Anitgen specific human T regulatory cell suppression of CCR6 positive Th17 cells

CCR6 阳性 Th17 细胞的抗原特异性人 T 调节细胞抑制

• 批准号: 9200215
• 负责人: David William Scott
• 金额: $ 8.39万
• 依托单位: HENRY M. JACKSON FDN FOR THE ADV MIL/MED
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-06 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9200215
• 关键词: Animal Model; Antibodies; Antibody Formation; Antibody Response; Antigens; Autoimmune Diseases; B-Cell Leukemia; B-Lymphocytes; Binding; Blocking Antibodies; Blood Coagulation Disorders; Blood Coagulation Factor; Blood coagulation; C2 Domain; CCR6 gene; CD4 Positive T Lymphocytes; Catabolism; Cell Proliferation; Cells; Chimeric Proteins; Clinic; Clinical Research; Coagulants; Coagulation Process; Data; Disease; Effector Cell; Engineering; Epitopes; Factor VIII; Frequencies; Future; Genes; Goals; Half-Life; Health; Hemophilia A; Hemorrhage; Human; Human Engineering; IL2RA gene; Immune; Immune response; Immunoglobulin G; Immunoglobulin Variable Region; Immunoglobulins; In Vitro; Lead; Lentivirus Vector; Life; Link; MHC Class II Genes; MS4A1 gene; Maintenance; Mediating; Modeling; Mus; Mutate; Mutation; Pathway interactions; Patients; Peptides; Plasma; Play; Prevention; Process; Proliferating; Protein Engineering; Proteins; Protocols documentation; Recombinants; Recycling; Regulatory T-Lymphocyte; Research; Role; Safety; Structure; T-Cell Receptor; T-Lymphocyte; Technology; Testing; Therapeutic; Tolerogen; Transgenes; Transgenic Mice; Translating; Translations; Treatment Efficacy; base; cellular transduction; chimeric antigen receptor; clinical efficacy; cytokine; design; gene therapy; immunogenic; in vivo; inhibitor/antagonist; leukemia; male; neonatal Fc receptor; novel; novel strategies; novel therapeutics; polypeptide; prevent; response; scaffold; targeted delivery; vector

 DESCRIPTION (provided by applicant): A major problem in the treatment of hemophilia A patients with factor VIIII (FVIII) is that up to 30% of these patients produce antibodies to therapeutic FVIII. These antibodies block (inhibit) the pro- coagulant function of FVIII and thus are termed "inhibitors". The focus of our lab has been to develop novel approaches for the induction of tolerance so that it can be applied to the prevention or reversal of undesirable immune responses, including the formation of hemophilia inhibitors. We have used immunoglobulin (Ig) fusion proteins expressed in B lymphocytes for the induction of tolerance in animal models of hemophilia. This technology is based on the well-known tolerogenicity of IgG carriers, onto which we engineer multiple epitope-containing polypeptides in frame at the N-terminus. We know that CD4+CD25+ regulatory T cells (Tregs) are required in our tolerogenic protocol and have shown that that the IgG scaffold increases the efficacy of this tolerance process. Independent data suggests that IgG domains contain epitopes, termed Tregitopes, which can activate Tregs. Indeed, recent clinical studies with FVIII-Fc fusion proteins designed for longer half-life appear to be less immunogenic, and may be tolerogenic. We hypothesize that the presence of Tregitopes and IgG processing mechanisms promote tolerogenic presentation. We focus in this proposal to take advantage of B-cell tolerogenic presentation of IgG fusion proteins (including a B-cell directed soluble fusion protein using a single chain anti-CD20) that can be utilized to induce tolerance to FVIII and prevent/reverse inhibitor formation. Moreover, T-cell receptors (TCR) from hemophilia patients will be used to create antigen-specific effector and regulatory CD4 T cells in analogy to the CAR19 T cells designed to treat B-cell leukemias. These will be used to test novel tolerogenic therapy and the efficacy of engineered human Tregs to prevent and reverse inhibitor formation. Our ultimate Aims, thus, are: (1) to use B-cell targeted fusion proteins to modulate anti-FVIII responsiveness, and finally (2) to express human TCR specific for FVIII in expanded human regulatory T cells to effectively suppress inhibitor responses to FVIII. Elucidating the mechanisms of these tolerogenic approaches will enhance our ability to optimize the efficacy and safety of this approach for translation in humans.

 描述（由申请方提供）：使用因子VIII治疗血友病A患者的一个主要问题是，高达30%的患者产生治疗性FVIII抗体。这些抗体阻断（抑制）FVIII的促凝血功能，因此被称为“抑制剂”。我们实验室的重点是开发新的方法来诱导耐受性，以便它可以应用于预防或逆转不良免疫反应，包括血友病抑制剂的形成。我们已经使用在B淋巴细胞中表达的免疫球蛋白（IG）融合蛋白在血友病动物模型中诱导耐受。该技术基于众所周知的IgG载体的致耐受性，我们在其上在N-末端设计了符合读框的多个含表位的多肽。我们知道，在我们的致耐受性方案中需要CD 4 + CD 25+调节性T细胞（T细胞），并且已经表明IgG支架增加了该耐受性过程的功效。独立的数据表明，IgG结构域含有表位，称为Tregitopes，其可以激活Tcl 3。事实上，最近的临床研究表明，设计用于更长半衰期的FVIII-Fc融合蛋白的免疫原性较低，并且可能是致耐受性的。我们假设Tregitopes和IgG加工机制的存在促进了致耐受性呈递。我们在该提案中集中利用IgG融合蛋白（包括使用单链抗CD 20的B细胞定向可溶性融合蛋白）的B细胞致耐受性呈递，其可用于诱导对FVIII的耐受性并防止/逆转抑制剂形成。此外，来自血友病患者的T细胞受体（TCR）将用于产生抗原特异性效应和调节性CD 4 T细胞，类似于设计用于治疗B细胞白血病的CAR 19 T细胞。这些将用于测试新的致耐受性疗法和工程化的人TCLB预防和逆转抑制剂形成的功效。因此，我们的最终目的是：（1）使用B细胞靶向融合蛋白来调节抗FVIII反应性，以及最后（2）在扩增的人调节性T细胞中表达对FVIII特异性的人TCR以有效抑制对FVIII的抑制剂反应。阐明这些致耐受性方法的机制将增强我们优化这种方法在人类中翻译的有效性和安全性的能力。