Abstract
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.
Highlights
Specialty section: This article was submitted to Alloimmunity and Transplantation, a section of the journal Frontiers in Immunology
The three phases are: 1) acute inflammation and tissue injury trigger inflammatory cytokine/chemokine patterns, mediated through the innate immune system, that recruit effector immune cell populations; 2) chronic inflammation causes a loss of tolerance that disrupts the homeostasis of the adaptive immune system leading to the emergence of pathogenic B and T cell populations; 3) the dysregulated immune response causes altered macrophage polarization causing an aberrant tissue repair mechanism leading to excessive end organ fibrosis and scarring
Ibrutinib treatment in chronic lymphocytic leukemia (CLL) patients markedly increases CD4+ and CD8+ T cell numbers, decreases the Treg/CD4+ T cell ratio and reduced PD-1 and Cytotoxic T lymphocyte antigen-4 (CTLA-4) expression in T cells [130]. It remains unclear if the efficacy of ibrutinib in targeting B cells in Chronic graft-versus-host disease (cGvHD) will be offset by changes in T cell populations, significant risk of bleeding and potential flares of autoimmunity
Summary
Chronic graft-versus-host disease (cGvHD) is the leading cause of morbidity and mortality post-hematopoietic stem cell transplantation [1, 2]. cGvHD is a pleomorphic syndrome that resembles autoimmune and other immunologic disorders that occurs between 3 and 15 months after HCT. The three phases are: 1) acute inflammation and tissue injury trigger inflammatory cytokine/chemokine patterns, mediated through the innate immune system, that recruit effector immune cell populations; 2) chronic inflammation causes a loss of tolerance that disrupts the homeostasis of the adaptive immune system leading to the emergence of pathogenic B and T cell populations; 3) the dysregulated immune response causes altered macrophage polarization causing an aberrant tissue repair mechanism leading to excessive end organ fibrosis and scarring Despite these insights, clinicians continue to struggle to identify the optimal therapy for patients with cGvHD who do not respond to front-line corticosteroids or patients who cannot be successfully weaned off corticosteroids
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