Development of tolerogenic dendritic cell-based immunotherapies and restorative insulin approaches to alleviate type 1 diabetes

开发基于耐受性树突状细胞的免疫疗法和恢复性胰岛素方法以缓解 1 型糖尿病

基本信息

批准号：
10189649
负责人：
Michael W Lipscomb
金额：
$ 37.75万
依托单位：
HOWARD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-01 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10189649
关键词：
Acute Address Adoptive Transfer Affinity Algorithmic Software Allogenic American Amino Acid Substitution Antigens Autoantigens Autoimmune Autoimmunity Beta Cell Binding Biocompatible Materials Blood Glucose Blood Vessels CD4 Positive T Lymphocytes Candidate Disease Gene Cell Compartmentation Cell Transplantation Cell physiology Cellular immunotherapy Chronic Clustered Regularly Interspaced Short Palindromic Repeats Computer software Coupled Dendritic Cells Development Diabetes Mellitus Disease Endocrine Endothelial Cells Engineering Event Generations Genes Glucose Goals Graft Rejection Haplotypes Health Hepatic Homologous Transplantation Hyperglycemia Hypoglycemia Immune Immune response Immunity Immunosuppressive Agents Immunotherapeutic agent Immunotherapy Impairment Implant In Vitro Inbred NOD Mice Infiltration Insulin Insulin-Dependent Diabetes Mellitus Investigation Knock-in Knock-out Laboratories Lead Legal patent Life MHC Class I Genes MHC Class II Genes Mediating Methods Opportunistic Infections Organ Pancreas Pathologic Pathology Peptides Physiological Production Recovery Signal Transduction Site-Directed Mutagenesis Structure of beta Cell of islet T cell response T-Lymphocyte Techniques Therapeutic Tissue Donors Tissues Transgenes Transplantation adaptive immunity autoreactive T cell autoreactivity base blood glucose regulation cell transformation clinically relevant combinatorial effector T cell efficacy evaluation genome editing immunogenic immunoregulation implantation in vivo indexing innovation insulin dependent diabetes mellitus onset medical complication mouse model novel pathogen prediction algorithm public health relevance response subcutaneous success

项目摘要

SUMMARY Type 1 diabetes (T1D) is characterized by an inability to achieve normoglycemia due to autoimmune events mistakenly targeting destruction of insulin-producing beta-cells of the pancreas. The major challenge of T1D is the two-fold onslaught whereby (1) chronic autoimmunity destroys beta-cells and (2) recovery is irreversibly lost due to the repeated chronic autoreactive attacks. Although current treatments do temperately reduce hyperglycemia, they can inadvertently lead to significant health complications (i.e. global immunosuppressive drugs impair natural host immunity and deregulate physiological functions and allogenic transplants are met with acute/chronic rejection). The long-term goals of the laboratory are to directly address these challenges of effectively alleviating T1D by developing antigen-specific tolerance to restrain autoimmune-mediated events coupled with insulin restorative strategies to alleviate hyperglycemia. The investigations have two principal aims to tackle this challenge: (1) engineering MHC class II-modified tolerogenic dendritic cell immunotherapies to specifically restrain autoreactive attacks in the beta-cell compartment without impairing natural host immunity (to pathogens or transformed cells), and (2) development of donor-derived MHC class I-matched beta-cells seeded in novel biomaterials to restore insulin production and normalize blood glucose levels. For the first aim, studies will reprogram DC towards tolerogenic states by knocking out key genes responsible for governing immunity. The approach is combined with silencing of endogenous MHC class II and replacing that with a transgene encoding a modified MHC class II that exclusively presents beta-cell autoantigen peptides with high affinity. Results will lead to tolerogenic DC solely presenting MHC class II-restricted beta-cell autoantigens upon adoptive transfer in vivo, leading to restrained autoreactive T cell responses without impairing normal host adaptive immunity. Even with success in stopping repeated autoreactive T cell attacks, tissue damage is often irreversible in mid- and late-stages of T1D. To address this challenge, the second aim will develop a restorative approach using donor-derived MHC class I-matched beta-cells seeded on novel biomaterials to restore insulin production in vivo. Donor-derived beta-cells will be genetically reprogrammed to express MHC class I matched to the recipient's haplotype; the approach will highlight the value in use of donor tissues for restorative applications. These insulin-producing donor-derived MHC class I-matched beta-cells will then be seeded in a novel patented biomaterial prior to implantation in the non-obese diabetic mouse model. Success of the approach will restrain diabetes progression by restoring normoglycemia through glucose- dependent insulin production. Findings generated from these studies will support development of innovative and novel translational and clinical-relevant therapeutic applications for combating T1D.

概括 1 型糖尿病 (T1D) 的特点是由于自身免疫事件而无法达到正常血糖错误地针对破坏胰腺中产生胰岛素的β细胞。 T1D 的主要挑战是双重攻击，其中（1）慢性自身免疫破坏β细胞和（2）不可逆转的恢复由于反复的慢性自身反应性发作而丢失。尽管目前的治疗方法确实会适度减少高血糖，它们可能会无意中导致严重的健康并发症（即全身免疫抑制药物损害自然宿主免疫力并失调生理功能并满足同种异体移植伴有急性/慢性排斥反应）。实验室的长期目标是直接应对这些挑战通过发展抗原特异性耐受来抑制自身免疫介导的事件，有效缓解 T1D 结合胰岛素恢复策略来缓解高血糖。调查有两个主要内容旨在应对这一挑战：（1）设计 MHC II 类修饰的耐受性树突状细胞免疫疗法特异性抑制 β 细胞区室中的自身反应攻击，而不损害自然宿主免疫（针对病原体或转化细胞），以及 (2) 开发供体来源的 MHC I 类匹配将β细胞植入新型生物材料中，以恢复胰岛素的产生并使血糖水平正常化。为了第一个目标，研究将通过敲除负责的关键基因将 DC 重新编程为耐受状态统治免疫力。该方法结合内源性 MHC II 类沉默并取代它转基因编码修饰的 MHC II 类，专门呈现 β 细胞自身抗原肽具有高亲和力。结果将导致仅呈现 MHC II 类限制性 β 细胞的耐受性 DC 体内过继转移后产生自身抗原，导致自身反应性 T 细胞反应受到抑制，而无需损害正常宿主的适应性免疫。即使成功阻止了反复的自身反应性 T 细胞攻击，在 T1D 的中期和晚期，组织损伤通常是不可逆转的。为了应对这一挑战，第二个目标将开发一种使用来自捐赠者的 MHC I 类匹配 β 细胞的恢复方法，这些细胞接种在新型生物材料恢复体内胰岛素的产生。捐赠者衍生的β细胞将被基因重编程为表达与受体单倍型相匹配的 MHC I 类；该方法将突出捐助者的使用价值用于修复应用的组织。这些产生胰岛素的供体来源的 MHC I 类匹配的 β 细胞将然后在植入非肥胖糖尿病小鼠模型之前，将其接种到一种新型专利生物材料中。该方法的成功将通过葡萄糖恢复正常血糖来抑制糖尿病进展。依赖胰岛素的产生。这些研究的结果将支持创新的发展以及对抗 T1D 的新型转化和临床相关治疗应用。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Drebrin 1 in dendritic cells regulates phagocytosis and cell surface receptor expression through recycling for efficient antigen presentation.

树突状细胞中的 Drebrin 1 通过回收来调节吞噬作用和细胞表面受体表达，以实现有效的抗原呈递。

DOI：
发表时间：
2019
期刊：
影响因子：
6.4
作者：
Elizondo, Diana M;Andargie, Temesgen E;Haddock, Naomi L;Boddie, Thomas A;Lipscomb, Michael W
通讯作者：
Lipscomb, Michael W

Leishmania donovani infection suppresses Allograft Inflammatory Factor-1 in monocytes and macrophages to inhibit inflammatory responses.

杜氏利什曼原虫感染抑制单核细胞和巨噬细胞中的同种异体移植物炎症因子 1，从而抑制炎症反应。

DOI：
发表时间：
2021
期刊：
影响因子：
4.6
作者：
da Silva, Ricardo Louzada;Elizondo, Diana M;Brandy, Nailah Z D;Haddock, Naomi L;Boddie, Thomas A;de Oliveira, Laís Lima;de Jesus, Amélia Ribeiro;de Almeida, Roque Pacheco;de Moura, Tatiana Rodrigues;Lipscomb, Michael W
通讯作者：
Lipscomb, Michael W

Antimony resistance associated with persistence of Leishmania (Leishmania) infantum infection in macrophages.

锑抗性与巨噬细胞中婴儿利什曼原虫（Leishmania）感染的持续存在相关。

DOI：
发表时间：
2021-08
期刊：
影响因子：
2
作者：
Magalhães, Lucas Sousa;Bomfim, Lays Gisele Santos;Santos, Camilla Natália Oliveira;Dos Santos, Priscila Lima;Tanajura, Diego Moura;Lipscomb, Michael Wheeler;de Jesus, Amélia Ribeiro;de Almeida, Roque Pacheco;de Moura, Tatiana Rodrigues
通讯作者：
de Moura, Tatiana Rodrigues

Space-time risk cluster of visceral leishmaniasis in Brazilian endemic region with high social vulnerability: An ecological time series study.

巴西高社会脆弱性流行地区内脏利什曼病时空风险集群：生态时间序列研究。

DOI：
发表时间：
2021
期刊：
影响因子：
3.8
作者：
Ribeiro, Caique J N;Dos Santos, Allan D;Lima, Shirley V M A;da Silva, Eliete R;Ribeiro, Bianca V S;Duque, Andrezza M;Peixoto, Marcus V S;Dos Santos, Priscila L;de Oliveira, Iris M;Lipscomb, Michael W;de Araújo, Karina C G M;de Moura, Tatiana R
通讯作者：
de Moura, Tatiana R

IL-10 producing CD8+ CD122+ PD-1+ regulatory T cells are expanded by dendritic cells silenced for Allograft Inflammatory Factor-1.

产生 IL-10 的 CD8 CD122 PD-1 调节性 T 细胞通过同种异体移植炎症因子 1 沉默的树突状细胞进行扩增。

DOI：
发表时间：
2019
期刊：
影响因子：
5.5
作者：
Elizondo, Diana M;Andargie, Temesgen E;Haddock, Naomi L;da Silva, Ricardo L Louzada;de Moura, Tatiana Rodrigues;Lipscomb, Michael W
通讯作者：
Lipscomb, Michael W