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Enhancing regeneration of stem cell-derived HIV-specific immune effectors

增强干细胞衍生的 HIV 特异性免疫效应器的再生

基本信息

批准号：
10601073
负责人：
David T Scadden
金额：
$ 58.87万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-15 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10601073
关键词：
Acute Adaptive Immune System Allogenic Animals Anti-HIV Therapy Antibodies Antibody-drug conjugates Autologous Award BMP2 gene Biomedical Engineering Biotechnology Bone Marrow CCR5 gene Cell Transplantation Cells Collaborations Common Lymphoid Progenitor Communication Competence Complement Complex Development Disease Doctor of Philosophy Engineering Gene Modified Generations Genes Grant Growth Factor HIV HIV Infections HIV resistance HIV-1 HIV/AIDS Hematopoiesis Hematopoietic Hematopoietic Stem Cell Transplantation Hematopoietic stem cells Human Human immunodeficiency virus test Immune Immune system Immunity Immunocompetence Immunocompetent Immunologics Individual Infection Injections Intervention Laboratories Ligands Lymphopoiesis Mature T-Lymphocyte Methods Modeling Mus Natural regeneration Nature Needles Organ Osteoblasts Osteocalcin PTPRC gene Participant Patients Preclinical Testing Primates Process Production Provider Publishing Reagent Resistance Resources Rosaniline Dyes Stromal Cells Subcutaneous Injections T-Lymphocyte T-cell receptor repertoire Techniques Technology Testing Therapeutic Thymus Gland Time Tissues Toxic effect Transplantation Transplantation Conditioning Viral reservoir Viremia Work antiretroviral therapy aspirate cell regeneration cell type chemotherapy conditioning cryogel engineered stem cells humanized mouse immune function immune reconstitution improved mouse model nonhuman primate notch protein novel osteogenic post-transplant pre-clinical progenitor stem cell self renewal stem cells subcutaneous success thymocyte

项目摘要

Project Summary In the previous U19 award, we developed a non-genotoxic antibody based method of conditioning animal recipients for hematopoietic stem/progenitor cell (HSPC) transplantation. This approach is now being developed for human use and non-human primate testing by Magenta Therapeutics, the commercial participant in this proposal. We also developed a method of enhancing T cell neogenesis post-transplantation that takes advantage of prior work defining the bone marrow niche for T-competent progenitors, creating an easy to administer, off the shelf bone marrow cryogel. Subcutaneous injection of the cryogel leads to improved T competent common lymphoid progenitor (CLP) production, increased thymocytes, TREC+ cells, mature T cells, expanded TCR repertoire and improved immune function in mouse models. Here, we will combine it with the gene modification technology of the Cannon and Kiem labs and the antibody-drug conjugate technology of Magenta to determine whether we can increase the regeneration of a functionally complex, HIV protected adaptive immune system to protect against acute HIV infection, control viremia in infected hosts and potentially, reduce the tissue reservoir of infected cells. The strengths of the Scadden lab in hematopoiesis and transplant and the Allen lab in HIV infection and immunity will complement each other in testing this approach in humanized mice. We will closely interact with the Cannnon and Kiem labs on gene modifying approaches to engineer anti-HIV HSPC and extend testing to the non-human primate. Collectively, these efforts will provide immediate pre-clinical testing a of a strategy to cure HIV through low-toxicity approaches to rebuild an infected individual’s immune system.

项目总结