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“免疫特权”。未能充分抑制眼免疫反应往往导致疾病，包括自身免疫性角膜炎，它可以作为存在自身免疫性疾病的个体的继发性症状，作为先前感染或损伤的结果，或自发地发展。自身免疫性角膜炎的小鼠模型将有助于更好地了解角膜的炎症过程，并设计治疗该疾病的潜在方法。在本提案中，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，哪缺？？和? ?分别是T细胞。这些小鼠自发发展角膜炎的几率非常高。许多出版物都指出了两者的作用？？和? ?T细胞在建立和维持眼部免疫特权中的作用。我们假设在b10。tcr ？-/-和B10.TCR？-/-小鼠品系，缺乏特定的免疫调节T细胞使他们的眼睛，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生的疾病，并验证我们的假设：确定B10.TCR中角膜炎是如何发生的？- / -小鼠。我们将研究女性激素是否易导致B10.TCR？-/-小鼠发生角膜炎，是否如人类角膜炎中常见的B10.TCR？-/-角膜炎小鼠的角膜敏感性也随之降低。我们还将描述自动攻击？？B10.TCR中的T细胞？-/-角膜炎小鼠导致角膜炎。此外，我们将描述具体的居民？？T细胞群通常存在于眼缘，并确定这些？？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分子的抗体是否在B10.TCR中角膜炎的发展或持续中发挥作用。- / -女性。具体目标2。确定B10.TCR中角膜炎是如何发生的？- / -小鼠。B10.TCR吗?-/-女性与B10.TCR一样容易患角膜炎？-/-女性，尽管她们的疾病在某些细节上有所不同。我们假设炎症细胞，由自体侵袭性诱导？？T细胞促进B10.TCR角膜炎症？-/-小鼠，由于缺乏调节（Treg）而无法解决？T细胞。为此，我们计划确定是否？？B10.TCR中的T细胞？-/-雌性具有自体攻击性，如果是这样，这些细胞的特征。我们还将测试这些小鼠充满treg样细胞是否可以减少或预防疾病。该提案是根据PA07-336“动物模型和相关生物材料的研究开发”提交的，因为它调查了调节性T细胞和眼睛的免疫力，因此与NIAID和NEI支持的研究相关。

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.