Immune Respone to Cat: Regulatory and Effector T Cells

高剂量暴露于猫的主要过敏原费尔德1，已与一个矛盾的降低致敏。许多暴露于高水平猫过敏原（>= 20 μ/g/g灰尘）但不过敏的儿童，其血清学特征（IgG阳性IgE/阴性）与过敏受试者（IgG p？是IgEP吗？S）;这被描述为修改后的Th 2 反应这种“高剂量”耐受性可以解释与猫生活在一起的受试者哮喘的减少。 调节性T细胞诱导的高剂量自然暴露于过敏原通常与哮喘还没有研究。Fel d 1链2的新的CD 4 + T细胞主要表位选择性诱导IL-10和IFN-γ（肽2：1和2：2）已涉及在对猫的免疫治疗（IT）期间诱导的耐受性。在患有特应性皮炎（AD）的高度过敏患者中，T细胞对这些表位的反应性降低（与猫相比，平均IgE ab- 21 IU/ml）。 表达主要HLA-DR等位基因的具有修饰的Th 2应答的患者“0701.在所提出的研究中，将使用用Fel d 1的重叠肽刺激的培养物来研究调节性细胞因子（IL-10和TGF-β）与Fel d 1特异性CD 4 + T细胞应答的相关性。研究的受试者将包括患有和不患有AD的过敏患者、DR 7+和DR 7修饰的Th 2应答者以及对照（IgG阴性IgE阴性）受试者。其他调解人 将使用基于抗体的蛋白质阵列来寻求耐受性。将包括接受猫高剂量IT的患者以比较全身（IT）和吸入（修饰的Th 2）耐受性，并且将通过每月监测开始IT的患者来研究与全身耐受性相关的T细胞表位。 将使用MHC限制性分析、通过使用ELISPOT测定计数细胞和通过使用流式细胞术研究表型特征来研究细胞对修饰的Th 2应答的反应。将检查调节性细胞因子对表位特异性T细胞应答的影响，还将分析费尔德1特异性细胞向肺（哮喘受试者）、肠（修饰的Th 2）或皮肤（AD）的组织特异性归巢。链2表位的天然形式将是 使用质谱法从抗原呈递细胞表面上的肽混合物中鉴定。最后，鉴于CD 8 + T细胞也可以靶向链2表位的证据，将检查Fel d 1的I类MHC肽体外诱导CD 8 + T细胞应答的能力，并通过肽-MHC四聚体染色分析表位特异性CD 8 + T细胞。确定控制对cat耐受性的细胞机制是理解cat的基础。 控制哮喘患病率和严重程度的因素以及新疗法的合理设计。

High dose exposure to the major cat allergen, Feld 1, has been associated with a paradoxical decrease in sensitization. Many children who are exposed to high levels of cat allergen (>=20mu/g/g dust), but who are not allergic, have a serologic profile (IgG pos IgE/neg) that is distinct from allergic subjects (IgG p?s IgEP?S); this has been described as a modified Th2 response. Such "high dose" tolerance could explain the decrease in asthma among subjects living with a cat. Regulatory T cells induced by high dose natural exposure to allergens commonly associated with asthma have not been studied. Novel CD4+ T cell major epitopes ofFel d 1 chain 2 which selectively induce IL-10 and IFN-gamma (peptides 2:1and 2:2) have been implicated in tolerance induced during immunotherapy (IT) for cat. T cell reactivity to these epitopes is diminished in highly allergic patients with atopic dermatitis (AD)(mean IgE ab to cat -- 21 IU/ml) compared to patients with a modified Th2 response who express the major HLA-DR allele "0701. In the proposed studies, the relevance of regulatory cytokines (IL-10 and TGF-[3) to Fel d 1-specific CD4+ T cell responses will be investigated using cultures stimulated with overlapping peptides of Fel d 1. Subjects studied will include allergic patients with and without AD, DR7+ and DR7- modified Th2 responders, and control (IgG neg IgE neg) subjects. Additional mediators of tolerance will be sought using antibody-based protein arrays. Patients receiving high dose IT for cat will be included in order to compare systemic (IT) and inhalational (modified Th2) tolerance and T cell epitopes relevant to systemic tolerance will be studied by monthly monitoring of patients starting IT. The relevance of chain 2 epitope-specific T cells to the modified Th2 response will be studied using MHC restriction analysis, by enumerating cells using ELISPOT assay, and by studying phenotypic characteristics using flow cytometry. Effects of regulatory cytokines on epitopespecific T cell responses will be examined and tissue-specific homing of Feld 1-specific cells to the lungs (asthmatic subjects), gut (modified Th2) or skin (AD) will also be analyzed. The natural forms of chain 2 epitopes will be identified from peptide mixtures on the surface of antigen presenting cells using mass spectrometry. Finally, given the evidence that CD8+ T cells may also target chain 2 epitopes, the ability for class I MHC peptides of Fel d 1 to induceCD8+ T cell responses in vitro will be examined and epitope-specific CD8+ T cells will be analyzed by peptide-MHC tetramer staining. Defining cellular mechanisms which govern tolerance to cat is fundamental to understanding the factors that control the prevalence and severity of asthma and to the rational design of new therapies.