Type V Collagen Prevents Lung Allograft Rejection

描述（申请人摘要）：肺移植是一种常用的 用于治疗终末期肺部疾病的方式。然而，肺 比其他实体器官同种异体移植更容易发生排斥反应。急性重复性 排斥反应发作导致慢性排斥反应，称为细支气管炎 闭塞性肺动脉炎是肺移植受者死亡的主要原因。 供体主要组织相容性复合体（MHC）抗原的呈递 抗原呈递细胞，如巨噬细胞和树突细胞， 淋巴细胞是排斥反应的刺激物。相反，同种异体移植 接受可以通过口服免疫受体来诱导， 供体来源的MHC蛋白/肽或MHC“样”蛋白， 移植这种现象被称为口服耐受，已被证明 防止肺以外的同种异体移植物的排斥反应，但尚未进行检查 肺移植排斥反应虽然供体MHC抗原是刺激物， 拒绝响应的目标，我们最近报告说，V型 胶原蛋白（col（V））可能是MHC-“样”的，也被认为是抗原 在人类肺同种异体移植排斥反应中， 小鼠肺同种异体抗原。此外，用col（V）免疫小鼠诱导 对肺同种异体抗原的免疫耐受性。然而，col（V）的能力， 诱导口服耐受，预防肺部免疫和病理 同种异体移植排斥是未知的。我们的实验室是少数几个 用F344大鼠肺（RT 1 lv 1）建立大鼠肺移植排斥模型， 原位移植到WKY（RT 1 I）受体中。利用这个模型， 目前的建议测试的假设，口服耐受诱导， col（V）通过以下方式防止肺同种异体移植物排斥的免疫学和病理学 目的1：确定口服免疫是否 与col（V）一起诱导对同种异体抗原的口服耐受，并阻止 在肺同种异体移植物中的排斥病理学中，大鼠将被喂食col（V），然后 对供体的迟发型超敏反应（DTH）的评估 同种异体抗原，急性排斥反应和闭塞性细支气管炎（BO）的发生， 同种异体移植肺。目的2：确定负责口腔粘膜上皮细胞的细胞类型， col（V）诱导的免疫耐受，特异性淋巴细胞亚群和APC的作用 下调肺移植排斥反应的免疫学和病理学 将进行调查。目标3。为了确定col（V）的肽， 同种异体肺移植的口服耐受性，col（V）特异性α链肽 将通过溴化氰消化产生，然后评估 这些肽诱导口服耐受性并防止免疫学， 排斥反应的病理学目标4。以确定可溶性的作用 col（V）诱导的口服耐受中的介质 接受者将用拮抗剂和中和抗体治疗， 细胞因子和其他介质被认为在口服耐受中起关键作用 然后评估排斥反应的免疫学和病理学 反应

DESCRIPTION (Applicant's abstract): Lung transplantation is a commonly utilized modality for the treatment of end stage pulmonary diseases. However, the lung is rejected more commonly than other solid organ allografts. Repeated acute rejection episodes result in chronic rejection known as bronchiolitis obliterans, the leading cause of death in lung allograft recipients. Presentation of donor major histocompatibility complex (MHC) antigens by antigen presenting cells, such as macrophages and dendritic cells, to recipient lymphocytes is the stimulus for rejection episodes. Conversely, allograft acceptance may be induced by immunizing the recipient, orally, with donor-derived MHC proteins/peptides or MHC-"like" proteins prior to transplantation. This phenomenon, known as oral tolerance, has been shown to prevent rejection in allografts other than the lung, but has not been examined in lung allograft rejection. Although donor MHC-antigens are the stimulus and target of the rejection response, we have reported recently that type V collagen (col(V)), which may be MHC-"like," is also recognized as an antigen during lung allograft rejection in humans, and the local immune response to lung alloantigens in mice. Also, immunizing mice with col(V) induces immunological tolerance to lung alloantigens. However, the ability of col(V) to induce oral tolerance and prevent the immunology and pathology of lung allograft rejection is unknown. Our laboratory is one of the few that developed the rat model of lung allograft rejection in which F344 rat lungs (RT1lv1) are transplanted orthotopically into WKY (RT1I) recipients. Utilizing this model, the current proposal tests the hypothesis that oral tolerance induction by col(V) prevents the immunology and pathology of lung allograft rejection by examining the following specific aims: Aim 1: To determine if oral immunization with col(V) induces oral tolerance to alloantigens and prevents the development of rejection pathology in lung allografts, rats will be fed col(V) followed by an assessment of delayed type hypersensitivity (DTH) responses to donor alloantigens, and onset of acute rejection and bronchiolitis obliterans (BO) in allograft lungs. Aim 2: To determine the cell types responsible for oral tolerance induced by col(V), the role of specific lymphocyte subsets and APC's in down regulating the immunology and pathology of lung allograft rejection will be investigated. Aim 3. To determine the peptides of col(V) that induce oral tolerance to lung allografts, peptides of specific alpha-chains of col(V) will be produced by cyanogen bromide digestion followed by an assessment of these peptides to induce oral tolerance and prevent the immunology and pathology of the rejection response. Aim 4. To determine the role of soluble mediators in oral tolerance induced by col(V), tolerized lung allograft recipients will be treated with antagonists and neutralizing antibodies to cytokines and other mediators believed to have key roles in oral tolerance followed by an assessment of the immunology and pathology of the rejection response.