Stress responses, M2 macrophages, and a distinct microbial signature in fatal intestinal acute graft-versus-host disease

Holtan, Shernan G.; Shabaneh, Ashraf; Betts, Brian C.; Rashidi, Armin; MacMillan, Margaret L.; Ustun, Celalletin; Amin, Khalid; Vaughn, Byron P.; Howard, Justin; Khoruts, Alexander; Arora, Mukta; DeFor, Todd E.; Johnson, Darrell; Blazar, Bruce R.; Weisdorf, Daniel J.; Wang, Jinhua

doi:10.1172/jci.insight.129762

Cited by 25 publications

(36 citation statements)

References 53 publications

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“…Consistent with this mouse study, tissue transcriptomics analysis from GVHD patients also showed no differences in T cells including CD8 + T cells, naïve CD4 + T cells, and memory CD4 + T cells between the new onset of aGVHD and SR-aGVHD, but multiple T cell-independent mechanisms were found to be related to SR-aGVHD (47). The study found that gut tissue repair-associated gene amphiregulin (AREG) and the aryl hydrocarbon receptor (AhR) expression levels were increased at aGVHD onset and remained elevated in SR-Gut-aGVHD, indicating potential interaction of host mucosa with microbiota (47). The study also identified higher expression levels of metallothioneins, metal-binding enzymes induced in stress responses, and M2 macrophage genes in SR-Gut-aGVHD (47).…”

Section: New Insights Into Steroid Refractory-gut-acute Graft-versus-...supporting

confidence: 83%

“…The study found that gut tissue repair-associated gene amphiregulin (AREG) and the aryl hydrocarbon receptor (AhR) expression levels were increased at aGVHD onset and remained elevated in SR-Gut-aGVHD, indicating potential interaction of host mucosa with microbiota (47). The study also identified higher expression levels of metallothioneins, metal-binding enzymes induced in stress responses, and M2 macrophage genes in SR-Gut-aGVHD (47). Furthermore, poorly surviving patients showed an indication of greater DNA damage and a distinct microbial signature at aGVHD onset as compared to prolonged surviving patients (47).…”

Section: New Insights Into Steroid Refractory-gut-acute Graft-versus-...mentioning

confidence: 99%

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Steroid-Refractory Gut Graft-Versus-Host Disease: What We Have Learned From Basic Immunology and Experimental Mouse Model

2022

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Intestinal graft-versus-host disease (Gut-GVHD) is one of the major causes of mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT). While systemic glucocorticoids (GCs) comprise the first-line treatment option, the response rate for GCs varies from 30% to 50%. The prognosis for patients with steroid-refractory acute Gut-GVHD (SR-Gut-aGVHD) remains dismal. The mechanisms underlying steroid resistance are unclear, and apart from ruxolitinib, there are no approved treatments for SR-Gut-aGVHD. In this review, we provide an overview of the current biological understanding of experimental SR-Gut-aGVHD pathogenesis, the advanced technology that can be applied to the human SR-Gut-aGVHD studies, and the potential novel therapeutic options for patients with SR-Gut-aGVHD.

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Section: New Insights Into Steroid Refractory-gut-acute Graft-versus-...supporting

confidence: 83%

Section: New Insights Into Steroid Refractory-gut-acute Graft-versus-...mentioning

confidence: 99%

Steroid-Refractory Gut Graft-Versus-Host Disease: What We Have Learned From Basic Immunology and Experimental Mouse Model

2022

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“…Recently, Holtan et al 34 showed that M2 macrophages accumulated in colonic mucosa during steroidrefractory acute GVHD and their presence may indicate incomplete tissue repair. In their report, it is not known whether M2 macrophages accumulated in colon are donor-derived or host-derived.…”

Section: Discussionmentioning

confidence: 99%

Donor‐derived M2 macrophages attenuate GVHD after allogeneic hematopoietic stem cell transplantation

Hanaki

Toyoda

Iwamoto

et al. 2021

Immunity Inflam & Disease

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Introduction: Graft-versus-host disease (GVHD) is frequent and fatal complication following allogeneic hematopoietic stem cell transplantation (HSCT) and characteristically involves skin, gut, and liver. Macrophages promote tissue regeneration and mediate immunomodulation. Macrophages are divided into two different phenotypes, classically activated M1 (pro-inflammatory or immunereactive macrophages) and alternatively activated M2 (anti-inflammatory or immune-suppressive macrophages). The anti-inflammatory effect of M2 macrophage led us to test its effect in the pathophysiology of GVHD. Methods: GVHD was induced in lethally irradiated BALB/c mice. M2 macrophages derived from donor bone marrow (BM) were administered intravenously, while controls received donor BM-mononuclear cells and splenocytes. Animals were monitored for clinical GVHD and analyzed.Results: We confirmed that administering donor BM-derived M2 macrophages attenuated GVHD severity and prolonged survival after HSCT. Moreover, donor BM-derived M2 macrophages significantly suppressed donor T cell proliferation by cell-to-cell contact in vitro. Conclusions: We showed the protective effects of donor-derived M2 macrophages on GVHD and improved survival in a model of HSCT. Our data suggest that donor-derived M2 macrophages offer the potential for cell-based therapy to treat GVHD.

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“…27 Gene expres sion stud ies from human colo rec tal biop sies showed that human SRaGVHD is char ac ter ized by tis sue response to dam age, cel lu lar stress, and mac ro phage accu mu la tion, not Tcell pro lif er a tion. 28 Collectively, these recent stud ies sug gest that future ther a peu tic efforts in SRaGVHD, in addi tion to targeting the ini tial Tcellmedi ated dam age and inflam ma tion, might also con sider stud ies of agents designed to enhance tis sue repair and to cor rect dysbiosis while try ing to avoid broad immu no sup pres sion and its inher ent risks of infec tion 17,[29][30][31][32][33][34] . Recently described tar gets such as CD83 sug gest this may be fea si ble.…”

Section: Treatment Options For Sr-agvhdmentioning

confidence: 99%

Acute GVHD: think before you treat

Newell

Holtan

2021

Hematology

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The treatment of acute graft-versus-host disease (aGVHD) has become more nuanced in recent years with the development of improved risk classification systems and a better understanding of its complex, multisystem pathophysiology. We review contemporary approaches to the risk stratification and initial treatment of aGVHD, including ongoing clinical trials. We summarize the findings that led to the first US Food and Drug Administration approval for steroid-refractory aGVHD (SR-aGVHD), ruxolitinib, as well as some of the challenges clinicians still face in treating SR-aGVHD. Finally, we discuss the evaluation and management of steroid-dependent aGVHD, which affects approximately one-third of patients who have long-term, waxing and waning symptoms distinct from chronic GVHD. Future clinical trials for aGVHD treatment may identify steroid-sparing approaches for patients who have a high likelihood of response and approaches to improve tissue repair and dysbiosis for those unlikely to respond to immunosuppression alone.

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Stress responses, M2 macrophages, and a distinct microbial signature in fatal intestinal acute graft-versus-host disease

Cited by 25 publications

References 53 publications

Steroid-Refractory Gut Graft-Versus-Host Disease: What We Have Learned From Basic Immunology and Experimental Mouse Model

Steroid-Refractory Gut Graft-Versus-Host Disease: What We Have Learned From Basic Immunology and Experimental Mouse Model

Donor‐derived M2 macrophages attenuate GVHD after allogeneic hematopoietic stem cell transplantation

Acute GVHD: think before you treat

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