展角膜炎。许多出版物都指出了两者的作用？？然后呢？T细胞在建立和维持眼部免疫豁免中的作用。我们假设在B10.TCR？-/-和B10.TCR？-/-在小鼠品系中，缺乏特定的免疫调节T细胞使它们的眼睛，特别是雌性的眼睛，特别容易受到自身免疫攻击。我们计划通过以下具体目标进一步表征在这些小鼠中发展的疾病，并测试我们的假设：具体目标1。确定角膜炎如何在B10.TCR？-/-中发生小鼠我们将研究女性激素是否易患B10.TCR？-/-小鼠发生角膜炎，以及是否像在人类角膜炎中经常发现的那样，B10.TCR？-/-角膜炎小鼠表现出角膜敏感性的伴随降低。我们还将描述自动攻击？？B10.TCR中的T细胞？-/-导致角膜炎的角膜炎小鼠。此外，我们将描述特定的居民？？T细胞群通常存在于眼睛的利姆布斯，并确定这些细胞群是否存在于眼睛的角膜缘。T细胞发挥免疫调节作用，防止角膜炎的发展。最后，我们将研究识别角膜中分子的抗体是否在B10角膜炎的发展或持续中起作用。TCR？-/-女性 具体目标2。确定角膜炎如何在B10.TCR？-/-中发生小鼠B10.TCR?-/-女性与B10.TCR？-/-一样易患角膜炎女性，尽管她们的疾病在一些细节上有所不同。我们假设，炎症细胞，诱导的自我攻击？？T细胞，促进B10.TCR？-/-中的角膜炎症小鼠，这并没有解决，由于他们缺乏监管（Treg）？？T细胞。在这个目标下，我们计划确定是否？B10.TCR中的T细胞？-/-女性是自我攻击的，如果是这样，以表征这些细胞。我们还将测试用Treg样细胞补充这些小鼠是否可以减少或预防疾病。 该提案是为了响应PA 07 -336“动物模型和相关生物材料的开发”而提交的，因为它研究了调节性T细胞和眼睛的免疫力，因此与NIAID和NEI支持的研究有关。

DESCRIPTION (provided by applicant): A variety of mechanisms contribute to "immune privilege" in the eye. Failure to adequately suppress occular immune responses often leads to disease, including autoimmune keratitis, which can develop either as a secondary symptom in individuals with an existing autoimmune disease, as a consequence of prior infection or injury, or spontaneously on its own. A mouse model for autoimmune keratitis would be useful in developing a better understanding of inflammatory processes in the cornea, and in devising potential ways of treating the disease. In this proposal, we introduce two new mouse models for autoimmune keratitis: B10.TCR?-/- and B10.TCR?-/- female mice, which lack ?? and ?? T cells, respectively. These mice develop keratitis spontaneously at a very high rate. Numerous publications have indicated roles for both ?? and ?? T cells in establishing and maintaining ocular immune privilege. We hypothesize that in the B10.TCR?-/- and B10.TCR?-/- mouse strains, the lack of particular immunoregulatory T cells renders their eyes, especially those of the females, exceptionally vulnerable to autoimmune attack. We plan to further characterize the disease that develops in these mice, and test our hypothesis, via the following specific aims: Specific Aim 1. To determine how keratitis arises in B10.TCR?-/- mice. We will examine whether female hormones predispose B10.TCR?-/- mice to develop keratitis, and whether as is often found in human keratitis, B10.TCR?-/- keratitic mice show a concomitant reduction in corneal sensitivity. We will also characterize the autoaggressive ?? T cells in B10.TCR?-/- keratitic mice that lead to keratitis. In addition, we will characterize the specific resident ?? T cell population normally present in the limbus of the eye, and determine whether these ?? T cells play an immunoregulatory role which prevents the development of keratitis. Finally, we will examine whether antibodies that recognize molecules in the cornea play a role in the development or persistence of keratitis in B10.TCR?-/- females. Specific Aim 2. To determine how keratitis arises in B10.TCR?-/- mice. B10.TCR?-/- females are as keratitis-susceptible as B10.TCR?-/- females, although their disease differs in some details. We hypothesize that inflammatory cells, induced by autoaggressive ?? T cells, promote corneal inflammation in B10.TCR?-/- mice, which does not resolve due to their lack of regulatory (Treg) ?? T cells. In this aim, we plan to determine whether ?? T cells in B10.TCR?-/- females are autoaggressive, and if so, to characterize these cells. We will also test whether repletion of these mice with Treg-like cells can reduce or prevent disease. This proposal is submitted in response to PA07-336, "Development of Animal Models and Related Biological Materials for Research," and because it investigates both regulatory T cells and the immunity of the eye, is pertinent to research supported by both the NIAID and NEI.