Alpha-1-antitrypsin for the improvement of autoimmunity and allograft rejection in beta cell transplantation

Ye, Jian; Liao, Yuting; Jian, You-Qiang; Zhang, Xiaodan; Pei, Wei; Qi, Hui; Deng, Chao; Li, Furong

doi:10.1016/j.imlet.2013.01.009

Cited by 15 publications

(13 citation statements)

References 35 publications

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“…Based on the widespread fluorescence in the liver, we speculated that Reg3g could also be coexpressed with EGFP in this organ. Importantly, AAT-1, as an important antiinflammatory and anti-apoptotic factor, is predominantly produced in the liver [25,26], whereas the JAK2/STAT3 signaling pathway is involved in AAT-1 production [27]. In Reg3g-Lv-treated mice, we confirmed the overexpression of Reg3g (P , 0.01) in liver, in contrast to PBS-treated mice or EGFP-Lv-treated mice.…”

Section: Elevated Level Of Aat-1 In Reg3g-lv Treated Micesupporting

confidence: 59%

“…It is plausible that the apoptotic process in b cells was inhibited either by the proliferative response to Reg3g treatment itself or because it is often difficult to detect dead b cells because of their rapid engulfment and disposal [32,33]. In addition, we determined the effects of Reg3g treatment on endogenous AAT-1 expression, a well-known liver-derived multifunctional serpin [25,26] with anti-inflammatory and antiapoptotic properties [31,[34][35][36]. The highest serum level of AAT-1 was found in Reg3g-Lv-treated mice, supporting the involvement of AAT-1 in the protection of b cell apoptosis.…”

Section: Discussionmentioning

confidence: 99%

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Reg3g overexpression promotes β cell regeneration and induces immune tolerance in nonobese-diabetic mouse model

Xia

Cao

et al. 2015

Journal of Leukocyte Biology

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The regenerating islet-derived gene was first isolated in regenerated pancreas tissues, greatly contributing to β cell regeneration. It is an anti-inflammatory in response to cellular stress. This encouraged us to investigate the exact role of a novel member of Reg family, regenerating islet-derived gene γ, in type 1 diabetes of nonobese-diabetic mice. For this, Reg3g gene was overexpressed in pancreatic islets, and conferred beneficial effects on β cell regeneration through activating the Janus kinase 2/signal transducer and activator of transcription 3/nuclear factor κB signaling pathway. Lentiviral vector-encoding regenerating islet-derived gene γ treatment also decreased lymphocyte infiltrates of the intra-islet and peri-islet by inducing both differentiation of regulatory T cell and immature dendritic cells of tolerogenic properties, which attenuated autoimmunity. This treatment further contributed to rebalanced levels of type 1/2 helper T cell cytokines and elevated α1-antitrypsin levels in the serum. These results were not observed in phosphate-buffered saline-treated mice or in lentivirus-control mice. We have shown, for the first time, to our knowledge, that regenerating islet-derived gene γ promotes β cell regeneration and preserves β cells from autoimmunity damage by increasing regulatory T cell differentiation and inducing tolerated dendritic cells. This regenerating islet-derived gene γ infusion could probably be developed into an optimal gene therapy for the prevention and reversal of type 1 diabetes.

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Section: Elevated Level Of Aat-1 In Reg3g-lv Treated Micesupporting

confidence: 59%

Section: Discussionmentioning

confidence: 99%

Reg3g overexpression promotes β cell regeneration and induces immune tolerance in nonobese-diabetic mouse model

Xia

Cao

et al. 2015

Journal of Leukocyte Biology

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“…NIT-1 cells were transfected with a vector encoding hAAT to generate a NIT–hAAT stable cell line. pDsRed–hAAT is a 55-kb plasmid that holds the entire human AAT sequence, including exons and introns, and the ability to self-replicate without integrating into the genome [17]. The expression of hAAT was verified by western blot.…”

Section: Discussionmentioning

confidence: 99%

The Immunoregulation Effect of Alpha 1-Antitrypsin Prolong β-Cell Survival after Transplantation

et al. 2014

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Islet transplantation has considerable potential as a cure for diabetes. However, the difficulties that arise from inflammation and the immunological rejection of transplants must be addressed for islet transplantation to be successful. Alpha 1-antitrypsin (AAT) inhibits the damage on β cells caused by inflammatory reactions and promotes β-cell survival and proliferation. This protein also induces specific immune tolerance to transplanted β cells. However, whether the expression of AAT in β cells themselves could eliminate or decrease immunological rejection of transplants is not clear. Therefore, we established a β cell line (NIT-hAAT) that stably expresses human AAT. Interestingly, in a cytotoxic T lymphocyte (CTL)-killing assay, we found that hAAT reduced apoptosis and inflammatory cytokine production in NIT-1 cells and regulated the Th1/Th2 cytokine balance in vitro. In vivo transplantation of NIT-hAAT cells into mice with diabetes showed hAAT inhibited immunological rejection for a short period of time and increased the survival of transplanted β cells. This study demonstrated that hAAT generated remarkable immunoprotective and immunoregulation effects in a model of β cell islet transplantation for diabetes model.

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“…Paraffin-embedded 5 µm sections were routinely stained with hematoxylin and eosin. The hematoxylin and eosin-stained kidney sections were analyzed by counting the number of inflammatory cells infiltrating into the left kidney in 10 high-power fields (×400) per sample (22). …”

Section: Methodsmentioning

confidence: 99%

Immunogenicity of insulin-producing cells derived from human umbilical cord mesenchymal stem cells

Yang

Chen

Ren

et al. 2017

Experimental and Therapeutic Medicine

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Mesenchymal stem cells (MSCs) have been considered as hypo-immunogenic and immunosuppressive. However, a thorough understanding of the immunological properties after MSC differentiation in vitro and in vivo has not been reached. We asked whether it would be immunogenic after differentiation or influenced by the immune microenvironment after transplantation. In different disease models, the immunological changes of MSCs after differentiation greatly varied, with contradicting results. In order to clarify this, we used a modified four-step induction method to induce human umbilical cord MSCs (hUCMSCs) to differentiate into insulin-producing cells (IPCs), and investigate the immunological changes after differentiation and immune reactions after transplantation into diabetic mice. We found that the induced IPCs are hypo-immunogenic, lacking HLA-DR, CD40 and CD80 expression. Of note, we observed immune cell infiltration to peritoneal cavity and left kidney capsule after local transplantation of induced IPCs. This indicated that hUCMSC-derived IPCs maintained hypo-immunogenic in vitro, but became immunogenic after transplanting to the host, possibly due to the changes of immune microenvironment and thereafter immunological enhancement and immune cell infiltration.

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Alpha-1-antitrypsin for the improvement of autoimmunity and allograft rejection in beta cell transplantation

Cited by 15 publications

References 35 publications

Reg3g overexpression promotes β cell regeneration and induces immune tolerance in nonobese-diabetic mouse model

Reg3g overexpression promotes β cell regeneration and induces immune tolerance in nonobese-diabetic mouse model

The Immunoregulation Effect of Alpha 1-Antitrypsin Prolong β-Cell Survival after Transplantation

Immunogenicity of insulin-producing cells derived from human umbilical cord mesenchymal stem cells

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