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Targeted cell-depleting immunotherapy for TB and HIV

结核病和艾滋病毒的靶向细胞消耗免疫疗法

基本信息

批准号：
10556322
负责人：
WILLIAM Ramses BISHAI
金额：
$ 67.28万
依托单位：
JOHNS HOPKINS UNIVERSITY
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：
2020-02-25 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10556322
关键词：
Acute Address Animals Bacille Calmette-Guerin vaccination Biological Products CD4 Positive T Lymphocytes Cells Chimeric Proteins Chronic Containment Data Denileukin Diftitox Diphtheria Toxin Disease FOXP3 gene Granuloma HIV HIV Infections HIV/TB Human IL2 gene IL2RA gene IL4 gene IL4R gene ITGAM gene Immunosuppressive Agents Immunotherapy Indoles Lung Maintenance Methods Modeling Mus Mycobacterium tuberculosis Myeloid-derived suppressor cells Necrosis Oryctolagus cuniculus Patients Peripheral Blood Mononuclear Cell Pharmaceutical Preparations Pharmacotherapy Play Process Proliferating Research Role Spleen Suppressor-Effector T-Lymphocytes System Technology Tuberculosis Vaccine Adjuvant Virus Replication cancer therapy efficacy evaluation global health improved novel novel therapeutics pathogen prevent reactivation from latency single-cell RNA sequencing translational applications tuberculosis drugs tuberculosis granuloma tuberculosis immunity

项目摘要

PROJECT SUMMARY Tregs and MDSCs have emerged as key suppressor cells that inhibit effector immunity in the TB granuloma. In addition, Tregs have been implicated in the maintenance of HIV latency. We have generated two selective biologic agents for potent depletion of Tregs and and MDSCs using diphtheria toxin (DT) fusion protein technology: DT-IL2 targets IL2-R-positive (CD25+) cells (Tregs), and DT-IL4 targets IL4-R positive (CD124+) cells (MDSCs). Our preliminary data demonstrate that: (i) DT-IL2 and DT-IL4 reduce the abundance of Treg and MDSC cells, respectively, in mouse lungs and spleens, (ii) DT-IL2 and DT-IL4 reduces the ability of M. tb to proliferate in an acute murine TB infection model, (iii) the drug, tasquinimod which has potent anti-MDSC activity, reduced the ability of M. tb to proliferate in an acute TB infection model with a concomitant reduction in MDSCs, and (iv) administration of DT-IL2 to CD4+ T cells from patients with controlled HIV reactivates viral replication. These data support the hypotheses that (1) Tregs and MDSCs play important inhibitory roles in M. tb containment, and (2) that Treg cells play a role in HIV latency maintenance. A central scientific premise of this application is that further definition of the immunosuppressive roles of Tregs and MDSCs in TB and HIV infection will reveal important immunopathogenesis mechanisms that may be exploited towards developing improved host-directed therapies (HDTs) for both diseases. In this proposal we seek to address this premise by pursuing the following aims. Aim 1: define the role of Treg cells in the TB granuloma using targeted CD25+ cell depletion with DT-IL2. We will (a) evaluate the cellular composition of both cellular (C57BL/6, WT which are sst1R) and necrotic (C57BL/6 sst1S) murine granulomas with and without CD25+ cell depletion using single-cell RNA-Seq (SSRS) as well as traditional methods, (b) evaluate the efficacy of targeted CD25+ cell depletion in chronic murine TB with and without anti-TB drug therapy, and (c) evaluate the contribution of Treg cells to the process of cavitation (granuloma breakdown) using a novel model of rabbit cavitary TB. Aim 2: define the role of MDSCs in the TB granuloma using targeted CD124+ cell depletion with DT-IL4. We will (a) evaluate the cellular composition of both cellular and necrotic murine granulomas with and without CD124+ cell depletion using SSRS as well as traditional methods, (b) evaluate the efficacy of targeted CD124+ cell depletion in chronic murine TB with and without anti-TB drug therapy, (c) assess the impact of dual CD25+ and CD124+ cell depletion in the TB granuloma with B6 sst1R and sst1S mice using SSRS as well as traditional methods, and (d) evaluate the efficacy of dual CD25+ and CD124+ cell depletion in chronic murine TB with and without anti-TB drug therapy. Aim 3: conduct translational applications of CD25+ cell depletion with (i) BCG vaccination and (ii) HIV reactivation. We will (a) evaluate the efficacy of targeted CD25+ cell depletion as a vaccine adjuvant prior to BCG vaccination and (b) evaluate the impact of targeted CD25+ cell depletion on HIV reactivation in PBMCs from patients with controlled HIV infection.

项目总结