Histologic features of graft-versus-host disease-associated angiomatosis: Insights into pathophysiology and treatment.
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ABSTRACT:
SUBMITTER: Li DJ
PROVIDER: S-EPMC7931771 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Allogeneic hematopoietic stem cell transplantation (HSCT) is a potentially curative therapy for many malignant and nonmalignant hematologic diseases. Donor T cells from the allografts are critical for the success of this effective therapy. Unfortunately these T cells not only recognize and attack the disease cells/tissues but also the other normal tissues of the recipient as "foreign" or "nonself" and cause severe, immune-mediated toxicity, graft-versus-host disease (GVHD). Several insights into the complex pathophysiology of GVHD have been gained from recent experimental observations, which show that acute GVHD is a consequence of interactions between both the donor and the host innate and adaptive immune systems. These insights have identified a role for a variety of cytokines, chemokines, novel T-cell subsets (na?ve, memory, regulatory, and NKT cells) and for non-T cells of both the donor and the host (antigen presenting cells, delta T cells, B cells, and NK cells) in modulating the induction, severity, and maintenance of acute GVHD. This review will focus on the immunobiology of experimental acute GVHD with an emphasis on the recent observations.
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Project description: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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Project description:graft versus host disease organoids were co-cultured with mesenchymal stem cells
2024-05-22 | PXD034822 | Pride
Project description:The pathologic interpretation of gut biopsies in hematopoietic cell transplant recipients to assess graft-versus-host disease (GVHD) is well accepted and supplements clinical and endoscopic findings. However, the histologic activity grading of GVHD is controversial, with attempts to predict prognosis or response to treatment largely unsuccessful. GVHD is being diagnosed earlier in its course, raising the possibility that the pathologic grading system can be profitably modified. We developed a histologic activity grading system designed to replace the commonly used modified Lerner grading systems. Our system stratifies the low-level Lerner grade I category into 4 activity grade categories, based on the average frequency of apoptotic cells. The results are expressed as ordinal categories: GVHD of minimal, mild, moderate, severe histologic activity, or severe histologic activity with destruction (activity grades 1 to 5). In a retrospective study, we studied 87 consecutive cases with 201 post-transplantation specimens (median, 48 days; range, 18 to 1479 days) of stomach, duodenum, and colorectum, which had been activity graded at the time of the original diagnosis. Most of the biopsies diagnosed as GVHD were low grade-minimal (11%) or mild (71%) histologic activity. We hypothesized that the higher activity grades would be associated with more therapeutic intervention. The odds of increased therapy in the combined all-site specimens were increased as activity grade increased (odds ratio,?2.9 [95% confidence interval {CI}, 1.9 to 4.5]; P?=?<?.0001). Thus, our grading system was validated. To investigate whether the activity grade was associated with therapy within the formerly undivided Lerner grade I category, the analysis was restricted to these 174 all-site specimens. The validation result was similar (odds ratio,?3.1 [95% CI, 1.3 to 7.2]; P?=?.009). This result interestingly suggests that there is useful information hidden in the Lerner grade I category, which could potentially guide immediately actionable treatment decisions. This histologic activity grade system has been in use at our institution for over 2 years with good acceptance.
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Project description:Dermatologists are ideally suited to manage the various cutaneous sequelae of graft-versus-host disease (GVHD) outlined in part I of this review. However, the complexity of the patient with GVHD, including comorbidities, potential drug interactions related to polypharmacy, and the lack of evidence-based treatment guidelines, are significant challenges to optimizing patient care. In this section, we will provide an outline for the role of the dermatologist in a multispecialty approach to caring for patients with GVHD.
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Project description:Chronic graft-versus-host disease (cGVHD) following allogeneic hematopoietic stem cell transplantation (HSCT) has emerged as a predominant complication following HSCT and has a distinct etiology. We and others have previously demonstrated that bortezomib, a proteasome inhibitor, can prevent but not treat acute GVHD in mice. To assess the effects of bortezomib on cGVHD, a mouse minor histocompatibility antigen-mismatched strain combination was used to mimic clinical cGVHD sclerodermatous pathogenesis and phenotype. Treatment of ongoing cGVHD with bortezomib ameliorated cutaneous lesions, which were also associated with a reduction in total numbers of germinal center B cells and lower B-cell activating factor gene expression levels in cutaneous tissues. Importantly, lymphoma-bearing mice receiving allogeneic HSCT with bortezomib preserved graft-versus-tumor (GVT) effects. Based on these animal studies, we initiated an intrapatient dose escalation clinical trial in patients with extensive steroid-intolerant, dependent, or resistant cGVHD. Marked clinical improvement was observed in patients, which was also associated with reductions of peripheral B cells and minimal toxicity. These results indicate that bortezomib can be of significant use in the treatment of cGVHD and may also allow for maintenance of GVT. This trial was registered at www.clinicaltrials.gov as #NCT01672229.
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Project description:Chronic graft-versus-host disease (cGVHD) is a life-threatening impediment to allogeneic hematopoietic stem cell transplantation, and current therapies do not completely prevent and/or treat cGVHD. CD4+ T cells and B cells mediate cGVHD; therefore, targeting these populations may inhibit cGVHD pathogenesis. Ibrutinib is an FDA-approved irreversible inhibitor of Bruton's tyrosine kinase (BTK) and IL-2 inducible T cell kinase (ITK) that targets Th2 cells and B cells and produces durable remissions in B cell malignancies with minimal toxicity. Here, we evaluated whether ibrutinib could reverse established cGVHD in 2 complementary murine models, a model interrogating T cell-driven sclerodermatous cGVHD and an alloantibody-driven multiorgan system cGVHD model that induces bronchiolar obliterans (BO). In the T cell-mediated sclerodermatous cGVHD model, ibrutinib treatment delayed progression, improved survival, and ameliorated clinical and pathological manifestations. In the alloantibody-driven cGVHD model, ibrutinib treatment restored pulmonary function and reduced germinal center reactions and tissue immunoglobulin deposition. Animals lacking BTK and ITK did not develop cGVHD, indicating that these molecules are critical to cGVHD development. Furthermore, ibrutinib treatment reduced activation of T and B cells from patients with active cGVHD. Our data demonstrate that B cells and T cells drive cGVHD and suggest that ibrutinib has potential as a therapeutic agent, warranting consideration for cGVHD clinical trials.
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Project 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.
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Project description: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-versus-host 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 low-dose 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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Project description:Allogeneic hematopoietic stem cell transplantation (HSCT) has been widely used for the treatment of hematologic malignant and non-malignant hematologic diseases and other diseases. However, acute graft-versus-host disease (GVHD) is a life-threatening complication of allogeneic transplantation. Acute GVHD may occur in 30% of transplant recipients, which is a syndrome of erythematous skin eruption, cholestatic liver disease and intestinal dysfunction, resulting from the activation of donor T lymphocytes by host antigen-presenting cells, resulting in an immune-mediated inflammatory response. Recent scientific advances in the understanding of the pathogenesis involved in the development of acute GVHD and clinical investigation have provided more effective therapeutic strategies for acute GVHD. This review focuses on major scientific and clinical advances in the treatment of acute GVHD.
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