Recipient-derived IL-22 alleviates murine acute graft-versus-host disease in association with reduced activation of antigen presenting cells

Pan, Bin; Xia, Fan; Wu, Yujing; Zhang, Fan; Lu, Zhigang; Fu, Ruixue; Shang, Longmei; Sun, Zengtian; Zeng, Lingyu; Xu, Kailin

doi:10.1016/j.cyto.2018.08.010

Cited by 8 publications

(3 citation statements)

References 35 publications

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“…Others have reported both proinflammatory and antiinflammatory functions of IL-22 in GVHD [36]. We recently reported an anti-inflammatory function of recipient antigenpresenting cells derived IL-22 from mice with acute GVHD [37]. Interestingly, recipient macrophage-derived Stat3 exerts an anti-GVHD effect [38].…”

Section: Discussionmentioning

confidence: 89%

IL-22 Accelerates Thymus Regeneration via Stat3/Mcl-1 and Decreases Chronic Graft-versus-Host Disease in Mice after Allotransplants

Pan

Wang

et al. 2019

Biology of Blood and Marrow Transplantation

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High-dose chemotherapy and/or radiation given before an allogeneic hematopoietic cell transplantation severely damage thymic epithelial cells (TECs), resulting in poor post-transplant immune recovery. IL-22 mediates recovery of TECs via a proregenerative effect, but the precise mechanism by which this occurs is unknown. In this study, we found IL-22 improved thymus recovery after damage from irradiation in association with increased number of TECs. This effect was blocked by ruxolitinib, a JAK1/JAK2 inhibitor. IL-22 increased the number of TECs via a Stat3dependent signaling in the mTEC1 murine thymic epithelial cell line. This, in turn, upregulated transcription of myeloid cell leukemia sequence 1 (Mcl1), resulting in increased number of TECs. Similar effects were seen in irradiated mice given IL-22. Defects in IL-22 resulted in delayed thymus recovery in irradiated mice and had an impact on levels of thymus function-related genes such as Foxn1, Aire, and Kgf. In mice, post-transplant use of IL-22 improved repair of TECs, increased the numbers of thymus T cells, increased the intrathymic levels of Aire, and increased the proportion of natural regulatory T cells, resulting in decreased severity of chronic graft-versus-host disease (GVHD). Our data highlight the critical role of the IL-22/Stat3/Mcl-1 pathway in the regeneration of TECs after damage from irradiation in mice and highlight circumstances where normalizing thymus T cell function with IL-22 decreases GVHD after allotransplants.

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Section: Discussionmentioning

confidence: 89%

IL-22 Accelerates Thymus Regeneration via Stat3/Mcl-1 and Decreases Chronic Graft-versus-Host Disease in Mice after Allotransplants

Pan

Wang

et al. 2019

Biology of Blood and Marrow Transplantation

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“…Loss of intestinal crypt cells, principally leucine-rich repeat-containing G-protein-coupled receptor 5 (Lgr5+) stem cells (17), is also detected after doses that produce death from gastrointestinal syndrome (4)(5)(6). Following irradiation, there is rapid depletion of intestinal immunocytes, prominently, γδT-cells and helper T-cells, which are known to produce interleukin-22 (IL-22) and other anti-inflammatory cytokines (18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28). IL-22 produced by anti-inflammatory immunocytes helps to stabilize both intestinal Paneth cells and Lgr5+ intestinal stem cells (17).…”

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confidence: 99%

Second-generation Probiotics Producing IL-22 Increase Survival of Mice After Total Body Irradiation

Zhang¹,

Fisher²,

Hou³

et al. 2019

In Vivo

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Background/Aim: Intestinal damage induced by total body irradiation (TBI) reduces leucine-rich repeatcontaining G-protein-coupled receptor 5 (Lgr5)-expressing stem cells, goblet, and Paneth cells, breaching the epithelial lining, and facilitating bacterial translocation, sepsis, and death. Materials and Methods: Survival was measured after TBI in animals that received wild-type or recombinant bacteria producing interleukin-22 (IL-22). Changes in survival due to microbially delivered IL-22 were measured. Lactobacillus reuteri producing IL-22, or Escherichia coli-IL-22 were compared to determine which delivery system is better. Results: C57BL/6 mice receiving IL-22 probiotics at 24 h after 9.25 Gy TBI, demonstrated green fluorescent protein-positive bacteria in the intestine, doubled the number of Lgr5+ intestinal stem cells, and increased 30-day survival. Bacteria were localized to the jejunum, ileum, and colon. Conclusion: Second-generation probiotics appear to be valuable for mitigation of TBI, and radiation protection during therapeutic total abdominal irradiation.

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“…Elevated levels of C20-OH/C18-DC and C22 at baseline (pre-HCT) were also associated with worsened OS and elevated levels of C18:1 and C18:2 were associated with increased cGVHD. Furthermore we found that baseline levels of several inflammatory markers previously linked to worsened HCT outcomes (including TNF-a [ 40 ], IL12/p70 [ 41 ], IL-6 [ 42 ], and IL22 [ 43 ]) were associated with decreased survival. Pre-HCT levels of REG3A in the pasireotide group (implicated as a marker for GI GVHD [ 44 , 45 ]) were also associated with the development of chronic GVHD.…”

Section: Discussionmentioning

confidence: 98%

A phase 2 trial of the somatostatin analog pasireotide to prevent GI toxicity and acute GVHD in allogeneic hematopoietic stem cell transplant

et al. 2021

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Background Allogeneic hematopoietic stem cell transplantation (HCT) is an often curative intent treatment, however it is associated with significant gastrointestinal (GI) toxicity and treatment related mortality. Graft-versus-host disease is a significant contributor to transplant-related mortality. We performed a phase 2 trial of the somatostatin analog pasireotide to prevent gastrointestinal toxicity and GVHD after myeloablative allogeneic HCT. Methods Patients received 0.9mg pasireotide every 12 hours from the day prior to conditioning through day +4 after HCT (or a maximum of 14 days). The primary outcomes were grade 3–4 gastrointestinal toxicity through day 30 and acute GVHD. Secondary outcomes were chronic GVHD, overall survival and relapse free survival at one year. Stool and blood samples were collected from before and after HCT for analyses of stool microbiome, local inflammatory markers, and systemic inflammatory and metabolic markers. Results were compared with matched controls. Results Twenty-six patients received pasireotide and were compared to 52 matched contemporaneous controls using a 1–2 match. Grade 3–4 GI toxicity occurred in 21 (81%) patients who received pasireotide and 35 (67%) controls (p = 0.33). Acute GVHD occurred in 15 (58%) patients in the pasireotide group and 28 (54%) controls (p = 0.94). Chronic GVHD occurred in 16 patients in the pasireotide group (64%) versus 22 patients in the control group (42%) (p = 0.12). Overall survival at 1 year in the pasireotide group was 63% (95% CI: 47%,86%) versus 82% (95% CI: 72%, 93%) in controls (log-rank p = 0.006). Relapse-free survival rate at one year was 40% (95% CI: 25%, 65%) in the pasireotide group versus 78% (95% CI: 68%, 91%) in controls (log-rank p = 0.002). After controlling for the effect of relevant covariates, patients in the pasireotide group had attenuated post-HCT loss of microbial diversity. Analysis of systemic inflammatory markers and metabolomics demonstrated feasibility of such analyses in patients undergoing allogeneic HCT. Baseline level and pre-to-post transplant changes in several inflammatory markers (including MIP1a, MIP1b, TNFa, IL8Pro, and IL6) correlated with likelihood of survival. Conclusions Pasireotide did not prevent gastrointestinal toxicity or acute GVHD compared to contemporaneous controls. Pasireotide was associated with numerically higher chronic GVHD and significantly decreased OS and RFS compared to contemporaneous controls. Pasireotide may provide a locally protective effect in the stool microbiome and in local inflammation as measured by stool calprotectin, stool beta-defensin, and stool diversity index.

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Recipient-derived IL-22 alleviates murine acute graft-versus-host disease in association with reduced activation of antigen presenting cells

Cited by 8 publications

References 35 publications

IL-22 Accelerates Thymus Regeneration via Stat3/Mcl-1 and Decreases Chronic Graft-versus-Host Disease in Mice after Allotransplants

IL-22 Accelerates Thymus Regeneration via Stat3/Mcl-1 and Decreases Chronic Graft-versus-Host Disease in Mice after Allotransplants

Second-generation Probiotics Producing IL-22 Increase Survival of Mice After Total Body Irradiation

A phase 2 trial of the somatostatin analog pasireotide to prevent GI toxicity and acute GVHD in allogeneic hematopoietic stem cell transplant

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