Dataset Information

Anti-IL-22 Antibody Attenuates Acute Graft-versus-Host Disease via Increasing Foxp3⁺ T Cell through Modulation of CD11b⁺ Cell Function.

ABSTRACT: Transfer of splenocytes isolated from B6 mice into normal B6D2F1 mice induces acute graft-versus-host disease (aGVHD), resulting in the expansion of donor cytotoxic T lymphocytes that eliminate recipient B cells. The cytokine IL-22, secreted by Th1 cells, Th17 cells, and innate immune cells, is structurally related to IL-10. To investigate the association between IL-22 and aGVHD, an anti-mouse IL-22 antibody (IL-22Ab) was used to ablate IL-22 activity in a mouse aGVHD model. Administration of IL-22Ab significantly reduced the progression of aGVHD in B6D2F1 recipients of B6 grafts. IL-22Ab treatment also decreased the percentage of interferon-?⁺ and tumor necrosis factor-?⁺ T cells but increased the number of forkhead box p3⁺ regulatory T cells (Tregs). In the presence of Tregs and donor CD11b⁺ cells, IL-22Ab protected against aGVHD. In vitro Treg induction was more efficient when CD4⁺CD25^- T cells differentiated in the presence of CD11b⁺ cells obtained from IL-22Ab-treated GVHD mice, compared with cocultured untreated control cells. Finally, IL-22Ab modulated the expression of cytokines and costimulatory molecules in CD11b⁺ cells in aGVHD mice. We therefore conclude that IL-22Ab administration represents a viable approach for treating aGVHD.

SUBMITTER: Wu J

PROVIDER: S-EPMC6109487 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Anti-IL-22 Antibody Attenuates Acute Graft-versus-Host Disease via Increasing Foxp3<sup>+</sup> T Cell through Modulation of CD11b<sup>+</sup> Cell Function.

Wu Jianbo J Gu Jian J Zhou Shun S Lu Hao H Lu Yunjie Y Lu Ling L Wang Xuehao X

Journal of immunology research 20180807

Transfer of splenocytes isolated from B6 mice into normal B6D2F1 mice induces acute graft-versus-host disease (aGVHD), resulting in the expansion of donor cytotoxic T lymphocytes that eliminate recipient B cells. The cytokine IL-22, secreted by Th1 cells, Th17 cells, and innate immune cells, is structurally related to IL-10. To investigate the association between IL-22 and aGVHD, an anti-mouse IL-22 antibody (IL-22Ab) was used to ablate IL-22 activity in a mouse aGVHD model. Administration of IL ...[more]

PMID: 30159338

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Project description:Cytokines are major players regulating immune responses toward inflammatory and tolerogenic results. In organ and bone marrow transplantation, new reagents are needed to inhibit tissue destructive mechanisms and eventually induce immune tolerance without overall immunosuppression. IL-34 is a cytokine with no significant homology with any other cytokine but that acts preferentially through CSF-1R, as CSF-1 does, and through PTPζ and CD138. Although IL-34 and CSF-1 share actions, a detailed analysis of their effects on immune cells needs further research. We previously showed that both CD4+ and CD8+ FOXP3+ Tregs suppress effector T cells through the production of IL-34, but not CSF-1, and that this action was mediated through antigen-presenting cells. We showed here by single-cell RNAseq and cytofluorimetry that different subsets of human monocytes expressed different levels of CSF-1R, CD138, and PTPζ and that both CD4+ and CD8+ FOXP3+ Tregs expressed higher levels of CSF-1R than conventional T cells. The effects of IL-34 differed in the survival of these different subpopulations of monocytes and RNAseq analysis showed several genes differentially expressed between IL-34, CSF-1, M0, M1, and also M2 macrophages. Acute graft-vs.-host disease (aGVHD) in immunodeficient NSG mice injected with human PBMCs was decreased when treated with IL-34 in combination with an anti-CD45RC mAb that depleted conventional T cells. When IL-34-differentiated monocytes were used to expand Tregs in vitro, both CD4+ and CD8+ FOXP3+ Tregs were highly enriched and this effect was superior to the one obtained with CSF-1. Human CD8+ Tregs expanded in vitro with IL-34-differentiated allogeneic monocytes suppressed human immune responses in an NSG mouse aGVHD model humanized with hPBMCs. Overall, we showed that IL-34 induced the differentiation of human monocytes with a particular transcriptional profile and these cells favored the development of potent suppressor FOXP3+ Tregs.

Project description:Interleukin 17 (IL-17) is a signature cytokine of Th17 cells. IL-17 level is significantly increased in inflammatory conditions of the CNS, including but not limited to post-stroke and multiple sclerosis. IL-17 has been detected direct toxicity on oligodendrocyte (Ol) lineage cells and inhibition on oligodendrocyte progenitor cell (OPC) differentiation, and thus promotes myelin damage. The cellular mechanism of IL-17 in CNS inflammatory diseases remains obscure. Voltage-gated K+ (Kv) channel 1.3 is the predominant Kv channel in Ol and potentially involved in Ol function and cell cycle regulation. Kv1.3 of T cells involves in immunomodulation of inflammatory progression, but the role of Ol Kv1.3 in inflammation-related pathogenesis has not been fully investigated. We hypothesized that IL-17 induces myelin injury through Kv1.3 activation. To test the hypothesis, we studied the involvement of OPC/Ol Kv1.3 in IL-17-induced Ol/myelin injury in vitro and in vivo. Kv1.3 currents and channel expression gradually decreased during the OPC development. Application of IL-17 to OPC culture increased Kv1.3 expression, leading to a decrease of AKT activation, inhibition of proliferation and myelin basic protein reduction, which were prevented by a specific Kv1.3 blocker 5-(4-phenoxybutoxy) psoralen. IL-17-caused myelin injury was validated in LPC-induced demyelination mouse model, particularly in corpus callosum, which was also mitigated by aforementioned Kv1.3 antagonist. IL-17 altered Kv1.3 expression and resultant inhibitory effects on OPC proliferation and differentiation may by interrupting AKT phosphorylating activation. Taken together, our results suggested that IL-17 impairs remyelination and promotes myelin damage by Kv1.3-mediated Ol/myelin injury. Thus, blockade of Kv1.3 as a potential therapeutic strategy for inflammatory CNS disease may partially attribute to the direct protection on OPC proliferation and differentiation other than immunomodulation.

Dataset Information

Anti-IL-22 Antibody Attenuates Acute Graft-versus-Host Disease via Increasing Foxp3⁺ T Cell through Modulation of CD11b⁺ Cell Function.

Publications

Anti-IL-22 Antibody Attenuates Acute Graft-versus-Host Disease via Increasing Foxp3<sup>+</sup> T Cell through Modulation of CD11b<sup>+</sup> Cell Function.

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Dataset Information

Anti-IL-22 Antibody Attenuates Acute Graft-versus-Host Disease via Increasing Foxp3+ T Cell through Modulation of CD11b+ Cell Function.

Publications

Anti-IL-22 Antibody Attenuates Acute Graft-versus-Host Disease via Increasing Foxp3<sup>+</sup> T Cell through Modulation of CD11b<sup>+</sup> Cell Function.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Anti-IL-22 Antibody Attenuates Acute Graft-versus-Host Disease via Increasing Foxp3⁺ T Cell through Modulation of CD11b⁺ Cell Function.