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 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 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 Rapid Engraftment Without Significant Graft-Versus-Host Disease After Allogeneic Transplantation of CD34+ Selected Cells From Peripheral Blood

Blood ◽  
1997 ◽  
Vol 89 (11) ◽  
pp. 3967-3973 ◽  
Author(s):  
Alvaro Urbano-Ispizua ◽  
Ciril Rozman ◽  
Carmen Martı́nez ◽  
Pedro Marı́n ◽  
Javier Briones ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Graft Versus Host Disease ◽  
Peripheral Blood ◽  
Allogeneic Transplantation ◽  
Median Number ◽  
Refractory Anemia ◽  
Host Disease ◽  
Graft Versus Host ◽  
Cd34 Cells

Abstract We have prospectively evaluated the feasibility and results of the biotin-avidin immunoadsorption method (Ceprate SC system) for a phase I/II study of T-cell depletion of granulocyte colony-stimulating factor (G-CSF ) mobilized peripheral blood progenitor cells (PBPC) for allogeneic transplantation. Twenty consecutive patients, median age, 40 years (21 to 54) and diagnoses of chronic myeloid leukemia in chronic phase (n = 5), acute myeloblastic leukemia (n = 7), acute lymphoblastic leukemia (n = 2), chronic myelomonocytic leukemia (n = 1), refractory anemia with excess of blasts in transformation (n = 3), histiocytosis X (n = 1), and chronic lymphocytic leukemia (n = 1), were conditioned with cyclophosphamide (120 mg/kg) and total body irradiation (13 Gy; 4 fractions). HLA identical sibling donors received G-CSF at 10 μg/kg/d subcutaneously (SC); on days 5 and 6 (19 cases) and days 5 to 8 (1 case) donors underwent 10 L leukapheresis. PBPC were purified by positive selection of CD34+ cells using immunoadsorption biotin-avidin method (Ceprate SC) and were infused in the patients as the sole source of progenitor cells. No growth factors were administered posttransplant. The median recovery of CD34+ cells after the procedure was of 65%. The median number of CD34+ cells infused in the patients was 2.9 (range, 1.5 to 8.6) × 106/kg. The median number of CD3+ cells administered was 0.42 × 106/kg (range, 0.1 to 2). All patients engrafted. Neutrophil counts <500 and <1,000/μL were achieved at a median of 14 days (range, 10 to 18) and 15 days (range, 11 to 27), respectively. Likewise, platelet counts <20,000 and <50,000/μL were observed at a median of 10 days (range, 6 to 23) and 17 days (range, 12 to 130), respectively. Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine plus methylprednisolone. No patient developed either grade II to IV acute or extensive chronic GVHD. After a median follow-up of 7.5 months (range, 2 to 22) three patients have relapsed, and one of them is again in hematologic and cytogenetic remission after infusion of the donor lymphocytes. Two patients died in remission: one on day +109 of pulmonary aspergillosis and the other on day +251 of metastasic relapse of a previous breast cancer. Sixteen of the 20 patients are alive in remission after a median follow-up of 7.5 months (range, 2 to 22). In conclusion, despite the small number of patients and limited follow-up, it appears that this method allows a high CD34+ cell recovery from G-CSF mobilized PBPC and is associated with rapid engraftment without significant GVHD, and with low transplant related mortality.

scholarly journals Unusual expansion of CD3+CD56+ natural killer T-like cells in peripheral blood after anticytokine treatment for graft-versus-host disease

Medicine ◽  
2018 ◽  
Vol 97 (38) ◽  
pp. e12429 ◽  
Author(s):  
Lixia Sheng ◽  
Huarui Fu ◽  
Yamin Tan ◽  
Yongxian Hu ◽  
Qitian Mu ◽  
...  
Keyword(s):  
Natural Killer ◽  
Graft Versus Host Disease ◽  
Peripheral Blood ◽  
Host Disease ◽  
Graft Versus Host ◽  
Natural Killer T

scholarly journals Expression of the T-Cell Activation Antigen, OX-40, Identifies Alloreactive T Cells in Acute Graft-Versus-Host Disease

Blood ◽  
1997 ◽  
Vol 89 (12) ◽  
pp. 4652-4658 ◽  
Author(s):  
Thomas V. Tittle ◽  
Andrew D. Weinberg ◽  
Cara N. Steinkeler ◽  
Richard T. Maziarz
Keyword(s):  
T Cells ◽  
T Cell Activation ◽  
Graft Versus Host Disease ◽  
Peripheral Blood ◽  
Cd4 T Cells ◽  
Cell Activation ◽  
Peripheral Blood Lymphocytes ◽  
Host Disease ◽  
Graft Versus Host ◽  
Acute Graft

Abstract The OX-40 molecule is expressed on the surface of recently activated T lymphocytes. The presence of OX-40 on CD4+ T cells was analyzed in a rat haplo-identical (parental → F1) bone marrow transplant model of acute graft-versus-host disease (aGVHD). Increased numbers of activated CD4+ T cells that expressed the OX-40 antigen were detected in peripheral blood soon after transplantation before the earliest sign of disease. The peak of OX-40 expression occurred 12 days posttransplantation with a range of 18% to 36% of circulating T cells and remained 10-fold above background, never returning to baseline. A slight increase in OX-40 expression (range, 1% to 6%) was also detected on peripheral blood lymphocytes from control syngeneic F1 → F1 recipients. OX-40+ T cells were isolated from spleen, skin, lymph node, and liver tissue of rats undergoing aGVHD, but not in syngeneic transplants. OX-40+ T cells isolated from these tissues were of donor origin and were shown to be allo-reactive. These data raise the possibility of using the OX-40 antibody to detect and deplete selectively the T cells that cause aGVHD.

Prediction of Acute Graft-Versus-Host Disease and Detection of Distinct End-Organ Targets by Enumeration of Peripheral Blood Cytokine Spot-Forming Cells

2005 ◽  
Vol 80 (1) ◽  
pp. 58-65 ◽  
Author(s):  
Masahiro Hirayama ◽  
Eiichi Azuma ◽  
Tadashi Kumamoto ◽  
Shotaro Iwamoto ◽  
Hiroshi Yamada ◽  
...  
Keyword(s):  
Graft Versus Host Disease ◽  
Peripheral Blood ◽  
Host Disease ◽  
Graft Versus Host ◽  
Acute Graft
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