Restoring anti-viral immunity during HTLV-associated neuroinflammatory disease

产品说明：在全球范围内，有2000万人感染了HTLV-1，其中大多数人仍然是无症状携带者（AC），而少数人发展为ATL或HAM/TSP，对这两种疾病状态都没有有效的治疗或疫苗。疾病病理生理学的确切机制仍未解决，尽管细胞免疫应答活跃（主要针对病毒反式激活蛋白Tax），但HAM/TSP患者的高前病毒载量仍是一个大问题？我们的初步研究表明，程序性死亡（PD）-1受体及其配体PD-L1是观察到的免疫细胞功能障碍的潜在潜在因素，导致病毒持续存在和疾病进展，主要是在HAM/TSP患者中。PD-1：PD-L1/PD-L2是免疫球蛋白超家族（IgSF）共信号分子的成员，并与慢性病毒感染期间的CD 8 T细胞耗竭有关。该家族的几个成员包括CTL-4：B7-1（CD 80）/B7-2（CD 86）、LAG-3：HLA-DR、Tim- 3：半乳糖凝集素-9、2B 4：CD 48和BTLA CD 160：HVEM在调节抗原特异性免疫应答中起关键作用。到目前为止，PD-1和CTLA-4通路已被广泛研究;针对这些通路的阻断抗体已在癌症背景下显示出临床益处。最近的进一步数据表明，同时阻断多种抑制性受体可能会改善基于T细胞的治疗，但需要进一步研究来阐明每个受体-配体对的作用。此外，PD-1和CTLA-4在人类慢性病毒感染以及神经炎性疾病（如HAM/TSP、NeuroAIDS等）方面的临床适用性仍有待测试。有趣的是，HTLV-1为两者提供了良好的模型，因此，我们发现研究HTLV中关键抑制性受体/配体的作用是重要的，1感染，并测试它们的联合阻断作为恢复HAM/TSP患者免疫细胞功能的潜在免疫策略。虽然这种方法应该有助于恢复患者预先存在的抗病毒免疫功能，但激活新的CTL以模拟AC中发现的多克隆CD 8 T细胞应答将是成功免疫干预HTLV相关疾病的关键。因此，我们建议系统地鉴定由HTLV-1感染细胞呈递的T细胞表位，这些表位在沉默携带者中定义保护性免疫，同时阻断抑制途径，以便完全恢复慢性感染患者的T细胞功能。实现这些目标的具体目的是1）研究IgSF负调节因子的共表达模式，并设计阻断策略以恢复HTLV-1患者组群中抗原特异性T细胞的多功能性和细胞溶解潜力; 2）对感染细胞上的MHC I类肽复合物进行广泛的免疫蛋白质组学分析，并通过在携带者与患病个体中进行比较免疫原性测试来鉴定抗HTLV-1多克隆T细胞应答的最佳候选者;和3）在HTLV-1感染的人源化小鼠的情况下，评价使用新表位恢复免疫细胞功能沿着细胞免疫应答扩展的组合策略。.

DESCRIPTION: Worldwide, 20 million people are infected with HTLV-1, a majority of which remain asymptomatic carriers (ACs), while a few develop ATL or HAM/TSP with no effective treatment or vaccine for either disease state. The exact mechanism(s) of disease pathophysiology remain unresolved with a big question of high proviral load in HAM/TSP patients despite vigorous cellular immune response (primarily directed towards viral transactivator protein Tax)? Our initial studies implicated programmed death (PD)-1 receptor and its ligand, PD-L1 as potential underlying factors for observed immune cells' dysfunctions leading to viral persistence and disease progression, primarily in HAM/TSP patients. PD-1:PD-L1/PD-L2 are the members of immunoglobulin superfamily (IgSF) co-signaling molecules and have been linked with CD8 T-cell exhaustion during chronic viral infections. Several members of this family including CTL-4:B7-1(CD80)/B7-2(CD86), LAG-3:HLA-DR, Tim- 3:Galectin-9, 2B4:CD48, and BTLA CD160:HVEM play critical role in regulating antigen-specific immune responses. Thus far, PD-1 and CTLA-4 pathways have been extensively studied; and blocking antibodies against these have shown clinical benefit in the setting of cancer. Further recent data suggest that blocking multiple inhibitory receptors simultaneously may improve T-cell based therapies, but further studies are required to clarify the role of each receptor-ligand pair. Moreover, the clinical applicability of PD-1 and CTLA-4 remains to be tested with respect to human chronic viral infections as well as neuroinflammatory diseases, such as HAM/TSP, NeuroAIDS, etc. Interestingly, HTLV-1 provides a good model for both and thus, we find it significant to investigate the role of key inhibitory receptors/ligands in HTLV-1 infection and tes their combined blockade as potential immunotherapeutic strategy to restore immune cell functions in HAM/TSP patients. While this approach should help in restoring functions of pre-existing antiviral immunity in patients, activating new CTLs to mimic polyclonal CD8 T-cell response found in ACs will be the key for a successful immunotherapeutic intervention of HTLV-associated diseases. Therefore, we propose to systematically identify T-cell epitopes presented by HTLV-1-infected cells that define protective immunity in silent carriers alongside blocking inhibitory pathways in order to fully restore T-cell functions in chronically infected patients. Th Specific Aims to achieve these goals are to 1) Investigate co-expression patterns of IgSF negative regulators and devise a blockade strategy to restore polyfunctionality and cytolytic potential of antigen-specific T-cells in HTLV-1 patient cohorts; 2) Perform extensive immunoproteomics analyses of MHC Class I:peptide complexes on the infected cells, and identify best candidate(s) for anti-HTLV-1 polyclonal T-cell response by comparative immunogenicity testing in carriers versus diseased individuals; and 3) Evaluate the combined strategy of restoring immune cell functions along with the expansion of cellular immune response using neo-epitopes in the context of HTLV-1-infected humanized mice. .