Monogenic Immune Diseases Provide Insights Into the Mechanisms and Treatment of Chronic Graft-Versus-Host Disease
Chronic graft-versus-host disease (GvHD) has become a leading cause of morbidity and mortality following allogeneic hematopoietic stem cell transplantation (HSCT) and can burden patients with devastating and lifelong health effects. Our understanding of the pathogenic mechanisms underlying chronic G...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2021-02-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2020.574569/full |
| _version_ | 1819119768293081088 |
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| author | Jacob Rozmus Jacob Rozmus |
| author_facet | Jacob Rozmus Jacob Rozmus |
| author_sort | Jacob Rozmus |
| collection | DOAJ |
| description | Chronic graft-versus-host disease (GvHD) has become a leading cause of morbidity and mortality following allogeneic hematopoietic stem cell transplantation (HSCT) and can burden patients with devastating and lifelong health effects. Our understanding of the pathogenic mechanisms underlying chronic GvHD remains incomplete and this lack of understanding is reflected by lack of clear therapeutic approaches to steroid refractory disease. Observations predominantly from mouse models and human correlative studies currently support a three phase model for the initiation and development of chronic GvHD: 1) early inflammation and tissue damage triggers the innate immune system. This leads to inflammatory cytokine/chemokine patterns that recruit effector immune cell populations; 2) chronic inflammation causes the loss of central and peripheral tolerance mechanisms leading to emergence of pathogenic B and T cell populations that promote autoimmune and alloimmune reactions; 3) the dysregulated immunity causes altered macrophage polarization, aberrant tissue repair leading to scarring and end organ fibrosis. This model has led to the evaluation of many new therapies aimed at limiting inflammation, targeting dysregulated signaling pathways and restoring tolerance mechanisms. However, chronic GvHD is a multisystem disease with complex clinical phenotypes and it remains unclear as to which cluster of patients will respond best to specific therapeutic strategies. However, it is possible to gain novel insights from immune-related monogenic diseases. These diseases either share common clinical manifestations, replicate steps from the three phase chronic GvHD model or serve as surrogates for perfectly targeted drugs being investigated in chronic GvHD therapy. In this review, we will summarize the evidence from these monogenic immune related diseases that provide insight into pathogenic pathways in chronic GvHD, rationales for current therapies and novel directions for future drug discovery. |
| first_indexed | 2024-12-22T06:10:01Z |
| format | Article |
| id | doaj.art-623a61c63c6c4417badd1675fe243705 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-22T06:10:01Z |
| publishDate | 2021-02-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-623a61c63c6c4417badd1675fe2437052022-12-21T18:36:16ZengFrontiers Media S.A.Frontiers in Immunology1664-32242021-02-011110.3389/fimmu.2020.574569574569Monogenic Immune Diseases Provide Insights Into the Mechanisms and Treatment of Chronic Graft-Versus-Host DiseaseJacob Rozmus0Jacob Rozmus1Division of Pediatric Hematology, Oncology & BMT, Department of Pediatrics, BC Children’s Hospital, University of British Columbia, Vancouver, BC, CanadaMichael Cuccione Childhood Cancer Research Program, BC Children’s Hospital Research Institute, Vancouver, BC, CanadaChronic graft-versus-host disease (GvHD) has become a leading cause of morbidity and mortality following allogeneic hematopoietic stem cell transplantation (HSCT) and can burden patients with devastating and lifelong health effects. Our understanding of the pathogenic mechanisms underlying chronic GvHD remains incomplete and this lack of understanding is reflected by lack of clear therapeutic approaches to steroid refractory disease. Observations predominantly from mouse models and human correlative studies currently support a three phase model for the initiation and development of chronic GvHD: 1) early inflammation and tissue damage triggers the innate immune system. This leads to inflammatory cytokine/chemokine patterns that recruit effector immune cell populations; 2) chronic inflammation causes the loss of central and peripheral tolerance mechanisms leading to emergence of pathogenic B and T cell populations that promote autoimmune and alloimmune reactions; 3) the dysregulated immunity causes altered macrophage polarization, aberrant tissue repair leading to scarring and end organ fibrosis. This model has led to the evaluation of many new therapies aimed at limiting inflammation, targeting dysregulated signaling pathways and restoring tolerance mechanisms. However, chronic GvHD is a multisystem disease with complex clinical phenotypes and it remains unclear as to which cluster of patients will respond best to specific therapeutic strategies. However, it is possible to gain novel insights from immune-related monogenic diseases. These diseases either share common clinical manifestations, replicate steps from the three phase chronic GvHD model or serve as surrogates for perfectly targeted drugs being investigated in chronic GvHD therapy. In this review, we will summarize the evidence from these monogenic immune related diseases that provide insight into pathogenic pathways in chronic GvHD, rationales for current therapies and novel directions for future drug discovery.https://www.frontiersin.org/articles/10.3389/fimmu.2020.574569/fullprimary immunodeficiency diseaseschronic graft-versus-host diseasehematopoietic stem cell transplantationinflammationT cellB cell |
| spellingShingle | Jacob Rozmus Jacob Rozmus Monogenic Immune Diseases Provide Insights Into the Mechanisms and Treatment of Chronic Graft-Versus-Host Disease Frontiers in Immunology primary immunodeficiency diseases chronic graft-versus-host disease hematopoietic stem cell transplantation inflammation T cell B cell |
| title | Monogenic Immune Diseases Provide Insights Into the Mechanisms and Treatment of Chronic Graft-Versus-Host Disease |
| title_full | Monogenic Immune Diseases Provide Insights Into the Mechanisms and Treatment of Chronic Graft-Versus-Host Disease |
| title_fullStr | Monogenic Immune Diseases Provide Insights Into the Mechanisms and Treatment of Chronic Graft-Versus-Host Disease |
| title_full_unstemmed | Monogenic Immune Diseases Provide Insights Into the Mechanisms and Treatment of Chronic Graft-Versus-Host Disease |
| title_short | Monogenic Immune Diseases Provide Insights Into the Mechanisms and Treatment of Chronic Graft-Versus-Host Disease |
| title_sort | monogenic immune diseases provide insights into the mechanisms and treatment of chronic graft versus host disease |
| topic | primary immunodeficiency diseases chronic graft-versus-host disease hematopoietic stem cell transplantation inflammation T cell B cell |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2020.574569/full |
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