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Role of Notch signaling during the early priming and activation of alloreactive T cells

Notch 信号在同种异体反应性 T 细胞早期启动和激活过程中的作用

基本信息

批准号：
10510497
负责人：
Ashley Nicole Vanderbeck
金额：
$ 0.71万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10510497
关键词：
Acute Graft Versus Host Disease Alloantigen Allogeneic Bone Marrow Transplantation Antibodies Antibody Therapy Biological Assay Blocking Antibodies Cell physiology Cells Chromatin Chronic Clinical Communication Complication Cytokine Gene Cytokine Signaling Data Disease Epigenetic Process Functional disorder Gastrointestinal tract structure Genes Genetic Transcription Goals Graft-Versus-Tumor Induction Homing Hour Immune Immune response Immune system Immunobiology Immunosuppression Impairment Inflammation Inflammatory Inflammatory Response Pathway Injections Integrins Interleukin-2 Intestinal Graft Versus Host Disease Intestines Laboratories Life Ligands Mature T-Lymphocyte Measures Mediating Modeling Molecular Monoclonal Antibodies Morbidity - disease rate Mus Organ Pathogenesis Pathogenicity Pathologic Pathway interactions Patients Peripheral Phase Physiologic pulse Play Prevention Production Prophylactic treatment Regulatory T-Lymphocyte Role Scientist Shapes Signal Pathway Signal Transduction T cell response T-Cell Activation T-Lymphocyte Techniques Testing Time Tissues Training Transplantation Transposase Tropism Tumor stage Work cytokine dimer disorder control disorder prevention effector T cell gastrointestinal genome-wide graft vs host disease immunoregulation in vivo infection risk inhibitor insight isoimmunity mortality new therapeutic target nonhuman primate notch protein novel nuclease preservation prevent programs prophylactic response secondary lymphoid organ side effect skills trafficking transcriptome sequencing treatment strategy tumor

项目摘要

PROJECT SUMMARY Graft-versus-host-disease (GVHD) is the most serious complication of allogeneic bone marrow transplantation (allo-BMT). GVHD pathogenesis is mediated by alloreactive T cells present in the graft that recognize alloantigens and damage host tissues. Most GVHD therapies rely on global immunosuppression and are associated with increased risks of infection and decreased graft-versus-tumor effects. New strategies for GVHD prevention that protect host tissues while simultaneously preserving the tumor-killing activity of alloimmune T cells are needed. Our laboratory identified Notch signaling and Delta-like1/4 (Dll1/Dll4) Notch ligands as critical regulators of the pathogenic allo-T cell response, and attractive new therapeutic targets. In both mouse and non-human primate models, Notch inhibition in donor T cells leads to long-term protection from GVHD morbidity and mortality. Short-term in vivo Notch blockade using monoclonal antibodies against specific Notch receptors or ligands blunts the pathogenicity of alloreactive effector T cells without eliciting broad immunosuppression, reducing GVT activity, or triggering toxic side effects of chronic Notch inhibition. While a single injection of anti-Dll1/Dll4 Notch ligand antibodies at the time of transplant was sufficient for long- term GVHD control, Dll1/Dll4 blockade administered >48 hours after transplant provided no protection against GVHD. Thus, an early pulse of Notch signaling during the initial stages of T cell activation is critical for establishing a pathogenic T cell state. However, we do not currently understand how short-term Notch inhibition exerts long-lasting GVHD protection. Alloreactive T cells rely on two central functions to mediate disease: trafficking to peripheral target organs and producing proinflammatory cytokines. Our preliminary data show that Notch inhibition preserves initial T cell IL-2 production and expansion in secondary lymphoid organs while impairing secretion of multiple inflammatory cytokines and homing to the gastrointestinal tract. Therefore, I hypothesize that Notch signals delivered to allo-T cells during early stages of T cell priming and activation are critical for trafficking to the gut and initiating a sustained inflammatory cytokine response. I speculate that these two key mechanisms explain why short-term Notch inhibition prevents many of the severe, pathological consequences of GVHD. To explore this hypothesis, I will use MHC-mismatched models of GVHD to investigate how Notch inhibition influences allo-T cell gut tropism. Moreover, I will use a combination of RNA sequencing, Assay for Transposase-Accessible Chromatin sequencing (ATAC-seq), and Cleave Under Targets and Release using Nuclease (CUT&RUN) chromatin profiling to provide a genome-wide view of the transcriptional and epigenetic effects of Notch signaling during early stages of allo-T cell priming/activation. Altogether, this proposal will elucidate the cellular and molecular mechanisms that underlie the impact of early Notch signals in shaping the alloimmune response after allo-BMT.

项目总结