Inhibition of Fas Ligand in NOD Mice Unmasks a Protective Role for IL-10 against Insulitis Development

Xiao, Zuoxiang; Mohamood, Abdiaziz S.; Uddin, Sophia; Gutfreund, Rachel; Nakata, Chiaki; Marshall, Andrew; Kimura, Hiroaki; Caturegli, Patrizio; Womer, Karl L.; Huang, Yanfei; Jie, Chunfa; Chakravarti, Shukti; Schneck, Jonathan P.; Yagita, Hideo; Hamad, Abdel Rahim A.

doi:10.1016/j.ajpath.2011.04.016

Cited by 25 publications

(28 citation statements)

References 47 publications

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“…Likewise, genetic deletion of IL-10 produced no detectable effects on the disease pathogenesis [69]. However, clues that the immunoregulatory effect of IL-10 might be pathogenically subverted in NOD mice were revealed by our finding that inactivation of Fas-mediated apoptosis restores a potent role for IL-10 in protecting pancreatic islets from infiltration by diabetogenic T cells [70]. The results also pointed to CD5+ B cells as the major local pancreatic source of protective IL-10 in NOD mice [70].…”

Section: Il-10 and Pathogenesis Of Autoimmune Diseasesmentioning

confidence: 99%

“…However, clues that the immunoregulatory effect of IL-10 might be pathogenically subverted in NOD mice were revealed by our finding that inactivation of Fas-mediated apoptosis restores a potent role for IL-10 in protecting pancreatic islets from infiltration by diabetogenic T cells [70]. The results also pointed to CD5+ B cells as the major local pancreatic source of protective IL-10 in NOD mice [70]. Thus, aberrant deletion of IL-10-producing B cells appears to be involved in breaking of self-tolerance against islet autoantigens and that rectifying of the underlying cause of their deficiency prevents the disease.…”

Section: Il-10 and Pathogenesis Of Autoimmune Diseasesmentioning

confidence: 99%

“…Instead, more efforts should be directed toward fortressing and protecting the endogenous IL-10 sources. Case in point, we found that aberrant Fas-mediated apoptosis compromises the protective role of IL-10 in autoimmune diseases by inadvertently depleting IL-10-producing B cells and that genetic or antibody blockade of FasL restores the IL-10 role in protecting pancreatic islets from diabetogenic T cell cells [70]. Thus, identifying pathogenic mechanisms that work to subvert the immunomodulatory function of IL-10 in susceptible individuals and animal models may lead to novel and effective therapeutic strategies.…”

Section: Challenges Facing Effective Therapeutic Utilization Of Ilmentioning

confidence: 99%

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Interleukin-10 paradox: A potent immunoregulatory cytokine that has been difficult to harness for immunotherapy

et al. 2015

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Interleukin-10 (IL-10) is arguably the most potent anti-inflammatory cytokine. It is produced by almost all the innate and adaptive immune cells. These cells also serve as its targets, indicating that IL-10 secretion and action is highly regulated and perhaps compartmentalized. Consistent with this notion, various efforts directed at systemic administration of IL-10 to modulate autoimmune diseases (type 1 diabetes, multiple sclerosis, rheumatoid arthritis, psoriasis) have produced conflicting and largely inconsequential effects. On the other hand, IL-10 can promote humoral immune responses, enhancing class II expression on B cells and inducing immunoglobulin (Ig) production. Consequently, the high IL-10 level in systemic lupus erythematosus (SLE) patients is considered pathogenic and its blockade ameliorates the disease. In this perspective, we review preclinical findings and results of recent clinical studies using exogenous IL-10 to treat the aforementioned autoimmune diseases. In addition, given the limited success of IL-10 supplementation, we suggest that future studies should be expanded beyond modulating the delivery modes to include developing new strategies to protect and replenish the endogenous sources of IL-10. As an example, we provide evidence that aberrant Fas-mediated deletion of IL-10-producing B cells subverts the immunoregulatory role of IL-10 in autoimmune diabetes and that modulation of the Fas pathway preserves the IL-10-producing B cells and completely protects NOD mice from developing the disease.

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Section: Il-10 and Pathogenesis Of Autoimmune Diseasesmentioning

confidence: 99%

Section: Il-10 and Pathogenesis Of Autoimmune Diseasesmentioning

confidence: 99%

Section: Challenges Facing Effective Therapeutic Utilization Of Ilmentioning

confidence: 99%

See 1 more Smart Citation

Interleukin-10 paradox: A potent immunoregulatory cytokine that has been difficult to harness for immunotherapy

et al. 2015

Self Cite

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“…In addition, IL-10 may be directly activated by the inhibitory signal transduction pathway in T cells. IL-10 may reduce Fas-mediated apoptosis by restricting caspase-3 activity through the upregulation of FLIP and downregulation of caspase-8 activity (11,12).…”

Section: Discussionmentioning

confidence: 99%

“…IL-10 can suppress the antigen presentation function by inhibiting the expression of MHC-Ⅱ molecules on the surface of mononuclear macrophages. In addition, IL-10 serves an important role in immunosuppression and anti-apoptosis by suppressing the release of inflammatory factors of mononuclear macrophages (10)(11)(12). Numerous autoimmune diseases are associated…”

Section: Introductionmentioning

confidence: 99%

Protective role of adenovirus vector-mediated interleukin-10 gene therapy on endogenous islet β-cells in recent-onset type 1 diabetes in NOD mice

Zhang

Chen

et al. 2016

Experimental and Therapeutic Medicine

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Abstract. The aim of the present study was to provide an animal experimental basis for the protective effect of the adenoviral vector-mediated interleukin-10 (Ad-mIL-10) gene on islet β-cells during the early stages of type 1 diabetes (T1D) in non-obese diabetic (NOD) mice. A total of 24 female NOD mice at the onset of diabetes were allocated at random into three groups (n=8 per group): Group 1, intraperitoneally injected with 0

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Regulatory B Cells in Type 1 Diabetes

Boldison

Rosa

Wong

2021

Methods in Molecular Biology

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Inhibition of Fas Ligand in NOD Mice Unmasks a Protective Role for IL-10 against Insulitis Development

Cited by 25 publications

References 47 publications

Interleukin-10 paradox: A potent immunoregulatory cytokine that has been difficult to harness for immunotherapy

Interleukin-10 paradox: A potent immunoregulatory cytokine that has been difficult to harness for immunotherapy

Protective role of adenovirus vector-mediated interleukin-10 gene therapy on endogenous islet β-cells in recent-onset type 1 diabetes in NOD mice

Regulatory B Cells in Type 1 Diabetes

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