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口服疫苗预防和逆转非肥胖糖尿病（NOD）小鼠1型糖尿病的作用机制

Mechanism of Action of Oral -Based Vaccine to Prevent and Reverse Type 1 Diabetes in NOD Mice.

作者信息

Cobb Jacob, Rawson Jeffrey, Gonzalez Nelson, Singer Mahmoud, Kandeel Fouad, Husseiny Mohamed I

机构信息

Department of Translational Research & Cellular Therapeutics, Arthur Riggs Diabetes & Metabolism Research Institute, Duarte, CA 91010, USA.

Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA.

出版信息

Vaccines (Basel). 2024 Mar 6;12(3):276. doi: 10.3390/vaccines12030276.

DOI:10.3390/vaccines12030276
PMID:38543910
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10975319/
Abstract

A combination therapy of preproinsulin (PPI) and immunomodulators (TGFβ+IL10) orally delivered via genetically modified and anti-CD3 promoted glucose balance in in NOD mice with recent onset diabetes. The bacteria were modified to express the diabetes-associated antigen PPI controlled by a bacterial promoter in conjunction with over-expressed immunomodulating molecules. The possible mechanisms of action of this vaccine to limit autoimmune diabetes remained undefined. In mice, the vaccine prevented and reversed ongoing diabetes. The vaccine-mediated beneficial effects were associated with increased numbers of antigen-specific CD4CD25Foxp3 Tregs, CD4CD49bLAG3 Tr1-cells, and tolerogenic dendritic-cells (tol-DCs) in the spleens and lymphatic organs of treated mice. Despite this, the immune response to infection was not altered. Furthermore, the vaccine effects were associated with a reduction in islet-infiltrating lymphocytes and an increase in the islet beta-cell mass. This was associated with increased serum levels of the tolerogenic cytokines (IL10, IL2, and IL13) and chemokine ligand 2 (CCL2) and decreased levels of inflammatory cytokines (IFNγ, GM-CSF, IL6, IL12, and TNFα) and chemokines (CXCL1, CXCL2, and CXCL5). Overall, the data suggest that the -based vaccine modulates the immune response, reduces inflammation, and promotes tolerance specifically to an antigen involved in autoimmune diabetes.

摘要

通过基因改造的抗CD3口服给予前胰岛素原（PPI）和免疫调节剂（TGFβ+IL10）的联合疗法可促进近期发病的NOD糖尿病小鼠的血糖平衡。对细菌进行改造，使其表达由细菌启动子控制的糖尿病相关抗原PPI，并同时过表达免疫调节分子。这种疫苗限制自身免疫性糖尿病的可能作用机制尚不清楚。在小鼠中，该疫苗可预防和逆转正在发生的糖尿病。疫苗介导的有益作用与治疗小鼠脾脏和淋巴器官中抗原特异性CD4CD25Foxp3调节性T细胞、CD4CD49bLAG3 Tr1细胞和耐受性树突状细胞（tol-DCs）数量的增加有关。尽管如此，对感染的免疫反应并未改变。此外，疫苗的作用与胰岛浸润淋巴细胞的减少和胰岛β细胞量的增加有关。这与耐受性细胞因子（IL10、IL2和IL13）和趋化因子配体2（CCL2）血清水平的升高以及炎性细胞因子（IFNγ、GM-CSF、IL6、IL12和TNFα）和趋化因子（CXCL1、CXCL2和CXCL5）水平的降低有关。总体而言，数据表明基于该疫苗可调节免疫反应、减轻炎症并特异性促进对自身免疫性糖尿病相关抗原的耐受性。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9770/10975319/6b04690e4551/vaccines-12-00276-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9770/10975319/56e1cf769665/vaccines-12-00276-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9770/10975319/064772ea329c/vaccines-12-00276-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9770/10975319/64ee2cfb12ea/vaccines-12-00276-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9770/10975319/2d810d10395e/vaccines-12-00276-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9770/10975319/b3a730f1dcab/vaccines-12-00276-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9770/10975319/84d88535cfc2/vaccines-12-00276-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9770/10975319/2324e0926885/vaccines-12-00276-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9770/10975319/6b04690e4551/vaccines-12-00276-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9770/10975319/56e1cf769665/vaccines-12-00276-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9770/10975319/064772ea329c/vaccines-12-00276-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9770/10975319/64ee2cfb12ea/vaccines-12-00276-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9770/10975319/2d810d10395e/vaccines-12-00276-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9770/10975319/b3a730f1dcab/vaccines-12-00276-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9770/10975319/84d88535cfc2/vaccines-12-00276-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9770/10975319/2324e0926885/vaccines-12-00276-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9770/10975319/6b04690e4551/vaccines-12-00276-g008.jpg

相似文献

[1]
Mechanism of Action of Oral -Based Vaccine to Prevent and Reverse Type 1 Diabetes in NOD Mice.

Vaccines (Basel). 2024-3-6

[2]
Reversal of New Onset Type 1 Diabetes by Oral -Based Combination Therapy and Mediated by Regulatory T-Cells in NOD Mice.

Front Immunol. 2019-2-26

[3]
Factors affecting Salmonella-based combination immunotherapy for prevention of type 1 diabetes in non-obese diabetic mice.

Vaccine. 2018-11-8

[4]
Tracking of an Oral -Based Vaccine for Type 1 Diabetes in Non-obese Diabetic Mice.

Front Immunol. 2020

[5]
An oral vaccine for type 1 diabetes based on live attenuated Salmonella.

Vaccine. 2014-3-12

[6]
Reversal of diabetes by an oral Salmonella-based vaccine in acute and progressive diabetes in NOD mice.

PLoS One. 2024

[7]
Granulocyte-macrophage colony-stimulating factor prevents diabetes development in NOD mice by inducing tolerogenic dendritic cells that sustain the suppressive function of CD4+CD25+ regulatory T cells.

J Immunol. 2007-9-15

[8]
Oral Mutant as a Carrier for a -Based Vaccine for Prevention and Reversal of Type 1 Diabetes.

Front Immunol. 2021

[9]
A GMCSF-Neuroantigen Tolerogenic Vaccine Elicits Systemic Lymphocytosis of CD4 CD25 FOXP3 Regulatory T Cells in Myelin-Specific TCR Transgenic Mice Contingent Upon Low-Efficiency T Cell Antigen Receptor Recognition.

Front Immunol. 2019-1-10

[10]
A GM-CSF-neuroantigen tolerogenic vaccine elicits inefficient antigen recognition events below the CD40L triggering threshold to expand CD4 CD25 FOXP3 Tregs that inhibit experimental autoimmune encephalomyelitis (EAE).

J Neuroinflammation. 2020-6-10

引用本文的文献

[1]
-Based Vaccine: A Promising Strategy for Type 1 Diabetes.

Vaccines (Basel). 2025-4-14

[2]
Immunological Considerations for the Development of an Effective Herpes Vaccine.

Microorganisms. 2024-9-6

[3]
Reversal of diabetes by an oral Salmonella-based vaccine in acute and progressive diabetes in NOD mice.

PLoS One. 2024

本文引用的文献

[1]
Th1 or Th2 cytokines are correlated with Tregs and T cell subsets and pregnancy outcomes in patients with autoimmune thyroid disease during early, middle, late pregnancy, and postpartum period.

Hum Immunol. 2023-10

[2]
Tregs with an MHC class II peptide-specific chimeric antigen receptor prevent autoimmune diabetes in mice.

J Clin Invest. 2023-9-15

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Immunother Adv. 2023-7-18

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Tolerogenic dendritic cells in type 1 diabetes: no longer a concept.

Front Immunol. 2023

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Changes in the gut microbiota of NOD mice in response to an oral Salmonella-based vaccine against type 1 diabetes.

PLoS One. 2023

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Human induced pluripotent stem cells (hiPSC), enveloped in elastin-like recombinamers for cell therapy of type 1 diabetes mellitus (T1D): preliminary data.

Front Bioeng Biotechnol. 2023-4-25

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Front Endocrinol (Lausanne). 2023

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Epidermal Growth Factor Receptor in Hepatic Endothelial Cells Suppresses MCP-1-Dependent Monocyte Recruitment in Diabetes.

J Immunol. 2023-5-1

[9]
Eomesodermin-expressing type 1 regulatory (EOMES Tr1)-like T cells: Basic biology and role in immune-mediated diseases.

Eur J Immunol. 2023-5

[10]
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