scholarly journals TFH cells in systemic sclerosis

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Pauline Beurier ◽  
Laure Ricard ◽  
Deborah Eshagh ◽  
Florent Malard ◽  
Lama Siblany ◽  
...  
Keyword(s):  
Systemic Sclerosis ◽  
B Cell ◽  
Graft Versus Host Disease ◽  
Cell Activation ◽  
Inflammatory Cells ◽  
T Follicular Helper Cells ◽  
Host Disease ◽  
Graft Versus Host ◽  
Helper Cells ◽  
Follicular Helper

AbstractSystemic sclerosis is an autoimmune disease characterized by excessive dermal fibrosis with progression to internal organs, vascular impairment and immune dysregulation evidenced by the infiltration of inflammatory cells in affected tissues and the production of auto antibodies. While the pathogenesis remains unclear, several data highlight that T and B cells deregulation is implicated in the disease pathogenesis. Over the last decade, aberrant responses of circulating T follicular helper cells, a subset of CD4 T cells which are able to localise predominantly in the B cell follicles through a high level of chemokine receptor CXCR5 expression are described in pathogenesis of several autoimmune diseases and chronic graft-versus-host-disease. In the present review, we summarized the observed alteration of number and frequency of circulating T follicular helper cells in systemic sclerosis. We described their role in aberrant B cell activation and differentiation though interleukine-21 secretion. We also clarified T follicular helper-like cells involvement in fibrogenesis in both human and mouse model. Finally, because T follicular helper cells are involved in both fibrosis and autoimmune abnormalities in systemic sclerosis patients, we presented the different strategies could be used to target T follicular helper cells in systemic sclerosis, the therapeutic trials currently being carried out and the future perspectives from other auto-immune diseases and graft-versus-host-disease models.

scholarly journals Circulating T follicular helper cells with increased function during chronic graft-versus-host disease

Blood ◽  
2016 ◽  
Vol 127 (20) ◽  
pp. 2489-2497 ◽  
Author(s):  
Edouard Forcade ◽  
Haesook T. Kim ◽  
Corey Cutler ◽  
Kathy Wang ◽  
Ana C. Alho ◽  
...  
Keyword(s):  
B Cell ◽  
Graft Versus Host Disease ◽  
T Follicular Helper Cells ◽  
Memory B Cell ◽  
Host Disease ◽  
Graft Versus Host ◽  
Helper Cells ◽  
Follicular Helper ◽  
Key Points ◽  
With Memory

Key Points cTFH are activated and skewed toward a Th2/Th17 phenotype promoting their B-cell help function during cGVHD. cTFH activation signature correlates with memory B-cell and plasmablast phenotype in cGVHD patients.

scholarly journals Loss of T Follicular Helper Cells in the Peripheral Blood of Patients with Chronic Graft-versus-Host Disease

2016 ◽  
Vol 22 (5) ◽  
pp. 825-833 ◽  
Author(s):  
David A. Knorr ◽  
Hongbo Wang ◽  
Mukta Aurora ◽  
Margaret L. MacMillan ◽  
Shernan G. Holtan ◽  
...  
Keyword(s):  
Graft Versus Host Disease ◽  
Peripheral Blood ◽  
T Follicular Helper Cells ◽  
Host Disease ◽  
Graft Versus Host ◽  
Helper Cells ◽  
Follicular Helper

scholarly journals Pirfenidone Reverses Murine Chronic Graft Versus Host Disease

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1158-1158
Author(s):  
Jing Du ◽  
Ryan P Flynn ◽  
Katelyn Paz ◽  
Ante Vulic ◽  
Tara M. Robinson ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
B Cells ◽  
Graft Versus Host Disease ◽  
Flow Cytometry Analysis ◽  
T Follicular Helper Cells ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Graft Versus Host ◽  
Helper Cells ◽  
Follicular Helper

Abstract Allogeneic hematopoietic stem cell transplantation (aHSCT) is hampered by chronic graft-versus-host disease (cGVHD), which results in multi-organ fibrosis and loss of function. In particular, bronchiolitis obliterans (BO) and scleroderma resulting from fibrotic bronchiolar and cutaneous response, respectively, are two devastating outcomes for cGVHD patients. Fibrotic manifestations often are considered irreversible and progressive. Therefore, new therapies targeting fibrosis are urgently needed. Pirfenidone (5-methyl-1-phenyl-2- (1H)-pyridone) exhibits a well-documented anti-inflammatory and anti-fibrosis function in multiple pre-clinical models and is the first and only FDA-approved drug for idiopathic pulmonary fibrosis. For this study, Pirfenidone was synthesized as a crystalline solid and found to be pure both by melting point and NMR spectroscopy. We evaluated Pirfenidone's anti-fibrosis function in 2 pathophysiologically distinct cGVHD murine models: 1. a major mismatched multi-organ system model (C57BL/6 to B10.BR) that induces BO as a result of a cGVHD-induced germinal center (GC) reaction, antibody deposition and fibrosis in the lung; and 2. a minor antigen mismatched model (B10.D2 to BALB/c) in which severe scleroderma is the major disease manifestation. In the BO model, pulmonary function loss in cGVHD mice (as reflected by increased resistance, elastance and decreased compliance of the lung) was restored by Pirfenidone treatment (400mg/kg) during both the early (day28-56) (Fig A, representative of 3 experiments with 5-8 mice per group) and late stages (day56-84) of the disease. Pathologic changes in the lung, such as collagen deposition and narrowing of bronchioles, were significantly reduced by Pirfenidone. The size and frequency of GCs in the spleen, and the frequency of GC B cells (Fig B, representative of 2 experiments with 5-8 mice per group) and T follicular helper cells were all significantly reduced in Pirfenidone- treated groups. To determine whether GCs were directly affected by Pirfenidone, we evaluated Pirfenidone in C57BL/6 mice immunized with sheep red blood cells (SRBC) to induce GCs. Interestingly, Pirfenidone did not reduce the SRBC-induced GC reaction (Fig C) (comparable frequencies of splenic GC B cells, T follicular helper cells and serum IgG levels were seen between Pirfenidone and vehicle-treated groups). These results suggested that Pirfenidone suppresses the GC reaction through a cGVHD-specific mechanism, rather than through immune regulation. Mechanistically, Pirfenidone administration attenuated the sequestration of pro-fibrogenic F4/80+ macrophages (Fig D, representative of 2 experiments) and TGF-β (Fig E, representative of 2 experiments) production within the lung. These results have led us to elucidate a potential mechanism of cGVHD: antibody deposition in the lung results in the activation of macrophages and TGF-β that drive fibrotic change and tissue damage, resulting in the exposure of auto- and allo- antigens to the immune system that support and sustain pathologic GC reactions. In the B10.D2 to BALB/c sclerodermatous cGVHD model, Pirfenidone treatment (400mg/kg, day21-55) improved clinical signs of scleroderma and reduced macrophage infiltration in the skin (Fig F). In summary, this is the first study evaluating a commercially available anti-fibrosis drug on pathologically distinct pre-clinical cGVHD models. Our data suggests Prifenidone reversed cGVHD in the BO model and, to a lesser extent, in the scleroderma model. Thus, Pirfenidone is a novel therapeutic agent for treating cGVHD patients with fibrosis that have been typically refractory to therapies. A. Resistance of lungs was measured on day56 of transplantation; Elastance and compliance correlated with resistance but were not shown here. B. Flow cytometry analysis of GC B cells of no cGVHD vs cGVHD mice treated with Pirfenidone or vehicle; C. Flow cytometry analysis of GC B cells from SRBC-immunized mice treated with Pirfenidone or vehicle; D and E. Macrophage F4/80 and TGF-β quantification of day56 lungs of no cGVHD vs cGVHD mice treated as indicated; F. Skin GVHD scores were recorded on indicated dates of irradiated BALB/c mice transplanted with B10.D2 donor BM alone or with T cells and treated as indicated. Unpaired student T test was used for statistical analysis. ****:P<0.0001; ***: P<0.001; **: P<0.01; *: P<0.05; ns: not significant. Figure Figure. Disclosures No relevant conflicts of interest to declare.

scholarly journals Targeting Syk-activated B cells in murine and human chronic graft-versus-host disease

Blood ◽  
2015 ◽  
Vol 125 (26) ◽  
pp. 4085-4094 ◽  
Author(s):  
Ryan Flynn ◽  
Jessica L. Allen ◽  
Leo Luznik ◽  
Kelli P. MacDonald ◽  
Katelyn Paz ◽  
...  
Keyword(s):  
Cell Death ◽  
B Cells ◽  
B Cell ◽  
Graft Versus Host Disease ◽  
Cell Activation ◽  
B Cell Activation ◽  
Host Disease ◽  
Graft Versus Host ◽  
Key Points ◽  
Syk Inhibitor

Key Points Syk is required for increased B-cell activation and cGVHD generation and maintenance. The Syk inhibitor fostamatinib can treat murine cGVHD and increase human cGVHD B-cell death.

scholarly journals OP0242 EFFECTS OF THE AUTOTAXIN INHIBITOR ZIRITAXESTAT ON SKIN AND LUNG FIBROSIS IN A MURINE GRAFT-VERSUS-HOST DISEASE MODEL OF SYSTEMIC SCLEROSIS

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 148.1-149
Author(s):  
Y. Zhang ◽  
L. Summa ◽  
B. Heckmann ◽  
J. H. W. Distler
Keyword(s):  
Systemic Sclerosis ◽  
Pulmonary Fibrosis ◽  
Graft Versus Host Disease ◽  
Murine Model ◽  
Allogeneic Bone Marrow Transplantation ◽  
Allogeneic Bone ◽  
Host Disease ◽  
Graft Versus Host ◽  
Dermal Thickness ◽  
Disease Modifying

Background:There is an unmet medical need for new drugs to treat systemic sclerosis (SSc). Autotaxin (ATX) is a widely expressed enzyme that regulates diverse cellular processes, including proliferation, differentiation and migration, and has been implicated in the pathogenesis of SSc. Targeting ATX is a promising new strategy for treating SSc. The autotaxin inhibitor ziritaxestat (GLPG1690) is a potential first-in-class disease-modifying drug for SSc that has been shown to improve skin score in the Phase 2a NOVESA (NCT03798366) trial in patients with SSc.Objectives:To investigate the effects of ziritaxestat in a chronic graft-versus-host disease (cGvHD) murine model of SSc.Methods:Effects of ziritaxestat (10 or 30 mg/kg twice daily [bid]) on disease activity were assessed in a cGvHD murine model of SSc (allogeneic bone marrow transplantation [BMT] with B10.D2 donor and BALB/c recipient; syngeneic mice as controls). Ziritaxestat or nintedanib (60 mg/kg once daily [qd]) as active comparator was administered 21 d after BMT and continued for 35 d. Effects of ziritaxestat were assessed by clinical monitoring, histologic assessment of skin and lungs (dermal thickness, Ashcroft scores and collagen-covered area), immunofluorescence staining with Trichrome and Sirius Red for myofibroblasts, and biochemical analysis of collagen content, as measured by hydroxyproline levels.Results:Ziritaxestat 30 mg/kg bid for 35 days significantly reduced the clinical cutaneous score in the murine cGvHD model by 57% (p<0.05) compared with vehicle, and to a similar extent when compared with nintedanib 60 mg/kg (38%; p<0.05). Dermal accumulation of collagen and dermal thickness (Figure) were reduced with ziritaxestat 10 and 30 mg/kg compared with vehicle. At 30 mg/kg, ziritaxestat reversed the increase in the allogeneic model (p<0.001), returning dermal thickness to the levels in non-fibrotic control mice. Ziritaxestat also significantly reduced pulmonary fibrosis in the cGvHD model, with reductions in the fibrotic lung area (ziritaxestat 10 and 30 mg/kg; p<0.001 for both) and Ashcroft scores (ziritaxestat 30 mg/kg; p<0.05). Ziritaxestat was generally well tolerated.Conclusion:Ziritaxestat improved the histological, biochemical and clinical symptom readouts of dermal and pulmonary fibrosis in a murine model, consistent with a broad and rapid disease-modifying effect in SSc.Acknowledgements:This study was funded by Galapagos NV (Mechelen, Belgium). Medical writing/editorial support was provided by Ian Faulkner, PhD (Aspire Scientific, Bollington, UK) funded by Galapagos NV.Disclosure of Interests:Yun Zhang Employee of: 4D Science, Lena Summa Employee of: 4D Science, Bertrand Heckmann Shareholder of: Galapagos, Employee of: Galapagos, Jörg H.W. Distler Shareholder of: 4D Science, Consultant of: Actelion, Active Biotech, Anamar, ARXX, Bayer Pharma, Boehringer Ingelheim, Celgene, Galapagos, GlaxoSmithKline, Inventiva, JB Therapeutics, Medac, Pfizer, RuiYi and UCB, Grant/research support from: Anamar, Active Biotech, Array Biopharma, ARXX, aTyr, Bristol Myers Squibb, Bayer Pharma, Boehringer Ingelheim, Celgene, Galapagos, GlaxoSmithKline, Inventiva, Novartis, Sanofi-Aventis, RedX and UCB

scholarly journals Comprehensive B Cell Phenotyping Profile for Chronic Graft-versus-Host Disease Diagnosis

2019 ◽  
Vol 25 (3) ◽  
pp. 451-458 ◽  
Author(s):  
Jacob Rozmus ◽  
Amina Kariminia ◽  
Sayeh Abdossamadi ◽  
Barry E. Storer ◽  
Paul J. Martin ◽  
...  
Keyword(s):  
B Cell ◽  
Graft Versus Host Disease ◽  
Disease Diagnosis ◽  
Host Disease ◽  
Graft Versus Host
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