Glucagon-like peptide 2 for intestinal stem cell and Paneth cell repair during graft-versus-host disease in mice and humans

Norona, Johana; Apostolova, Petya; Schmidt, Dominik; Ihlemann, Rebekka; Reischmann, Nadine; Taylor, Gregory A.; Stickel, Natalie; Heer, Jocelyn de; Heeg, Steffen; Andrieux, Geoffroy; Siranosian, Benjamin A.; Schmitt‐Graeff, Annette; Pfeifer, Dietmar; Catalano, Antonella; Frew, Ian J.; Proietti, Michele; Grimbacher, Bodo; Bulashevska, Alla; Bhatt, Ami S.; Brummer, Tilman; Clauditz, Till S.; Zabelina, Tatjana; Kröger, Nicolaus; Blazar, Bruce R.; Boerries, Melanie; Ayuk, Francis; Zeiser, Robert

doi:10.1182/blood.2020005957

Cited by 64 publications

(70 citation statements)

References 26 publications

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“…Glucagon-like-peptide-2 (GLP-2) is an enteroendocrine tissue hormone. Administration of GLP-2 promoted regeneration of ISCs and Paneth cells and restored intestinal homeostasis, resulting in amelioration of GVHD ( 141 ). IL-25 protects Goblet cells and also could improve transplant outcome ( 125 ).…”

Section: Acute Gvhdmentioning

confidence: 99%

The Pathophysiology and Treatment of Graft-Versus-Host Disease: Lessons Learnt From Animal Models

Teshima

Hill

2021

Front. Immunol.

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Allogeneic hematopoietic cell transplantation (HCT) is a curative treatment for hematologic malignancies, bone marrow failure syndromes, and inherited immunodeficiencies and metabolic diseases. Graft-versus-host disease (GVHD) is the major life-threatening complication after allogeneic HCT. New insights into the pathophysiology of GVHD garnered from our understanding of the immunological pathways within animal models have been pivotal in driving new therapeutic paradigms in the clinic. Successful clinical translations include histocompatibility matching, GVHD prophylaxis using cyclosporine and methotrexate, posttransplant cyclophosphamide, and the use of broad kinase inhibitors that inhibit cytokine signaling (e.g. ruxolitinib). New approaches focus on naïve T cell depletion, targeted cytokine modulation and the inhibition of co-stimulation. This review highlights the use of animal transplantation models to guide new therapeutic principles.

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Section: Acute Gvhdmentioning

confidence: 99%

The Pathophysiology and Treatment of Graft-Versus-Host Disease: Lessons Learnt From Animal Models

Teshima

Hill

2021

Front. Immunol.

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“…DPP4 inhibition might have further benefits by blocking glucagon-like-peptide 2 degradation, 17 which plays a pivotal role for regeneration of intestinal stem cells and paneth cells after GvHD-induced intestinal damage. 18 …”

Section: Dipeptidyl Peptidase 4 Inhibitionmentioning

confidence: 99%

Immunomodulatory Therapies for the Treatment of Graft-versus-host Disease

Braun

Zeiser

2021

HemaSphere

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Allogeneic hematopoietic stem cell transplantation (allo-HCT) is a potentially curative therapy for patients suffering from hematological malignancies, and its therapeutic success is based on the graft-versus-leukemia (GvL) effect. Severe acute and chronic graft-versushost disease (GvHD) are life-threatening complications after allo-HCT. To date, most of the approved treatment strategies for GvHD rely on broadly immunosuppressive regimens, which limit the beneficial GvL effect by reducing the cytotoxicity of anti-leukemia donor T-cells. Therefore, novel therapeutic strategies that rely on immunomodulatory rather than only immunosuppressive effects could help to improve patient outcomes. Treatments should suppress severe GvHD while preserving anti-leukemia immunity. New treatment strategies include the blockade of T-cell activation via inhibition of dipeptidyl peptidase 4 and cluster of differentiation 28-mediated co-stimulation, reduction of proinflammatory interleukin (IL)-2, IL-6 and tumor necrosis factor-α signaling, as well as kinase inhibition. Janus kinase (JAK)1/2 inhibition acts directly on T-cells, but also renders antigen presenting cells more tolerogenic and blocks dendritic cell-mediated T-cell activation and proliferation. Extracorporeal photopheresis, hypomethylating agent application, and lowdose IL-2 are powerful approaches to render the immune response more tolerogenic by regulatory T-cell induction. The transfer of immunomodulatory and immunosuppressive cell populations, including mesenchymal stromal cells and regulatory T-cells, showed promising results in GvHD treatment. Novel experimental procedures are based on metabolic reprogramming of donor T-cells by reducing glycolysis, which is crucial for cytotoxic T-cell proliferation and activity.

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“…Because GLP-2 is inactivated by DPP-4, a DPP-4-resistant GLP-2 analog, teduglutide, was tested for a GVHD prophylaxis. Peritransplant administration of teduglutide protected ISCs and Paneth cells against GVHD, and prolonged survival after mouse allo-SCT (9). Furthermore, GLP-2 and GLP-2 analogues enhance the expression of tight junction molecules such as claudin-4, possibly enhancing intestinal barrier function in GVHD (9,130).…”

Section: The Barrier Function Of Gut Epithelial Cells In Gvhdmentioning

confidence: 99%

Novel Insights Into the Mechanism of GVHD-Induced Tissue Damage

Ara

Hashimoto

2021

Front. Immunol.

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Prophylaxis for and treatment of graft-versus-host disease (GVHD) are essential for successful allogeneic hematopoietic stem cell transplantation (allo-SCT) and mainly consist of immunosuppressants such as calcineurin inhibitors. However, profound immunosuppression can lead to tumor relapse and infectious complications, which emphasizes the necessity of developing novel management strategies for GVHD. Emerging evidence has revealed that tissue-specific mechanisms maintaining tissue homeostasis and promoting tissue tolerance to combat GVHD are damaged after allo-SCT, resulting in exacerbation and treatment refractoriness of GVHD. In the gastrointestinal tract, epithelial regeneration derived from intestinal stem cells (ISCs), a microenvironment that maintains healthy gut microbiota, and physical and chemical mucosal barrier functions against pathogens are damaged by conditioning regimens and/or GVHD. The administration of growth factors for cells that maintain intestinal homeostasis, such as interleukin-22 (IL-22) for ISCs, R-spondin 1 (R-Spo1) for ISCs and Paneth cells, and interleukin-25 (IL-25) for goblet cells, mitigates murine GVHD. In this review, we summarize recent advances in the understanding of GVHD-induced tissue damage and emerging strategies for the management of GVHD.

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Glucagon-like peptide 2 for intestinal stem cell and Paneth cell repair during graft-versus-host disease in mice and humans

Cited by 64 publications

References 26 publications

The Pathophysiology and Treatment of Graft-Versus-Host Disease: Lessons Learnt From Animal Models

The Pathophysiology and Treatment of Graft-Versus-Host Disease: Lessons Learnt From Animal Models

Immunomodulatory Therapies for the Treatment of Graft-versus-host Disease

Novel Insights Into the Mechanism of GVHD-Induced Tissue Damage

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