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）：肺和心脏移植的免疫原性更强，比肾移植更不易诱导耐受。我们和其他人已经表明，自身免疫性Th 17和B细胞对V型胶原（α1）（“col V”）和Kα 1微管蛋白的反应通常伴随着肺移植，而心脏移植引起对col V和波形蛋白的反应。与对Col V、kα 1微管蛋白和波形蛋白的新生自身免疫相关的风险是相当大的-例如，移植后对Col V的Th 17应答与肺移植中最严重的纤维闭塞性慢性排斥反应（称为闭塞性细支气管炎综合征[BOS]）的10倍高风险相关。为什么这些特定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靶点，目前尚不清楚。我们最近发现，在去除CD 39+调节性T细胞（TcR）或阻断各种Treg功能后，正常健康个体中显示出对col V、kα 1微管蛋白和波形蛋白的记忆型Th 17免疫应答。这表明，自身免疫，而不是作为一个次要的后果同种免疫，可能先于同种免疫的情况下，心脏和肺移植。我们建议验证这样的假设，即Col V、k β 1微管蛋白和波形蛋白反应性T细胞是天然的17型TcRαβ记忆T细胞，在个体发育期间在胸腺中与天然Treg（nTreg）对应物沿着产生，其正常功能在于维持气道和血管的稳态。这一假设代表了当前对供体乘客T细胞在心脏和肺同种异体移植物中的观点的范式转变，从移植物免疫原性的无关紧要的组分转变为成功移植物结果的必要组分。我们提出了3个具体目标：1）进一步表征人类对col V、kα 1微管蛋白和波形蛋白的自然T记忆反应; 2）确定对这些抗原特异的nTh 17的胸腺内衍生和器官特异性;和3）确定移植供体对col V、kα 1微管蛋白和波形蛋白的免疫状态以及供体HLA-DR类型是否影响移植结果，如果影响，如何影响移植结果，以及供体或供体MHCII限制性宿主免疫状态的操作是否可以预防由诱导的（i）对col V特异的Th 17细胞和B细胞引起的急性/慢性排斥。在移植物受体的免疫管理的总体策略中增加天然Th 17和调节性T细胞可以保持对col V、kα 1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发展。