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Type 1 diabetes mellitus and its oral tolerance therapy

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World Journal of Diabetes 2020年第10期11卷 400-415页

作者： Rui-Feng Mao Ying-Ying Chen Ji Zhang Xin Chang Ye-Fu Wang Jiangsu Collaborative Innovation Center of Regional Modern Agriculture and Environmental Protection School of Life ScienceHuaiyin Normal UniversityHuai'an 223300Jiangsu ProvinceChina School of Life Sciences Huaiyin Normal UniversityHuai'an 223300Jiangsu ProvinceChina Department of Ultrasound Medicine Nanjing Lishui People’s HospitalZhongda Hospital Lishui BranchSoutheast UniversityNanjing 211200Jiangsu ProvinceChina College of Life Sciences Wuhan UniversityWuhan 430072Hubei ProvinceChina

As a T cell-mediated autoimmune disease,type 1 diabetes mellitus(T1DM)is marked by insulin defect resulting from the destruction of pancreaticβ-*** understanding of various aspects of T1DM,such as its epidemiology,pathobiology,pathogenesis,clinical manifestations,and complications,has been greatly promoted by valuable research performed during the past ***,these findings have not been translated into an effective *** ideal treatment should safely repair the destroyed immune balance in a longlasting manner,preventing or stopping the destruction ofβ-*** a type of immune hypo-responsiveness to the orally administrated antigen,oral tolerance may be induced by enhancement of regulatory T cells(Tregs)or by anergy/deletion of T cells,depending on the dosage of orally administrated *** as an antigen-specific immunotherapy,oral tolerance therapy for T1DM has been mainly performed using animal models and some clinical trials have been completed or are still *** on the review of the proposed mechanism of the development of T1DM and oral tolerance,we give a current overview of oral tolerance therapy for T1DM conducted in both animal models and clinical trials.

关键词： Type 1 diabetes mellitus Immunotherapy oral tolerance Regulatory T cells Antigen-specific immunotherapy

Colonization by Superantigen Producing Staphylococcus aureus in Mice Enhances the Capacity to Develop oral tolerance

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Open Journal of Immunology 2016年第3期6卷 79-92页

作者： Anna Stern Erika Lindberg Forough L. Nowrouzian Agnes E. Wold Sofia Östman Department of Infectious Medicine Institute of Biomedicine Sahlgrenska Academy University of Gothenburg Gothenburg Sweden

Microbial stimulation in early childhood may be necessary for proper maturation of the immune system. Infants colonized with Staphylococcus aureus have low risk of developing food allergy. Neonatal exposure to staphylococcal superantigen improves oral tolerance and enhances protection in experimental allergy models. Here, we used three wild-type strains of S. aureus, naturally harboring genes for different superantigens (SElM/SElO alone, or in combination with SEA or TSST-1). We first investigated their in vitro stimulatory capacity of splenocytes from germ-free mice. Secondly, germ-free mice were colonized with the strains and their capacity to develop oral tolerance was tested in a food allergy model. In vitro, S. aureus with only SElM/SElO genes promoted the strongest B-cell stimulation. S. aureus carrying gene for SEA induced the highest proportion of CD4+FoxP3+ T cells. The proportion of regulatory T cells was inversely correlated to B-cell proliferation, indicating suppressive ability of these cells. All strains were equally able to colonize the germ-free gut, initially achieving 1010CFU/g faeces, which decreased to 105 over a period of six weeks. Mice colonized with S. aureus carrying genes for SEA or TSST-1 had improved capacity to develop tolerance compared to germ-free mice. These results suggest that colonization by S. aureus producing superantigens may improve active tolerance to gut allergens.

关键词： oral tolerance Superantigen Staphylococcus aureus

New aspects in celiac disease

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World Journal of Gastroenterology 2007年第8期13卷 1156-1161页

作者： MI Torres MA López Casado A Ríos Department of Experimental Biology University of JaénJaén 23071Spain Department of Gastroenterology Pediatrics. Hospital Virgen de las Nieves Granada Department Cell Biology. University of Granada Granada

Celiac disease (CD) is a common autoimmune disorder characterized by an immune response to ingested gluten and has a strong HLA association with HLA- DQ2 and HLA-DQ8 molecules, but human HLA-DQ risk factors do not explain the entire genetic susceptibility to gluten intolerance. CD is caused by the lack of immune tolerance (oral tolerance) to wheat gluten. In this sense, the expression of soluble HLA-G in CD is of special interest because the molecule plays an important role in the induction of immune tolerance. The enhanced expression of soluble HLA-G found in CD may be part of a mechanism to restore the gluten intolerance. In this editorial, we review recent progress in understanding CD in relation to its prevalence, diagnosis and possible mechanisms of pathogenesis.

关键词： Celiac disease oral tolerance IL-10 TGF-beta Gluten intolerance

Construction of a Der p2-transgenic plant for the alleviation of airway inflammation

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Cellular & Molecular Immunology 2011年第5期8卷 404-414页

作者： CC Lee H Ho KT Lee ST Jeng BL Chiang Department of Microbiology and Immunology School of MedicineChina Medical UniversityTaichungTaiwan Graduate Institute of Immunology College of MedicineTaipeiTaiwan Institute of Microbiology and Biochemistry TaipeiTaiwan Institute of Plant Biology College of Life ScienceNational Taiwan UniversityTaipeiTaiwan Allergy Center TaipeiTaiwan Department of Pediatrics National Taiwan University HospitalTaipeiTaiwan Graduate Institute of Clinical Medicine TaipeiTaiwan

In clinical therapy,the amount of antigen administered to achieve oral tolerance for allergic diseases is large,and the cost is a major *** this study,we used tobacco plants to develop a large-scale protein production system for allergen-specific immunotherapy,and we investigated the mechanisms of oral tolerance induced by a transgenic plant-derived *** used plants(tobacco leaves)transgenic for the Dermatophagoides pteronyssinus 2(Der p2)antigen to produce Der *** received total protein extract from Der p2 orally once per day over 6 days(days 0–2 and days 6–8).Mice were also sensitized and challenged with yeast-derived recombinant Der p2(rDer p2),after which the mice were examined for airway hyper-responsiveness and airway *** sensitization and challenge with rDer p2,mice that were fed with total protein extracted from transgenic plants showed decreases in serum Der p2-specific IgE and IgG1 titers,decreased IL-5 and eotaxin levels in bronchial alveolar lavage fluid,and eosinophil infiltration in the *** addition,hyper-responsiveness was also decreased in mice that were fed with total protein extracted from transgenic plants,and CD4^(+)CD25^(+)Foxp3^(+) regulatory T cells were significantly increased in mediastinal and mesenteric lymph ***,splenocytes isolated from transgenic plant protein-fed mice exhibited decreased proliferation and increased IL-10 secretion after stimulation with rDer *** data here suggest that allergen-expressing transgenic plants could be used for therapeutic purposes for allergic diseases.

关键词： asthma Der p2 IL-10 oral tolerance transgenic plant

Changes of CD8＋ T cells in dextran sulfate sodium-induced colitis mice pretreated with oral immune regulation

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Chinese Medical Journal 2012年第12期125卷 2173-2179页

作者： YE Yue-fang JIN Xi CHEN Shao-hua YUE Min LI You-ming Department of Gastroenterology Affiliated Hospital HangzhouNormal University College of Medicine Hangzhou Zhejiang310015 China Department of Gastroenterology First Affiliated HospitalZhejiang University College of Medicine Hangzhou Zhejiang310003 China

Background It has been reported that CD8＋ regulatory cells could be induced upon oral tolerance. The purpose of this study was to investigate the changes of CD8a＋ T cells in dextran sulfate sodium （DSS）-induced colitis mice pretreated by oral immune regulation. Methods The effects of five low oral doses of colitis-extracted proteins （CEP） on colitis were evaluated by clinical manifestation and histological lesions. The percentages of CD8a＋ T cells gating on CD3＋ T cells were evaluated in the gut-associated lymphoid tissues （GALT） and the spleens by flow cytometry. Differences between the two groups were compared by Student＇s t test or Mann-Whitney U test. Results Compared to bovine serum albumin （BSA）-fed control mice, administration of CEP resulted in marked alleviation of colitis. The proportion of CDSa＋ T ceils, not only in intraepithelial lymphocytes （IELs） and lamina propria lymphocytes （LPLs） of the large intestine （LI） but also in spleen from CEP-fed colitis mice, was significantly higher than that from BSA-fed colitis mice （LI-IELs：（71.5±5.4）% vs. （60.1±4.3）%, P 〈0.01; LI-LPLs：（60.7±5.2）% vs. （51.9±4.7）%, P 〈0.01; spleen：（24.1±3.6）% vs. （20.3±4.1）%, P 〈0.05; n=8）. Mucosal repair in repair-period mice five days after termination of DSS treatment was also accompanied by an increase of CD8a＋ T cells in large intestinal mucosal lymphocytes （LI-IELs：（72.1±3.7）% vs. （61.5±4.5）%, P 〈0.01; LI-LPLs：（62.1±5.7）% vs. （52.7±3.6）%, P 〈0.01; n=8）. The proportion of CD3＋ T cells increased in Peyer＇s patches （PPs） and decreased in mesenteric lymph nodes （MLNs） from colitis mice compared to untreated mice, whereas the change pattern of CD3＋T cells in PPs and MLNs from CEP-fed colitis mice was just on the contrary. Conclusion Improvement of DSS-induced colitis resulted from oral immune regulation is associated with an increase in CD8a＋T cells in spleen and large intestinal mucosa.

关键词： dextran sulfate sodium colitis mouse oral tolerance CD8a+ T cells

oral administration of insulin to female nonobese diabetic mice inhibited diabetes and induced Fas ligand expression on islets of Langerhans

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Chinese Medical Journal 2000年第5期113卷 49-52页

作者：王姮李玉秀孙琦杨国华 Department of Endocrinology Peking Union Medical College Hospital Beijing 100730 China.

To detect oral administration of recombinant human insulin to nonobese diabetic (NOD) mice for preventing them from diabetes and insulitis and to detect the effects of oral administration of insulin on Fas and Fas ligand expression on islet of Langerhans Methods Sixty four female NOD mice were divided into two groups One group (34) was orally administered recombination human insulin 1?mg in 500?μl PBS and the other (30) 500?μl PBS only at age of 5 weeks old, twice a week for the first week, then weekly until 30 weeks of age Results oral administration of insulin to female NOD mice can significantly suppress diabetes and insulitis The insulitis was less severe in the group fed with insulin than that in the control group (score of insulitis: 1 25±0 45 vs 3 0±0 76 at 16 weeks of age, P oral insulin may induce Fas ligand expression on the islets and plays a role in protecting the pancreatic β cell from autoimmune destruction These results show that oral insulin affected autoimmune diabetes and insulitis in NOD mice The immune mechanism of oral tolerance is closely related to the change of Fas ligand and Fas system

关键词： Fas Fas ligand oral tolerance