Oral Tolerance for Hemophilia

血友病的口服耐受性

• 批准号: 9297901
• 负责人: HENRY DANIELL
• 金额: $ 66.84万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-10 至 2021-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9297901
• 关键词: Address; Affect; Anaphylaxis; Animal Model; Animals; Antibodies; Antigen-Presenting Cells; Antigens; B-Lymphocytes; Biomedical Engineering; Birth; Blood; Blood Coagulation Disorders; Bypass; CD3 Antigens; CD4 Positive T Lymphocytes; Canis familiaris; Cells; Cellular Metabolic Process; Chloroplasts; Clinical; Clinical Trials; Complication; Data; Dendritic Cells; Disease; Dose; Epithelium; F8 gene; FOXP3 gene; Factor IX; Factor VIII; Factor VIIa; Funding; Future; Future Generations; Genetic Engineering; Grant; Health Care Costs; Helper-Inducer T-Lymphocyte; Hemophilia A; Hemophilia B; Immune; Immune Tolerance; Immune response; Immune system; Immunosuppression; Injection of therapeutic agent; Interdisciplinary Study; Intravenous; Intravenous infusion procedures; Laboratories; Lamina Propria; Lettuce - dietary; Life; Light; Link; Liver; Methods; Modeling; Morbidity - disease rate; Mus; Nature; Nephrotic Syndrome; Oral; Ovalbumin; Pain; Patients; Pharmaceutical Preparations; Plants; Production; Proteins; Protocols documentation; Quality of life; Reagent; Recombinants; Regulatory T-Lymphocyte; Risk; Safety; Science; Site; Small Intestines; Structure of aggregated lymphoid follicle of small intestine; System; T-Lymphocyte; Temperature; Time; TimeLine; Transgenic Organisms; Transgenic Plants; Translations; Work; antibody inhibitor; base; cost; cytokine; editorial; genomic tools; immunoregulation; immunotoxicity; improved; inhibitor/antagonist; male; mortality; mouse model; next generation; novel; oral tolerance; overexpression; pediatric patients; prevent; prophylactic; public health relevance; recombinant antihemophilic factor VIII; response; scale up; single molecule; standard of care; success; therapeutic protein; tool; translational study; uptake

PROJECT SUMMARY/ABSTRACT. The current standard of care for the X-linked bleeding disorder hemophilia is intravenous (IV) infusion of recombinant factor VIII (FVIII, for hemophilia A) or factor IX (FIX for hemophilia B). These protein products are expensive, require frequent repeated IV injections (which is painful and inconvenient), and are often targeted by antibody (“inhibitor”) responses; thereby complicating/neutralizing therapy, creating immunotoxicities, and further increasing costs. In fact, inhibitor formation, an antigen-specific CD4+ T helper cell-driven B cell response, is widely considered the most serious complication of current therapy for hemophilia. Forming an interdisciplinary research team to address this problem, our laboratories have been closely collaborating since 2007 to develop a bioengineering-based approach. We conceived and now validated the concept that oral delivery of bioencapsulated FVIII and FIX antigens produced by the chloroplasts of transgenic plants could suppress inhibitor formation in animal models of hemophilia. FVIII and FIX antigens were effectively delivered to the epithelium of the small intestine when expressed as fusions to a transmucosal carrier, and subsequently taken up by dendritic cells (DCs) in the lamina propria (LP) and Peyer's patches (PP). Tolerance was established (over a wide range, including very low antigen doses) by induction of multiple subsets of regulatory T cells (Treg) in an IL-10 dependent manner. In addition, this approach prevented and also reversed anaphylaxis against FIX. Importantly, we were able to generate chloroplast transgenic edible crop plants (lettuce), and scale up of production was successful to a commercial system that is used to cost- effectively generate GMP material. To further advance this approach, we propose the following specific aims: 1. Generate the next generation of transplastomic edible crop plants expressing FVIII antigen using cutting-edge chloroplast genomics tools and alternative transmucosal carriers. 2. Continue to define the mechanism of oral tolerance induction/immune regulation, in part through use of a model antigen. 3. Identify optimal plants for oral tolerance induction in hemophilia A mice; perform translational studies in hemophilia A dogs; and further strengthen oral tolerance by enhancing immune regulation or manipulating T cell metabolism. This work will facilitate translation of oral tolerance for hemophilia into clinical trials, define the mechanism of how plant cell-based oral tolerance is accomplished, pave the way for future combination protocols for optimal oral tolerance induction, and further advance genetic engineering of plants for biomedical applications.

项目总结/抽象。