Natural vs. Pathogenic Th17 responses to col Va1, Ka1tubulin and vimentin

自然与致病性 Th17 对 col Va1、Ka1tubulin 和波形蛋白的反应

• 批准号: 9107128
• 负责人: William J Burlingham
• 金额: $ 36.72万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-03-01 至 2021-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9107128
• 关键词: Accounting; Acute; Air; Antibodies; Antigen Targeting; Antigens; Autoantigens; Autoimmune Process; Autoimmunity; B-Lymphocytes; Blood; Blood Vessels; Bronchiolitis Obliterans; CD4 Positive T Lymphocytes; Cells; Cessation of life; Chronic; Cicatrix; Collagen Type V; Derivation procedure; Development; Donor person; Excision; Growth; HLA-DR Antigens; Health; Heart Transplantation; Heart-Lung Transplantation; Helper-Inducer T-Lymphocyte; Homeostasis; Human; IL2RA gene; Immune; Immune response; Immune system; Immunosuppressive Agents; Individual; Kidney; Kidney Transplantation; Left; Leukocytes; Link; Lung; Lung Transplantation; Memory; Organ; Organ Donor; Organ Specificity; Outcome; Pathology; Patients; Peripheral; Predisposition; Proteins; Regulatory T-Lymphocyte; Resistance; Risk; Role; Sentinel; Syndrome; System; T cell response; T memory cell; T-Lymphocyte; Testing; Thymus Gland; Tissues; Transplant Recipients; Transplantation; Tubulin; Vascular Diseases; Vimentin; base; graft failure; heart allograft; heart-lung allograft; high risk; immunogenic; immunogenicity; isoimmunity; member; novel; prevent; response

 DESCRIPTION (provided by applicant): Lung and heart transplants are more immunogenic, and less prone to tolerance induction than kidney transplants. We and others have shown that an autoimmune Th17 and B cell response to collagen type V (α1)("col V") and Kα1tubulin often accompanies lung transplantation, while heart transplantation elicits a response to col V and vimentin. The risks associated with de novo autoimmunity to Col V, kα1tubulin, and vimentin are substantial - for example, post-transplant Th17 responses to col V were associated with a 10-fold higher risk of the most severe form of fibro-obliterative chronic rejection in lung transplants, known as bronchiolitis obliterans syndrome [BOS]. Why these particular self-antigens and not others are the main targets of autoimmunity in lung and heart transplants, is currently unknown. We recently discovered that memory-type Th17 immune responses to col V, kα1tubulin, and vimentin are revealed in normal healthy individuals upon removal of CD39+ regulatory T cells (Tregs) or blocking various Treg functions. This suggests that autoimmunity, rather than being a secondary consequence of alloimmunity, may precede alloimmunity in the case of heart & lung transplants. We propose to test the hypothesis that Col V, k1tubulin, and vimentin-reactive T cells are natural type 17 TcRαβ memory T cells, produced in the thymus during ontogeny along with natural Treg (nTreg) counterparts, the normal function of which lies in maintaining airway and vascular homeostasis. This hypothesis represents a paradigm shift in the current view of donor passenger T cells in heart & lung allografts, from that of an inconsequential component of graft immunogenicity, to that of a necessary component of successful graft outcome. We propose 3 specific aims: 1) to further characterize the human natural T memory response to col V, kα1tubulin, and vimentin; 2) to determine the intrathymic derivation and organ-specificity of nTh17 specific to these antigens; and 3) to determine whether, and if so, how, the transplant donor immune status vis a vis col V, kα1tubulin, and vimentin, and donor HLA-DR type influences transplant outcome, and whether manipulation of donor or donor MHCII-restricted host immune status can prevent acute/ chronic rejection, caused by induced (i)Th17 cells and B cells specific for col V . Incorporating natural Th17 and regulatory T cells in the overall strategy of immune management of the graft recipient may preserve well-regulated autoimmunity to col V, kα1tubulin, and vimentin and allow stable tolerance to develop.

 描述(由申请人提供)：肺和心脏移植比肾移植更具免疫原性，更不容易诱导耐受。我们和其他人已经证明，肺移植通常伴随着Th17和B细胞对V型胶原(α1)(“Col1”)和K-α1微管蛋白的自身免疫应答，而心脏移植则引起对ColV和波形蛋白的应答。与对Col V、kα1微管蛋白和波形蛋白的从头免疫相关的风险是巨大的--例如，移植后Th17对Col V的反应与肺移植中最严重的纤维阻塞性慢性排斥反应的风险增加了10倍，称为闭塞性细支气管炎综合征。为什么这些特殊的自身抗原而不是其他抗原是肺和心脏移植中自身免疫的主要目标，目前尚不清楚。我们最近发现，正常健康人在去除α+调节性T细胞(Treg)或阻断各种Treg功能后，对ColV、k CD39 1微管蛋白和波形蛋白的记忆型Th17型免疫反应被揭示出来。这表明，在心肺移植中，自身免疫可能先于同种免疫，而不是同种免疫的次要结果。我们建议检验这一假设，即Col V，k1微管蛋白和波形蛋白反应性T细胞是自然型αβ记忆T细胞，在个体发育过程中在胸腺产生，与自然Treg(NTreg)类似物，其正常功能在于维持呼吸道和血管内稳态。这一假设代表了目前对同种异体心肺移植中供者乘客T细胞的看法的一种范式转变，从移植物免疫原性的一个无关紧要的组成部分，转变为移植物成功结局的一个必要组成部分。我们提出了三个特定的目标：1)进一步表征人类对ColV、kα1微管蛋白和波形蛋白的自然T记忆反应；2)确定针对这些抗原的nTh17的胸腺内来源和器官特异性；3)确定移植供者的免疫状态是否以及如何影响移植结果，以及供者α-DR类型对移植结果的影响，以及对供者或供者MHCII限制性宿主免疫状态的操纵是否可以防止由诱导的(I)Th17细胞和V型胶原特异的B细胞引起的急性/慢性排斥反应。在移植受者的整体免疫管理策略中结合自然的Th17和调节性T细胞，可能会保持对ColV、kα1微管蛋白和波形蛋白的良好调节的自身免疫，并允许稳定的耐受性。