Mast Cells Are Mediators of Fibrosis and Effector Cell Recruitment in Dermal Chronic Graft-vs.-Host Disease

Allogeneic hematopoietic stem cell transplant (allo-HSCT) is often used to treat acute leukemia or defects of hematopoiesis. Its widespread use is hampered by graft-vs.-host disease (GVHD), which has high morbidity and mortality in both acute and chronic subtypes. Chronic GVHD (cGVHD) occurs most frequently in skin and often is characterized by pathogenic fibrosis. Mast cells (MCs) are known to be involved in the pathogenesis of other fibrotic diseases. In a murine model of cGVHD after allo-HSCT, C57BL/6J recipients of allogeneic LP/J donor cells develop sclerodermatous dermal cGVHD which is significantly decreased in mast cell-deficient B6.Cg-KitW−sh/HNihrJaeBsmGlliJ recipients. The presence of MCs is associated with fibrosis, chemokine production, and recruitment of GVHD effector cells to the skin. Chemokine production by MCs is blocked by drugs used to treat cGVHD. The importance of MCs in skin cGVHD is mirrored by increased MCs in the skin of patients with dermal cGVHD. We show for the first time a role for MCs in skin cGVHD that may be targetable for preventive and therapeutic intervention in this disease.
Source: Frontiers in Immunology - Category: Allergy & Immunology Source Type: research

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Discussion Suppressor of cytokine signaling 1 is an essential molecule for maintaining immune homeostasis and subverting inflammation. Disorders arising from excess inflammation or SOCS1 deficiency can be potentially treated with SOCS1 mimetics (Ahmed et al., 2015). While SOCS1 has promising potential in many disorders, it should be noted that new targets and actions of SOCS1 are still being discovered and not all the effects of this protein are beneficial in autoimmune diseases and cancer. For instance, SOCS1 degrades IRS1 and IRS2, required for insulin signaling, via the SOCS Box domain, thus, limiting its potential in ...
Source: Frontiers in Pharmacology - Category: Drugs & Pharmacology Source Type: research
Monica Parodi1, Herman Favoreel2, Giovanni Candiano3, Silvia Gaggero4, Simona Sivori4,5, Maria Cristina Mingari1,4,5, Lorenzo Moretta6, Massimo Vitale1 and Claudia Cantoni4,5,7* 1Immunology Operative Unit, IRCCS Ospedale Policlinico San Martino, Genoa, Italy 2Department of Virology, Parasitology and Immunology, Faculty of Veterinary Medicine, Ghent University, Merelbeke, Belgium 3Laboratory of Molecular Nephrology, IRCCS Istituto Giannina Gaslini, Genoa, Italy 4Department of Experimental Medicine, University of Genoa, Genoa, Italy 5Center of Excellence for Biomedical Research, University of Genoa, Genoa, Italy ...
Source: Frontiers in Immunology - Category: Allergy & Immunology Source Type: research
IntroductionChronic graft-versus-host disease (cGVHD) affects up to 50% of the long-term survivors of allogeneic hematopoietic stem cell transplantation (HCT), and is the leading cause of mortality in patients who survive to two years post-transplant. Unlike acute GVHD (aGVHD), the primary pathology in cGVHD is fibrotic, affecting the skin, and lacrimal and salivary glands, and shares many features with the autoimmune conditions Sjogrens syndrome and systemic sclerosis. Certain gastrointestinal microbiota compositions have been associated with these autoimmune conditions, and we thus hypothesized that the configuration of ...
Source: Blood - Category: Hematology Authors: Tags: 722. Clinical Allogeneic Transplantation: Acute and Chronic GVHD, Immune Reconstitution: Biomarkers and the Microbiome Source Type: research
Background: Allogeneic hematopoietic stem cell transplantation (HSCT) from an HLA-haploidentical relative (haplo-HSCT) is a suitable option for children/young adults with acute leukemia (AL) either relapsed or at high-risk of treatment failure and in urgent need of an allograft. A novel method of graft manipulation based on the selective, negative depletion of αβ T and B cells has been recently developed. We published the results of a prospective trial (ClinicalTrial.gov identifier: NCT01810120) enrolling 80 children with AL transplanted until September/2014 using this approach (Locatelli, Blood 2017). In the pr...
Source: Blood - Category: Hematology Authors: Tags: 732. Clinical Allogeneic Transplantation: Results: Poster I Source Type: research
Conclusion: Combined treatment with ruxolitinib and etanercept resulted in a rapid CR to visceral aGVHD and meanwhile reserve graft anti-leukemia (GVL) effect as the relapse rate of primary disease is relatively lower. The various infection complications associated with ruxolitinib merit more attention.Figure.DisclosuresNo relevant conflicts of interest to declare.
Source: Blood - Category: Hematology Authors: Tags: 722. Clinical Allogeneic Transplantation: Acute and Chronic GVHD, Immune Reconstitution: Poster III Source Type: research
Conclusion: Overall, we herein observed reduced proportions and absolute cell counts of NK cells and NKG2A+ subsets in patients with acute GVHD after allo-HSCT. The causative association between NK cell numbers, NKG2A+ subsets and GVHD remains debatable. Based on our results, speculating that reduced proportions of NKG2A+ subsets in patients after allo-HSCT are associated with acute GVHD due to their interplay with the patient's donor-derived alloreactive T cells is tempting.DisclosuresNo relevant conflicts of interest to declare.
Source: Blood - Category: Hematology Authors: Tags: 722. Clinical Allogeneic Transplantation: Acute and Chronic GVHD, Immune Reconstitution: Poster III Source Type: research
With traditional therapies, the prognosis of relapsed acute lymphoblastic leukemia (ALL) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is extremely poor. Chimeric antigen receptor (CAR) T cell therapy targeting at CD19 has demonstrated a significant efficacy on refractory/relapsed (r/r) B-ALL, but single-target CART could not maintain a long-term remission. Recently, CD22-CART has also shown an exciting result in r/r B-ALL. Here we sequentially applied CD19- and CD22-specific CART cells to treat relapsed B-ALL post-HSCT and observed the therapeutic effect.From June 30,2017 through May 31,2018, twenty...
Source: Blood - Category: Hematology Authors: Tags: 723. Clinical Allogeneic and Autologous Transplantation: Late Complications and Approaches to Disease Recurrence: Poster I Source Type: research
Conclusion. New immunosuppressive approaches are now available for GVHD prophylaxis for patients who undergoes allo-HSCT from mismatched or haplo- donors that provides comparable results with classical immunosuppression in case of matched allo-HSCT. However Tnv+Tscm is the progenitor subset for all memory T-cells and its prompt recovery after allo-HSCT seems to be crucial for graft-versus-leukemia effect. Here we show the lowest number of Tnv+Tscm after alternative GVHD prophylaxis regimens that can be explained by more sever immunoablation. Through this it may lead to delayed reconstitution of adaptive immunity after alte...
Source: Blood - Category: Hematology Authors: Tags: 722. Clinical Allogeneic Transplantation: Acute and Chronic GVHD, Immune Reconstitution Source Type: research
Introduction:Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative treatment option for patients with high-risk or relapsed hematologic malignancies. Development of acute graft-vs-host disease (aGVHD) is a risk factor for nonrelapse mortality after allo-HSCT. Systemic corticosteroids (CS) are recommended first-line treatment for aGVHD, but
Source: Blood - Category: Hematology Authors: Tags: 722. Clinical Allogeneic Transplantation: Acute and Chronic GVHD, Immune Reconstitution: GVHD Treatment and Prevention Strategies Source Type: research
Conclusion:We confirm that ECP is an effective treatment for GVHD in a good proportion of patients with overall response rate of 59%. Interestingly, we observed a better PFS in patients receiving ECP for longer time as in the case of chronic GVHD, which could be related to the GVL effect itself but also a possible involvement of the ECP. As patients with advanced phase of GVHD were poor responders, we suggest that an early use of ECP in the acute phase of the inflammation before organ damage, could lead to optimal results.DisclosuresMichallet: Novartis: Research Funding; Octapharma: Membership on an entity's Board of Direc...
Source: Blood - Category: Hematology Authors: Tags: 722. Clinical Allogeneic Transplantation: Acute and Chronic GVHD, Immune Reconstitution Source Type: research
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