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Chen Y, Yu X, Cai Y, Jin Z, Xu Y. Large-scale mediator Mendelian randomization analysis identifies multiple immune cells mediating the causal link between gut microbes and chronic graft-versus-host disease risk. Exp Hematol 2025; 147:104794. [PMID: 40316245 DOI: 10.1016/j.exphem.2025.104794] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2024] [Revised: 04/03/2025] [Accepted: 04/20/2025] [Indexed: 05/04/2025]
Abstract
Disorders of gut microbiota and immune cells have been observed to be involved in the occurrence of chronic graft-versus-host disease (cGVHD), but their causal connections have yet to be fully understood. This study utilized Mendelian randomization (MR), integrating genome-wide association study (GWAS) meta-analyses from the MiBioGen consortium (microbial taxa), the SardiNIA project (immune traits), and disease data from the Fred Hutchinson Cancer Research Center (FHCRC) cohort to investigate their relationships. The aim was to explore the causal effects of microbiota and immune traits on the incidence of cGVHD, using mediation analysis to identify which immune traits might mediate the effects of microbiota on this condition. The main analysis observed significant causal associations of 3 specific microbial taxa with cGVHD: Lactococcus.id.1851 (odds ratio [OR] = 1.989, 95% confidence interval [CI] = 1.311-3.019, p = 0.001), Ruminiclostridium9.id.11357 (OR = 3.273, 95% CI = 1.604-6.679, p = 0.001), and Intestinimonas.id.2062 (OR = 0.400, 95% CI = 0.230-0.697, p = 0.001). Sensitivity analysis and multivariable MR analysis ruled out possible horizontal pleiotropy and bias. Additionally, 10 immune traits, predominantly covering regulatory T cells (Tregs) and B cells, were identified as influencing cGVHD risk. The two-step mediation MR analysis presented the effect of identified microbial taxa on Tregs and B cells and detailed the pathways through which Intestinimonas impacts cGVHD via CD27 on memory B cells (proportion mediated = 4.2%). Similarly, the role of interactions between Ruminiclostridium9 and effector memory double-negative T cells in mediating cGVHD was quantified, accounting for 9.5% of the total effect.
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Affiliation(s)
- Yiyin Chen
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou, China; Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
| | - Xinghao Yu
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou, China; Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China.
| | - Yiming Cai
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou, China; Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
| | - Zhou Jin
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou, China; Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
| | - Yang Xu
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou, China; Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China.
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Kantor NB, Sepulveda-Beltran PA, Valdés-Arias D, Locatelli EVT, Mulpuri L, Gunawardene AN, Amescua G, Perez VL, Tonk R, Wang T, Galor A. Epidemiology and risk factors for the development of cicatrizing conjunctivitis in chronic ocular graft-versus-host disease. Ocul Surf 2024; 34:341-347. [PMID: 39276859 PMCID: PMC11625611 DOI: 10.1016/j.jtos.2024.09.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2024] [Revised: 08/30/2024] [Accepted: 09/11/2024] [Indexed: 09/17/2024]
Abstract
PURPOSE To evaluate the incidence of chronic cicatrizing conjunctivitis (CCC) and its associated risk factors in the context of chronic ocular graft-vs-host disease (coGVHD). METHODS A retrospective chart review of individuals diagnosed with coGVHD following hematopoietic stem cell transplantation (HSCT) who were seen at the Bascom Palmer Eye Institute between May 2010 and November 2021 was performed. Data regarding baseline demographic characteristics, systemic co-morbidities, lid margin abnormalities, ocular cicatricial changes, transplant information, immunosuppressive therapy, and GVHD severity assessments were collected. The incidence of cicatricial conjunctivitis was estimated with Kaplan-Meier survival analysis. A Cox regression model was used to assess the contribution of demographic and systemic variables to the development of CCC. RESULTS 167 individuals were included (53.9 ± 14.7 years old; 60.5 % male). 65 individuals presented with features suggestive of CCC an average of 60.9 ± 53.8 months after HSCT, with 60-month and 120-month incidences of 29.3 % and 48.9 %, respectively. Multivariable analysis demonstrated that age younger than 50 at the time of the first eye visit was associated with a higher chance of CCC development (Hazard Ratio (HR): 2.14, 95 % Confidence Interval (CI): 1.16-3.97, p = 0.02). CONCLUSION Clinically detected cicatrizing conjunctivitis is an ocular manifestation of coGVHD, with an incidence that increases over time. Younger individuals may be at higher risk for CCC development.
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Affiliation(s)
- Nicole B Kantor
- Bascom Palmer Eye Institute, Department of Ophthalmology, University of Miami Miller School of Medicine, Miami, FL, 33136, USA; Surgical and Research Services, Miami Veterans Administration Medical Center, 1201 NW 16th St, Miami, FL, 33125, USA
| | - Paula A Sepulveda-Beltran
- Bascom Palmer Eye Institute, Department of Ophthalmology, University of Miami Miller School of Medicine, Miami, FL, 33136, USA; Surgical and Research Services, Miami Veterans Administration Medical Center, 1201 NW 16th St, Miami, FL, 33125, USA
| | - David Valdés-Arias
- Bascom Palmer Eye Institute, Department of Ophthalmology, University of Miami Miller School of Medicine, Miami, FL, 33136, USA; Surgical and Research Services, Miami Veterans Administration Medical Center, 1201 NW 16th St, Miami, FL, 33125, USA
| | - Elyana V T Locatelli
- Bascom Palmer Eye Institute, Department of Ophthalmology, University of Miami Miller School of Medicine, Miami, FL, 33136, USA; Surgical and Research Services, Miami Veterans Administration Medical Center, 1201 NW 16th St, Miami, FL, 33125, USA
| | - Lakshman Mulpuri
- Bascom Palmer Eye Institute, Department of Ophthalmology, University of Miami Miller School of Medicine, Miami, FL, 33136, USA
| | - Araliya N Gunawardene
- Surgical and Research Services, Miami Veterans Administration Medical Center, 1201 NW 16th St, Miami, FL, 33125, USA
| | - Guillermo Amescua
- Bascom Palmer Eye Institute, Department of Ophthalmology, University of Miami Miller School of Medicine, Miami, FL, 33136, USA
| | - Victor L Perez
- Bascom Palmer Eye Institute, Department of Ophthalmology, University of Miami Miller School of Medicine, Miami, FL, 33136, USA
| | - Rahul Tonk
- Bascom Palmer Eye Institute, Department of Ophthalmology, University of Miami Miller School of Medicine, Miami, FL, 33136, USA
| | - Trent Wang
- Sylvester Comprehensive Cancer Center, Division of Transplant and Cell Therapy, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Anat Galor
- Bascom Palmer Eye Institute, Department of Ophthalmology, University of Miami Miller School of Medicine, Miami, FL, 33136, USA; Surgical and Research Services, Miami Veterans Administration Medical Center, 1201 NW 16th St, Miami, FL, 33125, USA.
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Gandhi AP, Newell LF, Maziarz RT. A new beginning: can omidubicel emerge as the next, viable alternative donor source? Ther Adv Hematol 2023; 14:20406207231192146. [PMID: 37664800 PMCID: PMC10469227 DOI: 10.1177/20406207231192146] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2023] [Accepted: 07/19/2023] [Indexed: 09/05/2023] Open
Abstract
Umbilical cord blood (UCB) transplantation (CBT) has been an important alternative donor option for patients lacking matched related donor (MRD) or unrelated donor (URD) grafts. Only 30% of patients with high-risk hematologic malignancies have a human leukocyte antigen (HLA)-identical sibling; subjects without a MRD option are referred for HLA-matched URD selection, or utilize alternative donor sources such as HLA-mismatched URD, UCB, or haploidentical donor grafts. While CBT demonstrates an excellent graft-versus-leukemia (GVL) effect, use of UCB as a graft source is limited due to a lower cell dose that can result in delayed engraftment and an immature immune system with increased infectious risk as a consequence. Together, increased transplant related mortality (TRM) has been associated with UCB allografts. Omidubicel is an ex vivo expanded single cord blood product that has demonstrated rapid engraftment, improved immune reconstitution, and reduced infectious complications in clinical trials. Omidubicel has now been granted U.S. Food & Drug Administration approval to enhance neutrophil recovery and decrease infectious risk. This review will focus on CBT, benefits and barriers to using this alternative donor source, and finally the potential advancements with incorporation of omidubicel in the transplant setting for malignant and non-malignant diseases.
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Affiliation(s)
- Arpita P. Gandhi
- Center for Hematologic Malignancies, Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA
| | - Laura F. Newell
- Center for Hematologic Malignancies, Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA
| | - Richard T. Maziarz
- Knight Cancer Institute, Oregon Health and Science University, Mail code: OC14HO, 3181 S.W. Sam Jackson Park Road, Portland, OR 97239, USA
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Haroun E, Agrawal K, Leibovitch J, Kassab J, Zoghbi M, Dutta D, Lim SH. Chronic graft-versus-host disease in pediatric patients: Differences and challenges. Blood Rev 2023; 60:101054. [PMID: 36805299 DOI: 10.1016/j.blre.2023.101054] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Revised: 01/31/2023] [Accepted: 02/02/2023] [Indexed: 02/10/2023]
Abstract
Despite the use of high-resolution molecular techniques for tissue typing, chronic graft-versus-host disease (cGVHD) remains a major complication following allogeneic hematopoietic stem cell transplant. cGVHD adversely affects the life-expectancy and quality of life. The latter is particularly important and functionally relevant in pediatric patients who have a longer life-expectancy than adults. Current laboratory evidence suggests that there is not any difference in the pathophysiology of cGVHD between adults and pediatric patients. However, there are some clinical features and complications of the disease that are different in pediatric patients. There are also challenges in the development of new therapeutics for this group of patients. In this review, we will discuss the epidemiology, pathophysiology, clinical features and consequences of the disease, and highlight the differences between pediatric and adult patients. We will examine the current treatment options for pediatric patients with moderate to severe cGVHD and discuss the challenges facing therapeutic development for cGVHD in the pediatric population.
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Affiliation(s)
- Elio Haroun
- Division of Hematology and Oncology, State University of New York Upstate Medical University, Syracuse, NY, United States of America
| | - Kavita Agrawal
- Division of Hematology and Oncology, State University of New York Upstate Medical University, Syracuse, NY, United States of America
| | - Jennifer Leibovitch
- Division of Hematology and Oncology, State University of New York Upstate Medical University, Syracuse, NY, United States of America
| | - Joseph Kassab
- Department of Medicine, Saint-Joseph University of Beirut, Beirut, Lebanon
| | - Marianne Zoghbi
- Department of Medicine, Saint-Joseph University of Beirut, Beirut, Lebanon
| | - Dibyendu Dutta
- Division of Hematology and Oncology, State University of New York Upstate Medical University, Syracuse, NY, United States of America
| | - Seah H Lim
- Division of Hematology and Oncology, State University of New York Upstate Medical University, Syracuse, NY, United States of America,; Sanofi Oncology, Cambridge, MA, United States of America.
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Nasr W, Filippi MD. Acquired and hereditary bone marrow failure: A mitochondrial perspective. Front Oncol 2022; 12:1048746. [PMID: 36408191 PMCID: PMC9666693 DOI: 10.3389/fonc.2022.1048746] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Accepted: 10/17/2022] [Indexed: 11/22/2022] Open
Abstract
The disorders known as bone marrow failure syndromes (BMFS) are life-threatening disorders characterized by absence of one or more hematopoietic lineages in the peripheral blood. Myelodysplastic syndromes (MDS) are now considered BMF disorders with associated cellular dysplasia. BMFs and MDS are caused by decreased fitness of hematopoietic stem cells (HSC) and poor hematopoiesis. BMF and MDS can occur de novo or secondary to hematopoietic stress, including following bone marrow transplantation or myeloablative therapy. De novo BMF and MDS are usually associated with specific genetic mutations. Genes that are commonly mutated in BMF/MDS are in DNA repair pathways, epigenetic regulators, heme synthesis. Despite known and common gene mutations, BMF and MDS are very heterogenous in nature and non-genetic factors contribute to disease phenotype. Inflammation is commonly found in BMF and MDS, and contribute to ineffective hematopoiesis. Another common feature of BMF and MDS, albeit less known, is abnormal mitochondrial functions. Mitochondria are the power house of the cells. Beyond energy producing machinery, mitochondrial communicate with the rest of the cells via triggering stress signaling pathways and by releasing numerous metabolite intermediates. As a result, mitochondria play significant roles in chromatin regulation and innate immune signaling pathways. The main goal of this review is to investigate BMF processes, with a focus mitochondria-mediated signaling in acquired and inherited BMF.
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Affiliation(s)
- Waseem Nasr
- Division of Experimental Hematology and Cancer Biology, Cincinnati Children’s Research Foundation, Cincinnati, OH, United States,University of Cincinnati College of Medicine, Cincinnati, OH, United States
| | - Marie-Dominique Filippi
- Division of Experimental Hematology and Cancer Biology, Cincinnati Children’s Research Foundation, Cincinnati, OH, United States,University of Cincinnati College of Medicine, Cincinnati, OH, United States,*Correspondence: Marie-Dominique Filippi,
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Colella MP, Morini BC, Niemann F, Lopes MR, Vigorito AC, Aranha FJP, Machado-Neto JA, Saad SO, Favaro P. Expression of transforming growth factor β pathway components in chronic graft-versus-host disease after allogeneic hematopoietic cell transplantation. Transpl Immunol 2021; 70:101514. [PMID: 34922025 DOI: 10.1016/j.trim.2021.101514] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Revised: 10/27/2021] [Accepted: 12/09/2021] [Indexed: 10/19/2022]
Abstract
Chronic graft-versus-host disease (cGvHD), an immunological complication of allogeneic cell transplantation, is the principal cause of non-relapse mortality and morbidity. Even though advances have been made in understanding the pathophysiology of this disorder, many questions remain. We sought to evaluate gene expression of transforming growth factor β (TGF-β) pathway components, through quantitative RT-PCR and PCR array, in patients with cGvHD with different disease activity. We observed an upregulation of SMAD3, BMP2, CDKN1A, IL6, and TGF-β2 genes in the clinical tolerance group, which had never developed cGvHD, or which had been withdrawn from all immunosuppressive treatments (IST) for at least 1 year. In addition, SMAD5 gene upregulation was observed in cGvHD patients undergoing IST, and ordinal regression showed a correlation between SMAD5 expression and disease severity. Our data support the evidence of the important role of TGF-β effects in the pathological process of cGvHD.
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Affiliation(s)
| | | | - Fernanda Niemann
- Hematology and Hemotherapy Center, University of Campinas, Campinas, Brazil
| | | | | | | | | | - Sara Olalla Saad
- Hematology and Hemotherapy Center, University of Campinas, Campinas, Brazil
| | - Patricia Favaro
- Hematology and Hemotherapy Center, University of Campinas, Campinas, Brazil; Department of Biological Sciences, Federal University of São Paulo, Diadema, Brazil.
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Wolff D, Fatobene G, Rocha V, Kröger N, Flowers ME. Steroid-refractory chronic graft-versus-host disease: treatment options and patient management. Bone Marrow Transplant 2021; 56:2079-2087. [PMID: 34218265 PMCID: PMC8410585 DOI: 10.1038/s41409-021-01389-5] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Revised: 06/14/2021] [Accepted: 06/22/2021] [Indexed: 02/05/2023]
Abstract
Chronic graft-versus-host disease (cGVHD) is one of the major causes of late mortality after allogenic hematopoietic stem cell transplantation. Moderate-to-severe cGVHD is associated with poor health-related quality of life and substantial disease burden. While corticosteroids with or without calcineurin inhibitors comprise the first-line treatment option, the prognosis for patients with steroid-refractory cGVHD (SR-cGVHD) remains poor. The mechanisms underlying steroid resistance are unclear, and there are no standard second-line treatment guidelines for patients with SR-cGVHD. In this review, we provide an overview on current treatment options of cGVHD and use a series of theoretical case studies to elucidate the rationale of choices of second- and third-line treatment options for patients with SR-cGVHD based on individual patient profiles.
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Affiliation(s)
- Daniel Wolff
- grid.411941.80000 0000 9194 7179Department of Internal Medicine III, University Hospital Regensburg, Regensburg, Germany
| | - Giancarlo Fatobene
- grid.411074.70000 0001 2297 2036Hospital das Clinicas da Faculdade de Medicina da Universidade de São Paulo (HC-FMUSP), São Paulo, Brazil ,Vila Nova Star Hospital and IDOR, Rede D’Or, São Paulo, Brazil
| | - Vanderson Rocha
- grid.411074.70000 0001 2297 2036Hospital das Clinicas da Faculdade de Medicina da Universidade de São Paulo (HC-FMUSP), São Paulo, Brazil ,Vila Nova Star Hospital and IDOR, Rede D’Or, São Paulo, Brazil
| | - Nicolaus Kröger
- grid.13648.380000 0001 2180 3484Department of Stem Cell Transplantation, University Medical Center Hamburg, Hamburg, Germany
| | - Mary E. Flowers
- grid.34477.330000000122986657Clinical Research Division, Fred Hutchinson Cancer Research Center and Department of Medicine, University of Washington, Seattle, Seattle, WA USA
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8
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Hammer L, Furtado S, Mathiowitz E, Auci DL. Oral encapsulated transforming growth factor β1 reduces endogenous levels: Effect on inflammatory bowel disease. World J Gastrointest Pharmacol Ther 2020; 11:79-92. [PMID: 33251033 PMCID: PMC7667406 DOI: 10.4292/wjgpt.v11.i5.79] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2020] [Revised: 06/18/2020] [Accepted: 10/09/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND TreXTAM® is a combination of the key regulatory cytokine transforming growth factor beta (TGFβ) and all trans retinoic acid (ATRA) microencapsulated for oral delivery to immune structures of the gut. It is in development as a novel treatment for inflammatory bowel disease (IBD).
AIM To measure TGFβ levels in blood and tissue after oral administration of encapsulated TGFβ.
METHODS Animals were orally administered encapsulated TGFβ by gavage. Levels of drug substance in blood and in gut tissues at various times after administration were measured by ELISA.
RESULTS We made the surprising discovery that oral administration of TreXTAM dramatically (approximately 50%) and significantly (P = 0.025) reduced TGFβ levels in colon, but not small intestine or mesenteric lymph nodes. Similarly, levels in rat serum after 25 d of thrice weekly dosing with either TreXTAM, or microencapsulated TGFβ alone (denoted as TPX6001) were significantly (P < 0.01) reduced from baseline levels. When tested in the SCID mouse CD4+CD25- adoptive cell transfer (ACT) model of IBD, oral TPX6001 alone provided only a transient benefit in terms of reduced weight loss.
CONCLUSION These observations suggest a negative feedback mechanism in the gut whereby local delivery of TGFβ results in reduced local and systemic levels of the active form of TGFβ. Our findings suggest potential clinical implications for use of encapsulated TGFβ, perhaps in the context of IBD and/or other instances of fibrosis and/or pathological TGFβ signaling.
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Affiliation(s)
- Laura Hammer
- Department of Research and Development, TherapyX, Buffalo, NY 14214, United States
| | - Stacia Furtado
- Department of Research and Development, TherapyX, Buffalo, NY 14214, United States
- Department of Molecular Pharmacology, Brown University, Providence, RI 02912, United States
| | - Edith Mathiowitz
- Department of Molecular Pharmacology, Brown University, Providence, RI 02912, United States
| | - Dominick L Auci
- Department of Research and Development, TherapyX, Buffalo, NY 14214, United States
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Investigation of TGFB1 -1347C>T variant as a biomarker after allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant 2019; 55:215-223. [PMID: 31527815 DOI: 10.1038/s41409-019-0656-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2018] [Revised: 06/05/2019] [Accepted: 06/30/2019] [Indexed: 01/21/2023]
Abstract
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative therapeutic option for malignant hematopoietic diseases. Cytokines including transforming growth factor β1 (TGFβ1) play a pivotal role in immune reconstruction, and the development of graft versus host disease (GvHD) or infections. The aim of this study was to investigate the role of TGFB1 gene -1347C>T variant in the outcome of HSCT in a cohort of 409 adult recipient-donor pairs. TGFB1 variant was analysed from genomic DNA with LightCycler hybridisation probe method. In case of myeloablative conditioning, donor TGFB1 genotype correlated with overall survival (60-month OS for CC: 62.1 ± 4.8%; CT: 46.8 ± 4.8%; TT: 35.6 ± 9.3%; p = 0.032), which was independent of age, donor type and GvHD prophylaxis in multivariate analysis (HR:2.35, 95%CI:1.35-4.10, p = 0.003). The cumulative incidence of acute GvHD grade III-IV [CC:10%; CT:17%; TT:24%], and non-relapse mortality was higher in TT-carriers (24-month NRM: CC:24%; CT:26%; TT:46%, p = 0.035). We did not find any association between recipient TGFB1 -1347C>T polymorphism and HSCT outcome. Our results suggest that donor TGFB1 -1347C>T may exert an adverse influence on the outcome of myeloablative conditioning transplantation.
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MacDonald KP, Blazar BR, Hill GR. Cytokine mediators of chronic graft-versus-host disease. J Clin Invest 2017; 127:2452-2463. [PMID: 28665299 DOI: 10.1172/jci90593] [Citation(s) in RCA: 72] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
Substantial preclinical and clinical research into chronic graft-versus-host disease (cGVHD) has come to fruition in the last five years, generating a clear understanding of a complex cytokine-driven cellular network. cGVHD is mediated by naive T cells differentiating within IL-17-secreting T cell and follicular Th cell paradigms to generate IL-21 and IL-17A, which drive pathogenic germinal center (GC) B cell reactions and monocyte-macrophage differentiation, respectively. cGVHD pathogenesis includes thymic damage, impaired antigen presentation, and a failure in IL-2-dependent Treg homeostasis. Pathogenic GC B cell and macrophage reactions culminate in antibody formation and TGF-β secretion, respectively, leading to fibrosis. This new understanding permits the design of rational cytokine and intracellular signaling pathway-targeted therapeutics, reviewed herein.
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Affiliation(s)
- Kelli Pa MacDonald
- Antigen Presentation and Immunoregulation Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Australia
| | - Bruce R Blazar
- Masonic Cancer Center; and Division of Blood and Marrow Transplantation, Department of Pediatrics; University of Minnesota, Minneapolis, USA
| | - Geoffrey R Hill
- Bone Marrow Transplantation Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Australia.,Royal Brisbane and Women's Hospital, Brisbane, Australia
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11
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Transforming growth factor-β1 functional polymorphisms in myeloablative sibling hematopoietic stem cell transplantation. Bone Marrow Transplant 2017; 52:739-744. [PMID: 28134923 DOI: 10.1038/bmt.2016.355] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2016] [Revised: 10/13/2016] [Accepted: 11/25/2016] [Indexed: 12/11/2022]
Abstract
Hematopoietic stem cell transplantation (HSCT) with sibling donors (s.d.) is a life-saving intervention for patients with hematological malignancies. Numerous genetic factors have a role in transplant outcome. Several functional polymorphisms have been identified in TGF-β1 gene, such as single-nucleotide polymorphism (SNP) at +29C>T within exon 1. Two hundred and forty five patient/donor pairs who underwent a s.d. HSCT in our centers were genotyped for this SNP. In the myeloablative cohort, +29CC donors were associated with an increase in severe chronic GvHD (32% vs 16%, hazard ratio (HR) 9.0, P=0.02). Regarding survival outcomes, +29CC patients developed higher non relapse mortality (NRM) (1-5 years CC 28-32% vs TC/TT 7-10%; HR 5.1, P=0.01). Recipients of +29TT donors experienced a higher relapse rate (1-5 years TT 37-51% vs TC 19-25% vs CC 13%-19%; HR 2.4, P=0.01) with a decreased overall survival (OS) (1-5 years TT 69-50% vs TC/CC 77-69%; HR 1.9, P=0.05). Similar to previous myeloablative unrelated donors HSCT results, we confirmed that +29CC patients had higher NRM. In addition we found that +29TT donors might be associated with a higher relapse rate and lower OS. These results should be confirmed in larger series. Identification of these SNPs will allow personalizing transplant conditioning and immunosuppressant regimens, as well as assisting in the choice of the most appropriate donor.
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12
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Auci DL, Egilmez NK. Synergy of Transforming Growth Factor Beta 1 and All Trans Retinoic Acid in the Treatment of Inflammatory Bowel Disease: Role of Regulatory T cells. ACTA ACUST UNITED AC 2016; 3. [PMID: 28603774 DOI: 10.15226/2374-815x/3/4/00166] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Affiliation(s)
| | - Nejat K Egilmez
- University of Louisville, Department of Microbiology and Immunology, Louisville, KY
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13
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Maloney JP, Narasimhan J, Biller J. Decreased TGF-β1 and VEGF Release in Cystic Fibrosis Platelets: Further Evidence for Platelet Defects in Cystic Fibrosis. Lung 2016; 194:791-8. [PMID: 27423781 DOI: 10.1007/s00408-016-9925-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2016] [Accepted: 07/11/2016] [Indexed: 12/11/2022]
Abstract
PURPOSE Cystic fibrosis (CF) patients suffer from chronic lung inflammation. This inflammation may activate platelets. There are limited data on the role of platelet-secreted cytokines in CF. Platelet cytokines with inflammatory effects include vascular endothelial growth factor (VEGF) and transforming growth factor-β1 (TGF-β1). As levels of these cytokines are tenfold greater in serum than plasma due to platelet release, serum levels may be one index of platelet content, but a more specific index is release during the aggregation of isolated platelets. We postulated that altered release of these platelet cytokines occurs in CF. METHODS We obtained sera and plasma from CF outpatients (n = 21) and from healthy controls (n = 20), measured VEGF and TGF-β1, assessed for correlations with platelet number, analyzed cytokine release during platelet aggregation to collagen, and analyzed differences in maximal platelet aggregation. RESULTS Platelet number and maximal aggregation levels were higher in CF. Plasma and serum levels of TGF-β1 and VEGF were higher in CF, but these levels were similar after adjusting for platelet number (serum cytokines correlated with platelet count). The release of VEGF and TGF-β1 during aggregation was decreased in CF platelets (by 52 and 29 %, respectively). CONCLUSION Platelet release is not a source of the elevated blood proinflammatory cytokines TGF-β1 and VEGF in CF, as platelets from CF patients actually release less of these cytokines. These data provide further evidence for platelet defects in CF.
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Affiliation(s)
- James P Maloney
- Divisions of Pulmonary and Critical Care Medicine, University of Colorado, Denver, 12700 East 19th Avenue, C-272, Aurora, Denver, CO, 80045, USA.
| | | | - Julie Biller
- The Medical College of Wisconsin, Milwaukee, WI, USA
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14
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Conway TF, Hammer L, Furtado S, Mathiowitz E, Nicoletti F, Mangano K, Egilmez NK, Auci DL. Oral Delivery of Particulate Transforming Growth Factor Beta 1 and All-Trans Retinoic Acid Reduces Gut Inflammation in Murine Models of Inflammatory Bowel Disease. J Crohns Colitis 2015; 9:647-58. [PMID: 25987350 PMCID: PMC4817304 DOI: 10.1093/ecco-jcc/jjv089] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2015] [Accepted: 05/05/2015] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND AIMS We investigated oral delivery of transforming growth factor beta 1 [TGFβ]- and all-trans retinoic acid [ATRA]-loaded microspheres as therapy for gut inflammation in murine models of inflammatory bowel disease [IBD]. METHODS ATRA and TGFβ were separately encapsulated in poly [lactic-co-glycolic] acid or polylactic acid microspheres [respectively]. TGFβ was encapsulated using proprietary phase-inversion nanoencapsulation [PIN] technology. RESULTS PIN particles provided sustained release of bioactive protein for at least 4 days and were stable for up to 52 weeks when stored at either 4(0)C or -20(0)C. In the SCID mouse CD4 + CD25- T cell transfer model of IBD, oral treatment starting at disease onset prevented weight loss, significantly reduced average disease score [~ 50%], serum amyloid A levels [~ 5-fold], colon weight-to-length ratio [~ 50%], and histological score [~ 5-fold]. CONCLUSIONS Both agents given together outperformed either separately. Highest TGFβ doses and most frequent dose schedule were most effective. Activity was associated with a significant increase [45%] in Foxp3 expression by colonic lamina propria CD4+ CD25+ T-cells. Activity was also demonstrated in dextran sulphate sodium-induced colitis. The data support development of the combination product as a novel, targeted immune based therapy for treatment for IBD.
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Affiliation(s)
- Thomas F. Conway
- TherapyX, Buffalo, NY, USA,State University of New York, at Buffalo, NY, USA
| | | | - Stacia Furtado
- TherapyX, Buffalo, NY, USA,Brown University, Department Biomedical and Molecular Pharmacology, Providence, RI, USA
| | - Edith Mathiowitz
- Brown University, Department Biomedical and Molecular Pharmacology, Providence, RI, USA
| | - Ferdinando Nicoletti
- University of Catania, Department of Biomedical and Biotechnological Sciences, Catania, Italy
| | - Katia Mangano
- University of Catania, Department of Biomedical and Biotechnological Sciences, Catania, Italy
| | - Nejat K. Egilmez
- TherapyX, Buffalo, NY, USA,State University of New York, at Buffalo, NY, USA
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15
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Regulatory B cells are enriched within the IgM memory and transitional subsets in healthy donors but are deficient in chronic GVHD. Blood 2014; 124:2034-45. [PMID: 25051962 DOI: 10.1182/blood-2014-04-571125] [Citation(s) in RCA: 162] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
A subset of regulatory B cells (Bregs) in mice negatively regulate T-cell immune responses through the secretion of regulatory cytokines such as IL-10 and direct cell-cell contact and have been linked to experimental models of autoimmunity, inflammation, and cancer. However, the regulatory function of Bregs in human disease is much less clear. Here we demonstrate that B cells with immunoregulatory properties are enriched within both the CD19(+)IgM(+)CD27(+) memory and CD19(+)CD24(hi)CD38(hi) transitional B-cell subsets in healthy human donors. Both subsets suppressed the proliferation and interferon-γ production of CD3/CD28-stimulated autologous CD4(+) T cells in a dose-dependent manner, and both relied on IL-10 secretion as well as cell-cell contact, likely mediated through CD80 and CD86, to support their full suppressive function. Moreover, after allogeneic stem cell transplantation, Bregs from patients with chronic graft-versus-host disease (cGVHD) were less frequent and less likely to produce IL-10 than were Bregs from healthy donors and patients without cGVHD. These findings suggest that Bregs may be involved in the pathogenesis of cGVHD and support future investigation of regulatory B cell-based therapy in the treatment of this disease.
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16
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Lunn RA, Sumar N, Bansal AS, Treleaven J. Cytokine profiles in stem cell transplantation: Possible use as a predictor of graft-versus-host disease. Hematology 2013; 10:107-14. [PMID: 16019456 DOI: 10.1080/10245330400001975] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
Graft-versus-host disease (GvHD) complicates many allogeneic stem cell transplants (alloSCT), and several factors are known to be associated with the development of GvHD besides human leucocyte antigen (HLA) incompatibility. We investigated whether changes in serum levels of soluble IL-2 receptor (sIL-2Ralpha), tumour necrosis factor-alpha (TNF-alpha), transforming growth factor-beta (TGF-beta), vascular endothelial growth factor (VEGF) and soluble Fas (sFas) correlated with the development of GvHD in patients undergoing SCT, and might thus be potentially of use to anticipate the development of GvHD, allowing early modification of immunosuppressive therapy.sIL2Ralpha and sFas levels were significantly raised in allograft, autograft (allo and auto) and non-graft groups compared to the normal controls (HC), but there was no statistical difference between the three patient groups. TNF-alpha was raised in the auto and allo groups and the non-graft patients compared to the HC group (median 4.37 pg/ml), but only reached significance in the allo group (median 6.02 pg/ml; p = 0.008) when this was compared with the non-graft patients. There was no significant difference in TGF-ss levels between any of the groups. The median serum VEGF levels were decreased in allo and auto patients compared to HC, (31 and 62 pg/ml versus 90 pg/ml, respectively), with a significant difference in the auto group (p = 0.007). VEGF levels were significantly lower in the auto versus the allo group (p = 0.008) and also in the auto versus the non-graft group (median 104 pg/ml; p = 0.011). When the allo group was divided into patients who developed GvHD and those who did not, serum VEGF levels were significantly higher in those with GvHD (p = 0.028).
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Affiliation(s)
- R A Lunn
- Department of Clinical Immunology, St Helier Hospital, Surrey, SM5 1AA, Carshalton, UK
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17
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Wiegering V, Winkler B, Haubitz I, Wölfl M, Schlegel PG, Eyrich M. Lower TGFß serum levels and higher frequency of IFNγ-producing T cells during early immune reconstitution in surviving children after allogeneic stem cell transplantation. Pediatr Blood Cancer 2013; 60:121-8. [PMID: 22623061 DOI: 10.1002/pbc.24208] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2012] [Accepted: 05/02/2012] [Indexed: 01/22/2023]
Abstract
BACKGROUND Allogeneic hematopoietic stem cell transplantation (SCT) is increasingly used as a salvage therapy for patients with high-risk malignancies as well as life-threatening non-malignant diseases. However, only limited data about the association between outcome and functional parameters of recovering lymphocytes are available so far. PROCEDURES In this prospective study of 19 pediatric SCT recipients, we serially evaluated immune parameters quantitatively and qualitatively before and throughout allogeneic SCT. These data were analyzed with respect to survival. RESULTS Age, gender, GvHD, and type of graft were not different between surviving and non-surviving patients. Notably, in our cohort there was no case of transplant-related or infectious mortality. However, with the exception of two patients with advanced MDS, all patients not in complete remission (CR) relapsed in addition to three patients in higher CR (n = 7). All seven patients relapsing after allogeneic SCT later succumbed to their disease recurrence. Uni- and multivariate analysis showed that relapsing patients had higher TGFß serum levels as well as lower percentages of IFNγ-producing T cells before and early after transplantation. Furthermore, relapsing patients had a further decline in their thymic function between day 60 and 120 whereas non-relapsing patients already showed increasing TREC values during this time interval. CONCLUSIONS Collectively, patients who later relapse show a different pattern of immune reconstitution before and at early time points post-transplantation.
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Affiliation(s)
- Verena Wiegering
- Pediatric Stem Cell Transplant Unit, University Children's Hospital, Germany
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18
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Papewalis C, Topolar D, Götz B, Schönberger S, Dilloo D. Mesenchymal stem cells as cellular immunotherapeutics in allogeneic hematopoietic stem cell transplantation. ADVANCES IN BIOCHEMICAL ENGINEERING/BIOTECHNOLOGY 2013; 130:131-62. [PMID: 23455489 DOI: 10.1007/10_2012_158] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative treatment option in hematopoietic disorders, immunodeficiencies and leukemia. To date graft-versus-host disease (GvHD) represents a life-threatening complication even if associated with beneficial antileukemic reactivity. GvHD is the clinical manifestation of donor cells reacting against host tissue. Because of their ability to facilitate endogenous repair and to attenuate inflammation, MSC have evolved as a highly attractive cellular therapeutic in allo-HSCT. Here we report on the clinical experience in the use of MSC to enhance engraftment and prevent and treat acute and chronic GvHD. In early clinical trials, MSC have shown considerable benefit in the setting of manifest GvHD. These encouraging results warrant further exploration.
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Affiliation(s)
- Claudia Papewalis
- Department of Pediatric Hematology and Oncology, Center for Pediatrics, University Hospital, Friedrich-Wilhelm University, Bonn, Germany
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19
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Carli C, Giroux M, Delisle JS. Roles of Transforming Growth Factor-β in Graft-versus-Host and Graft-versus-Tumor Effects. Biol Blood Marrow Transplant 2012; 18:1329-40. [DOI: 10.1016/j.bbmt.2012.01.020] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2011] [Accepted: 01/27/2012] [Indexed: 01/07/2023]
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20
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Chronic GVHD: Where are we? Where do we want to be? Will immunomodulatory drugs help? Bone Marrow Transplant 2012; 48:203-9. [DOI: 10.1038/bmt.2012.76] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
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21
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Arrieta-Bolaños E, Alejandro Madrigal J, Shaw BE. Transforming growth factor-β1 polymorphisms and the outcome of hematopoietic stem cell transplantation. Int J Immunogenet 2012; 39:192-202. [DOI: 10.1111/j.1744-313x.2012.01089.x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
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22
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Isik S, Ozuguz U, Tutuncu YA, Erden G, Berker D, Acar K, Aydin Y, Akbaba G, Helvaci N, Guler S. Serum transforming growth factor-beta levels in patients with vitamin D deficiency. Eur J Intern Med 2012; 23:93-7. [PMID: 22153539 DOI: 10.1016/j.ejim.2011.09.017] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2011] [Revised: 08/23/2011] [Accepted: 09/27/2011] [Indexed: 01/28/2023]
Abstract
BACKGROUND Transforming growth factor-beta 1 (TGF-β1) contributes to tissue repair by promoting tissue fibrosis, and elevations have been reported in patients with bone marrow fibrosis. The aim of this study was to evaluate the relationship between TGF-β1 levels and vitamin D deficiency. METHODS All patients presenting to the outpatient Endocrinology and Metabolic Diseases clinic between June and September of 2008 were approached, and consenting patients who were deemed suitable candidates were enrolled. Hematological parameters were measured, along with serum levels of total and ionized calcium, phosphorus, parathyroid hormone, iron, folic acid vitamin B12 levels, 25 OH vitamin D3 (25OHD(3)) and TGF-β1. RESULTS A total of 132 patients were included in the study. Patients were divided into 4 groups based on levels of 25OHD(3) [group 1 (<5 ng/ml), 20 patients; group 2 (5-15 ng/ml), 38 patients; group 3 (16-30 ng/ml); and group 4 (>30 ng/ml), 28 patients]. TGF-β1 levels were higher in patients in group 1 compared to the other groups. Transforming growth factor-beta levels correlated negatively with vitamin D3 and positively with leukocyte count, platelet count, of MCV and MCH. Multiple regression analyses revealed TGF-β1 levels to be associated with 25OHD(3) as well as with platelet count. CONCLUSIONS Results of this study are suggestive of the presence of a significant relationship between TGF-β and vitamin D deficiency. Increased TGF-β1 and platelet count may be an early indicator of bone marrow fibrosis in patients with vitamin D deficiency.
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Affiliation(s)
- Serhat Isik
- Ministry Of Health, Ankara Numune Research and Training Hospital, Department of Endocrinology and Metabolism, Ankara, Turkey.
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23
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Grkovic L, Baird K, Steinberg SM, Williams KM, Pulanic D, Cowen EW, Mitchell SA, Hakim FT, Martires KJ, Avila DN, Taylor TN, Salit RB, Rowley SD, Zhang D, Fowler DH, Bishop MR, Gress RE, Pavletic SZ. Clinical laboratory markers of inflammation as determinants of chronic graft-versus-host disease activity and NIH global severity. Leukemia 2011; 26:633-43. [PMID: 22005783 PMCID: PMC3262945 DOI: 10.1038/leu.2011.254] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
Chronic graft versus host disease (cGVHD) remains a major cause of non-relapse morbidity and mortality after allogeneic hematopoietic stem cell transplantation. Currently there are no accepted measures of cGVHD activity to aid in clinical management and disease staging. We analyzed clinical markers of inflammation in the sera of patients with established cGVHD and correlated those with definitions of disease activity. 189 adults with cGVHD (33% moderate and 66% severe according to NIH global scoring) were consecutively enrolled onto a cross-sectional prospective cGVHD natural history study. At the time of evaluation, 80% were receiving systemic immunosuppression and failed a median of 4 prior systemic therapies (PST) for their cGVHD. Lower albumin (p<0.0001), higher CRP (C-reactive protein; p=0.043), higher platelets (p=0.030) and higher number of PST (p<0.0001) were associated with active disease defined as clinician's intention to intensify or alter systemic therapy due to the lack of response. Higher platelet count (p=0.021) and higher number of PST (p<0.0001) were associated with more severe diseased defined by NIH global score. This study identified common laboratory indicators of inflammation that can serve as markers of cGVHD activity and severity.
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Affiliation(s)
- L Grkovic
- Graft-versus-Host and Autoimmunity Unit, Experimental Transplantation and Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
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24
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Kyrcz-Krzemień S, Helbig G, Zielińska P, Markiewicz M. The kinetics of mRNA transforming growth factor beta1 expression and its serum concentration in graft-versus-host disease after allogeneic hemopoietic stem cell transplantation for myeloid leukemias. Med Sci Monit 2011; 17:CR322-8. [PMID: 21629186 PMCID: PMC3539544 DOI: 10.12659/msm.881804] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Abstract
Background Graft-versus-host disease (GVHD) is still a major complication following allogeneic hematopoietic stem cell transplantation (alloHSCT). Recent data indicates that transforming growth factor beta1 (TGF-β1) may play a role in development of GVH reaction. Material/Methods Forty patients with acute myeloid leukemia (AML) and chronic myeloid leukemia (CML) were included. Quantitative real time polymerase chain reaction (RT-qPCR) was performed to assess the expression of mRNA TGF-β1. TGF-β1 serum concentration was assessed using a commercial ELISA. Results In all patients, a prompt decrease in TGF-β1 mRNA expression and its serum concentration was demonstrated after conditioning. In patients with acute GVHD, TGF-β1 mRNA expression and its serum concentration remained low until day +30 after transplant as compared to the day of transplant (p<0.03 and p<0.006, respectively). TGF-β1 mRNA expression and its serum concentration significantly increased on day +100 in patients who developed chronic GVHD as compared to the day of transplant (p<0.0009 and p<0.02, respectively). Conclusions TGF-β1 seems to be an additional regulator of donor engraftment; its low levels probably being one of the factors contributing to the development of acute GVHD. On the other hand, chronic GVHD symptoms seem to correlate with high TGF-β1 mRNA expression and its serum concentration in patients who underwent bone marrow transplantation for myeloid leukemias. Nevertheless, further studies with greater numbers of patients are needed to establish the role of TGF-β1 in graft-versus-host disease pathophysiology.
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Affiliation(s)
- Sławomira Kyrcz-Krzemień
- Department of Hematology and Bone Marrow Transplantation, Medical University of Silesia, Katowice, Poland.
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Min CK. The pathophysiology of chronic graft-versus-host disease: the unveiling of an enigma. THE KOREAN JOURNAL OF HEMATOLOGY 2011; 46:80-7. [PMID: 21747879 PMCID: PMC3128905 DOI: 10.5045/kjh.2011.46.2.80] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/09/2011] [Accepted: 06/10/2011] [Indexed: 12/27/2022]
Abstract
Chronic graft-versus-host disease (CGVHD) is one of the most significant complications of long-term survivors after allogeneic hematopoietic stem cell transplantation (allo-HSCT). CGVHD may have protean manifestations and can pose unique diagnostic and therapeutic challenges. New recommendations that emphasize the importance of qualitative differences, as opposed to time of onset after HSCT, are now being used to standardize the diagnosis and clinical assessment of CGVHD, but they require validation. During the past 3 decades, experimental studies and clinical observations have elucidated the mechanisms of acute GVHD, but its biology is much less well-understood. Experimental studies have generated at least 4 theories to explain the pathophysiology of CGVHD: (1) thymic damage and the defective negative selection of T cells, (2) regulatory T cell deficiencies, (3) auto-antibody production by aberrant B cells, and (4) the formation of profibrotic lesions. Mouse models have provided important insights into the pathophysiology of CGVHD, and these have helped improve clinical outcomes following allo-HSCT, but no animal model fully replicates all of the features of CGVHD in humans. In this article, recent clinical changes, the pathogenesis of CGHVD, the cellular and cytokine networks implicated in its pathogenesis, and the animal models used to devise strategies to prevent and treat CGVHD are reviewed.
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Affiliation(s)
- Chang-Ki Min
- Division of Hematology, Department of Internal Medicine, The Catholic University of Korea, Seoul, Korea
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27
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Poloni A, Sartini D, Emanuelli M, Trappolini S, Mancini S, Pozzi V, Costantini B, Serrani F, Berardinelli E, Renzi E, Olivieri A, Leoni P. Gene expression profile of cytokines in patients with chronic graft-versus-host disease after allogeneic hematopoietic stem cell transplantation with reduced conditioning. Cytokine 2011; 53:376-83. [PMID: 21211989 DOI: 10.1016/j.cyto.2010.12.008] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2010] [Revised: 07/22/2010] [Accepted: 12/02/2010] [Indexed: 11/27/2022]
Abstract
There are no reliable markers useful to predict the onset or the evolution of chronic graft-versus-host disease (cGVHD) after allogeneic hematopoietic stem cell transplantation (HSCT), although several candidate biomarkers have been identified from limited hypothesis-driven studies. In this study we evaluated 14 patients who received a reduced intensity conditioning HSCT. Seven patients had cGVHD, whereas 7 never developed cGVHD during the period of observation. The expression of 114 cytokines in immunoselected cell populations was explored by microarray analysis and 11 cytokines were selected for further evaluation by real-time PCR. Differential gene expression measurements showed a significant up-regulation for INFγ (interferon, gamma) in CD8+ and for TNFSF3 (tumor necrosis factor superfamily, member 3) and for TNFSF10 (tumor necrosis factor superfamily, member 10) in CD14+ cell population when comparing cGVHD with control samples. The expression levels were significantly decreased for TNFSF10 in CD8+ cell population and for TNFSF12 (tumor necrosis factor superfamily, member 12) and for PDGFβ (platelet-derived growth factor, beta) in CD4+. Our data seem to suggest that different immune populations can play a role in cGVHD pathogenesis and the early detection of gene expression profile in these patients could be useful in the monitoring of GVHD. We hypothesized that PDGFβ down-regulation could represent a negative feedback to compensate for enhanced expression of its receptor recently reported.
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Affiliation(s)
- Antonella Poloni
- Dipartimento di Scienze Mediche e Chirurgiche-Sezione di Ematologia, Università Politecnica delle Marche, Ancona, Italy
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Coomes SM, Moore BB. Pleiotropic effects of transforming growth factor-β in hematopoietic stem-cell transplantation. Transplantation 2010; 90:1139-44. [PMID: 20671593 PMCID: PMC2995826 DOI: 10.1097/tp.0b013e3181efd018] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Transforming growth factor (TGF)-β is a pleiotropic cytokine with beneficial and detrimental effects posthematopoietic stem-cell transplantation. TGF-β is increased in specific sites postengraftment and can suppress immune responses and maintain peripheral tolerance. Thus, TGF-β may promote allograft acceptance. However, TGF-β is also the central pathogenic cytokine in fibrotic disease and likely promotes pneumonitis. Although TGF-β can enhance leukocyte recruitment and IgA production, it inhibits both innate and adaptive immune cell function and antiviral host defense posthematopoietic stem-cell transplantation. This review will focus on the current understanding of TGF-β biology and the numerous ways it can impact outcomes posttransplant.
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Affiliation(s)
- Stephanie M Coomes
- University of Michigan Program in Biomedical Sciences, Ann Arbor, MI, USA
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Wu JM, Thoburn CJ, Wisell J, Farmer ER, Hess AD. CD20, AIF-1, and TGF-beta in graft-versus-host disease: a study of mRNA expression in histologically matched skin biopsies. Mod Pathol 2010; 23:720-8. [PMID: 20190732 PMCID: PMC3075614 DOI: 10.1038/modpathol.2010.48] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
Graft-versus-host disease is the leading cause of non-relapse mortality after allogeneic bone marrow transplantation. The cell-mediated immune mechanisms that underlie the pathogenesis of graft-versus-host disease remain unclear. In this study, 47 skin biopsies representing graft-versus-host disease grades 0-III, lichenoid, and sclerodermoid were included from 31 allogeneic bone marrow transplantation recipients. RNA from paraffin-embedded tissue was harvested. Transcript levels of the following markers were assessed and correlated with grade and survival: CD3, CD20, FoxP3, IL-17, gamma-interferon (IFN-gamma), transforming growth factor-beta (TGF-beta), IL-6, connective tissue growth factor (CTGF), allograft inflammatory factor-1(AIF-1), and IL-13. Levels of three markers significantly correlated with the length of survival (TGF-beta, correlation coefficient -20.8, P=0.016; AIF-1, 13.2, P=0.016; and CD20, 66, P=0.027). CD20 expression was limited to lichenoid cases. Levels of TGF-beta, AIF-1, and IFN-gamma appeared to correlate with histological progression, but did not reach statistical significance. Expression of FoxP3 correlated with worse survival, and approached statistical significance (P=0.053). Two potential mechanistic pathways were identified: the 'scleroderma' group (AIF-1 and TGF-beta) and the 'B-cell' group (CD20). Transcript levels of these markers were implicated in the progression from acute to chronic disease, and also correlated significantly with the duration of survival. Identification of these three markers may direct therapy selection with targeted agents, including the use of rituximab when B-lymphocytes are implicated.
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Affiliation(s)
- Julie M Wu
- Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD 21287, USA
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Li Q, Zhai Z, Xu X, Shen Y, Zhang A, Sun Z, Liu H, Geng L, Wang Y. Decrease of CD4(+)CD25(+) regulatory T cells and TGF-beta at early immune reconstitution is associated to the onset and severity of graft-versus-host disease following allogeneic haematogenesis stem cell transplantation. Leuk Res 2010; 34:1158-68. [PMID: 20409584 DOI: 10.1016/j.leukres.2010.03.017] [Citation(s) in RCA: 63] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2009] [Revised: 03/06/2010] [Accepted: 03/09/2010] [Indexed: 11/25/2022]
Abstract
Graft-versus-host disease (GVHD) is a frequent and life threatening complication of allogeneic haematogenesis stem cell transplantation (aHSCT). The correlation of CD4(+)CD25(+) regulatory T cells (Tregs) in the patients after aHSCT to the occurrence and severity of acute and chronic GVHD (aGVHD and cGVHD) is not fully investigated. Here, we examined the levels of CD4(+)CD25(+) Tregs by assessment of CD4(+)CD25(high) and CD4(+)CD25(+)CD127(low) in peripheral blood, and the levels of serum TGF-beta and TNF-alpha in 56 patients at early immune reconstitution following aHSCT. Our data showed a significant reduction in the frequency of Tregs in patients with grades II-IV aGVHD and extensive cGVHD compared to healthy controls. Moreover, a decreased level of CD4(+)CD25(+) Tregs was correlated to increased severity of GVHD. The levels of CD4(+)CD25(+) Tregs in non-GVHD groups were however significantly higher than that in healthy controls. A significant decrease in the levels of TGF-beta and a significant increase the levels of TNF-alpha was also seen with increased severity of GVHD. This study suggested that measurement of CD4(+)CD25(+) Tregs along with serum TGF-beta and TNF-alpha at early immune reconstruction after aHSCT may indicate the onset and severity of both aGVHD and cGVHD.
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Affiliation(s)
- Qing Li
- The Central Laboratory of Medical Research Center in the Affiliated Anhui Provincial Hospital of Anhui Medical University, Hefei City, China
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31
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Feily A, Namazi MR. Why is graft-versus-host disease sometimes associated with leukoderma and fewer melanocytic naevi? J Cosmet Dermatol 2010; 9:64-5. [PMID: 20367675 DOI: 10.1111/j.1473-2165.2010.00482.x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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Pulanic D, Lozier JN, Pavletic SZ. Thrombocytopenia and hemostatic disorders in chronic graft versus host disease. Bone Marrow Transplant 2009; 44:393-403. [PMID: 19684626 DOI: 10.1038/bmt.2009.196] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
Chronic graft versus host disease (cGVHD) is a major and frequent late complication in allogeneic stem cell transplantation recipients. Although thrombocytopenia in cGVHD patients is among the most consistent and strongest predictors of poor survival across many cGVHD studies, such correlation is still neither clearly explained nor well understood. Low platelet counts in the setting of cGVHD are associated with an increase in complications and treatment-related mortality, but usually not with higher relapse rate or engraftment failure rate. Bleeding might be occasionally increased along with, paradoxically, thrombosis. Hemostatic disorders in the context of cGVHD are significant complications with multifactorial etiology, including tissue injury with releasing microparticles, cytokine release, macrophage/monocyte clearance, CMV infection, production of transforming growth factor-beta, and low levels of thrombopoietin. Future clinical trials with agents that stimulate megakaryocytopoiesis or influence underlying impaired hemostasis mechanisms should investigate whether such interventions may improve outcomes in patients with cGVHD.
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Affiliation(s)
- D Pulanic
- Graft-versus-Host and Autoimmunity Unit, Experimental Transplantation and Immunology Branch, National Cancer Institute, Center for Cancer Research, National Institutes of Health, Bethesda, MD, USA
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Pohlers D, Brenmoehl J, Löffler I, Müller CK, Leipner C, Schultze-Mosgau S, Stallmach A, Kinne RW, Wolf G. TGF-beta and fibrosis in different organs - molecular pathway imprints. Biochim Biophys Acta Mol Basis Dis 2009; 1792:746-56. [PMID: 19539753 DOI: 10.1016/j.bbadis.2009.06.004] [Citation(s) in RCA: 477] [Impact Index Per Article: 29.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2009] [Revised: 06/11/2009] [Accepted: 06/12/2009] [Indexed: 12/25/2022]
Abstract
The action of transforming-growth-factor (TGF)-beta following inflammatory responses is characterized by increased production of extracellular matrix (ECM) components, as well as mesenchymal cell proliferation, migration, and accumulation. Thus, TGF-beta is important for the induction of fibrosis often associated with chronic phases of inflammatory diseases. This common feature of TGF-related pathologies is observed in many different organs. Therefore, in addition to the description of the common TGF-beta-pathway, this review focuses on TGF-beta-related pathogenetic effects in different pathologies/organs, i. e., arthritis, diabetic nephropathy, colitis/Crohn's disease, radiation-induced fibrosis, and myocarditis (including their similarities and dissimilarities). However, TGF-beta exhibits both exacerbating and ameliorating features, depending on the phase of disease and the site of action. Due to its central role in severe fibrotic diseases, TGF-beta nevertheless remains an attractive therapeutic target, if targeted locally and during the fibrotic phase of disease.
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Affiliation(s)
- Dirk Pohlers
- Experimental Rheumatology Unit, Department of Orthopedics, Waldkrankenhaus Rudolf Elle Eisenberg, University Hospital Jena, Friedrich Schiller University, Jena, Germany
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34
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Affiliation(s)
- Paul J Martin
- Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
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Abstract
Hematopoietic cell transplantation (HCT) is frequently complicated by graft-versus-host disease (GVHD). During the past three decades, experimental studies and clinical observations have elucidated the pathophysiology of acute GVHD, but the biology of chronic GVHD is much less well understood. Recommendations of the NIH Consensus Development Project on Criteria for Clinical Trials in Chronic GVHD have begun to standardize the diagnosis and clinical assessment of the disease. These criteria have emphasized the importance of qualitative differences, as opposed to time of onset after HCT, in making the distinction between acute and chronic GVHD. Experimental studies have generated at least four theories to explain the pathophysiology of chronic GVHD. These theories include 1) thymic damage and defective negative selection of T cells generated from marrow progenitors after HCT, 2) aberrant production of transforming growth factor-beta, 3) auto-antibody production, and 4) deficiency of T-regulatory cells. Recent studies in humans have corroborated a possible role for each of these mechanisms in humans. No animal model fully replicates all of the features of chronic GVHD in humans, and it appears likely that multiple biological mechanisms account for the diverse features the disease. Chronic GVHD may represent a "syndrome" with diverse causes among individual patients. In the future, it might become possible to tailor specific therapeutic interventions for patients as individually needed for each distinct pathophysiologic mechanism involved in development of the disease.
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Affiliation(s)
- Paul J Martin
- Division of Clinical Research, Department of Medicine, Fred Hutchinson Cancer Research Center, University of Washington, Seattle, WA 98109-1024, USA.
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Chen HW, Yang SF, Chang YC, Wang TY, Chen YJ, Hwang JJ. Epstein-Barr virus infection and plasma transforming growth factor-beta1 levels in head and neck cancers. Acta Otolaryngol 2008; 128:1145-51. [PMID: 18720060 DOI: 10.1080/00016480701714293] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
CONCLUSIONS In addition to the correlation of transforming growth factor (TGF)-beta1 levels to the radiation toxicity, both Epstein-Barr virus (EBV) infection and postoperative status play roles in the change in plasma TGF-beta1 levels in patients with head and neck cancers. OBJECTIVES To assess the parameters involved in the change in plasma TGF-beta1 level during concurrent chemoradiotherapy (CCRT). PATIENTS AND METHODS Blood samples (n=307) before, during, and after treatment were obtained from 39 patients with head and neck cancers treated with definitive or adjuvant CCRT. In situ hybridization (ISH) was used to identify EBV-encoded RNA (EBER) in tissues from the primary tumor or metastatic lymph nodes. Plasma TGF-beta1 level, white blood cell (WBC), and platelet count were assayed immediately before the first fraction of radiotherapy (RT), once a week during RT, and at the end of the RT course. The grades of mucositis and dermatitis were recorded weekly during CCRT. RESULTS Pretreatment TGF-beta1 level and radiation toxicity were found to be significantly correlated with the increase of the plasma TGF-beta1 level during CCRT (p<0.05), but correlation of platelet count was only found in patients whose tumors were EBV-positive (p=0.0042), and WBC count in those treated with postoperative adjuvant CCRT (p=0.004).
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Chu YW, Gress RE. Murine models of chronic graft-versus-host disease: insights and unresolved issues. Biol Blood Marrow Transplant 2008; 14:365-78. [PMID: 18342778 PMCID: PMC2376050 DOI: 10.1016/j.bbmt.2007.12.002] [Citation(s) in RCA: 105] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2007] [Accepted: 12/02/2007] [Indexed: 11/26/2022]
Abstract
Chronic graft-versus-host-disease (cGVHD) is a major barrier to successful allogeneic hematopoietic stem cell transplantation (allo-HSCT), with highly variable clinical presentations. The pathophysiology of cGVHD remains relatively poorly understood. The utilization of murine models to study cGVHD encompasses experimental challenges distinct from those that have been successfully used to study acute GVHD (aGVHD). Nevertheless, despite these challenges, murine models of cGVHD have contributed to the understanding of cGVHD, and highlight its mechanistic complexity. In this article, insights into the pathophysiology of cGVHD obtained from murine studies are summarized in the context of their relevancy to clinical cGVHD. Despite experimental limitations, current and future models of murine cGVHD will continue to provide insights into the understanding of clinical cGVHD and provide information for new therapeutic interventions.
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Affiliation(s)
- Yu-Waye Chu
- Experimental Transplantation and Immunology Branch, Center for Cancer Research, NIH, Bethesda 20892-1360, Maryland, USA.
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Viel DO, Tsuneto LT, Sossai CR, Lieber SR, Marques SBD, Vigorito AC, Aranha FJP, de Brito Eid KA, Oliveira GB, Miranda ECM, de Souza CA, Visentainer JEL. IL2 and TNFA gene polymorphisms and the risk of graft-versus-host disease after allogeneic haematopoietic stem cell transplantation. Scand J Immunol 2008; 66:703-10. [PMID: 18021367 DOI: 10.1111/j.1365-3083.2007.02021.x] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
This study aimed to analyse the association of gene polymorphisms with the outcome of allogeneic haematopoietic stem cell transplantation. We studied 122 donor/recipient pairs who received HLA-identical transplants from siblings at the Universidade Estadual de Campinas, Brazil, between June 1996 and June 2006. Donor/recipient alleles for TNFA-238 and IL2-330/+166 single-nucleotide polymorphisms (SNP) were analysed by PCR-SSP. No association was observed between the risk of acute graft-versus-host disease (GVHD) and these SNP. However, our findings suggest that the polymorphism of promoter gene TNFA-238GA is associated with the occurrence and severity of chronic GVHD. The probability of chronic GVHD in patients with GA genotype at position -238 of TNFA gene is 91.7% in contrast to 59.4% in patients with GG genotype (P = 0.038). In patients with donor GA genotype the probability of chronic GVHD is 90.8%, and 57.9% in patients with donor GG genotype (P = 0.038). The probability of extensive chronic GVHD in patients with TNFA-238GA is 91.7% compared with 46.3% in patients with TNFA-238GG (P = 0.0046). In patients with donor GA genotype at position -238 of the TNFA gene, it is 81.7%, compared with 44.5% in patients with donor GG genotype (P = 0.016). However, further studies with more patients are required to identify cytokine gene polymorphisms and their association with transplant-related complication in Brazil, particularly due to ethnic background, the relatively low power of detection of genetic markers of this study, and the complexity of the MHC region.
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Affiliation(s)
- D O Viel
- Laboratório de Imunogenética, Departamento de Análises Clínicas, Universidade Estadual de Maringá, Maringá, PR, Brazil
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Abstract
Despite advances in the procedure and posttransplantation immunosuppressive therapy, more than half of allogeneic hematopoietic stem cell transplant (HSCT) recipients develop graft-versus-host disease (GVHD), which remains a major cause of morbidity and mortality. Modern HSCT protocols have resulted in substantial alterations in the timing and relative incidences of acute and chronic GVHD, making traditional classification schemes obsolete. This article reviews major changes in HSCT during the past decade, evolving concepts of acute and chronic GVHD (including new diagnostic criteria) and the expanding spectrum of cutaneous GVHD. It focuses on observations that have led to a better delineation of the full constellation of skin findings in chronic cutaneous GVHD, including lichen sclerosus, morpheaform lesions, and eosinophilic fasciitis. Recent insights into pathogenesis of GVHD, lessons from GVHD arising in settings outside HSCT, and therapeutic advances also are highlighted.
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Affiliation(s)
- Julie V Schaffer
- Ronald O. Perelman Department of Dermatology, New York University School of Medicine, New York, NY 10016, USA.
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40
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Schultz KR, Miklos DB, Fowler D, Cooke K, Shizuru J, Zorn E, Holler E, Ferrara J, Shulman H, Lee SJ, Martin P, Filipovich AH, Flowers MED, Weisdorf D, Couriel D, Lachenbruch PA, Mittleman B, Vogelsang GB, Pavletic SZ. Toward biomarkers for chronic graft-versus-host disease: National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: III. Biomarker Working Group Report. Biol Blood Marrow Transplant 2006; 12:126-37. [PMID: 16443511 DOI: 10.1016/j.bbmt.2005.11.010] [Citation(s) in RCA: 121] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2005] [Accepted: 11/11/2005] [Indexed: 12/22/2022]
Abstract
Biology-based markers that can be used to confirm the diagnosis of chronic graft-versus-host disease (GVHD) or monitor progression of the disease could help in the evaluation of new therapies. Biomarkers have been defined as any characteristic that is objectively measured and evaluated as an indicator of a normal biologic or pathogenic process, a pharmacologic response to a therapeutic intervention, or a surrogate end point intended to substitute for a clinical end point. The following applications of biomarkers could be useful in chronic GVHD clinical trials or management: (1) predicting response to therapy; (2) measuring disease activity and distinguishing irreversible damage from continued disease activity; (3) predicting the risk of developing chronic GVHD; (4) diagnosing chronic GVHD: (5) predicting the prognosis of chronic GVHD; (6) evaluating the balance between GVHD and graft-versus-leukemia effects (graft-versus-leukemia or GVT); and (7) serving as a surrogate end point for therapeutic response. Such biomarkers can be identified by either hypothesis-driven testing or by high-throughput discovery-based methods. To date, no validated biomarkers have been established for chronic GVHD, although several candidate biomarkers have been identified from limited hypothesis-driven studies. Both approaches have merit and should be pursued. The consistent treatment and standardized documentation needed to support biomarker studies are most likely to be satisfied in prospective clinical trials.
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Affiliation(s)
- Kirk R Schultz
- British Columbia Children's Hospital, University of British Columbia, Vancouver, British Columbia, Canada.
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Sakoda Y, Hashimoto D, Asakura S, Takeuchi K, Harada M, Tanimoto M, Teshima T. Donor-derived thymic-dependent T cells cause chronic graft-versus-host disease. Blood 2006; 109:1756-64. [PMID: 17032915 DOI: 10.1182/blood-2006-08-042853] [Citation(s) in RCA: 118] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Abstract
Chronic graft-versus-host disease (GVHD) is the most common cause of poor long-term outcomes after allogeneic bone marrow transplantation (BMT), but the pathophysiology of chronic GVHD still remains poorly understood. We tested the hypothesis that the impaired thymic negative selection of the recipients will permit the emergence of pathogenic T cells that cause chronic GVHD. Lethally irradiated C3H/HeN (H-2k) recipients were reconstituted with T-cell–depleted bone marrow cells from major histocompatibility complex [MHC] class II–deficient (H2-Ab1−/−) B6 (H-2b) mice. These mice developed diseases that showed all of the clinical and histopathological features of human chronic GVHD. Thymectomy prevented chronic GVHD, thus confirming the causal association of the thymus. CD4+ T cells isolated from chronic GVHD mice were primarily donor reactive, and adoptive transfer of CD4+ T cells generated in these mice caused chronic GVHD in C3H/HeN mice in the presence of B6-derived antigen-presenting cells. Our results demonstrate for the first time that T cells that escape from negative thymic selection could cause chronic GVHD after allogeneic BMT. These results also suggest that self-reactivity of donor T cells plays a role in this chronic GVHD, and improvement in the thymic function may have a potential to decrease chronic GVHD.
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Affiliation(s)
- Yukimi Sakoda
- Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Science, and Center for Cellular and Molecular Medicine, Kyushu University Hospital, Fukuoka, Japan
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Schaffer JV, McNiff JM, Seropian S, Cooper DL, Bolognia JL. Lichen sclerosus and eosinophilic fasciitis as manifestations of chronic graft-versus-host disease: expanding the sclerodermoid spectrum. J Am Acad Dermatol 2006; 53:591-601. [PMID: 16198778 DOI: 10.1016/j.jaad.2005.06.015] [Citation(s) in RCA: 48] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2005] [Revised: 05/16/2005] [Accepted: 06/15/2005] [Indexed: 11/21/2022]
Abstract
Chronic cutaneous graft-versus-host disease (GVHD) is classically divided into two major clinical categories--lichenoid and sclerodermoid. Although diffuse areas of sclerosis as in scleroderma characterize the more advanced stages of the sclerodermoid form, the initial circumscribed plaques would be more correctly described as morpheaform. Eosinophilic fasciitis (EF) (a fibrosing disorder related to deep morphea) and lichen sclerosus (LS) have also been reported as manifestations of sclerodermoid GVHD. However, these two presentations of GVHD have not been emphasized in the dermatologic literature. We describe 6 patients, all of whom developed LS and two of whom also developed EF in the context of chronic GVHD. Each patient presented clinically with hypopigmented plaques that exhibited wrinkling, scaling, and follicular plugging. These lesions demonstrated the classic histologic features of LS including epidermal atrophy; a subepidermal zone of pale-staining, homogenized collagen; and a bandlike lymphocytic infiltrate. Although all patients eventually developed morpheaform and/or sclerodermoid GVHD, LS was a prominent part of the initial presentation of chronic cutaneous GVHD in every case. The LS lesions tended to occur on the neck and upper to mid aspect of the trunk, whereas morpheaform lesions favored the lower aspect of the trunk. EF involved the extremities (sparing the hands and feet), and was characterized clinically by an acute onset of pain and edema followed by induration with a rippled appearance. This case series serves to expand the spectrum of sclerodermoid GVHD, with LS as the most superficial and EF as its deepest manifestation.
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Affiliation(s)
- Julie V Schaffer
- Department of Dermatology, Yale University School of Medicine, New Haven, Connecticut, USA.
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Zanninelli G, Vetuschi A, Sferra R, D'Angelo A, Fratticci A, Continenza MA, Chiaramonte M, Gaudio E, Caprilli R, Latella G. Smad3 knock-out mice as a useful model to study intestinal fibrogenesis. World J Gastroenterol 2006; 12:1211-8. [PMID: 16534873 PMCID: PMC4124431 DOI: 10.3748/wjg.v12.i8.1211] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To evaluate the possible differences in morphology and immunohistochemical expression of CD3, transforming growth factor β1(TGF-β1), Smad7, α-smooth muscle actin (α-Sma), and collagen types I-VII of small and large intestine in Smad3 null and wild-type mice.
METHODS: Ten null and ten wild-type adult mice were sacrificed at 4 mo of age and the organs (esophagus, small and large bowel, ureters) were collected for histology(hematoxylin and eosin, Masson thrichrome, silver staining), morphometry and immunohistochemistry analysis. TGF-β1 levels of intestinal tissue homogenates were assessed by ELISA.
RESULTS: No macroscopic intestinal lesions were detected both in null and wild-type mice. Histological and morphometric evaluation revealed a significant reduction in muscle layer thickness of small and large intestine in null mice as compared to wild-type mice. Immunohistochemistry evaluation showed a significant increase of CD3+T cell, TGF-β1 and Smad7 staining in the small and large intestine mucosa of Smad3 null mice as compared to wild-type mice. α-Sma and collagen I-VII staining of small and large intestine did not differ between the two groups of mice. TGF-β1 levels of colonic tissue homogenates were significantly higher in null mice than in wild-type mice. In preliminary experiments a significant reduction of TNBS-induced intestinal fibrosis was observed in null mice as compared to wild-type mice.
CONCLUSION: Smad3 null mice are a useful model to investigate the in vivo role of the TGF-β/Smad signalling pathway in intestinal inflammation and fibrosis.
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MESH Headings
- Actins/analysis
- Animals
- CD3 Complex/analysis
- Collagen/analysis
- DNA/analysis
- Disease Models, Animal
- Enzyme-Linked Immunosorbent Assay
- Female
- Fibrosis/pathology
- Fibrosis/physiopathology
- Immunity, Innate/genetics
- Immunity, Innate/physiology
- Immunohistochemistry
- Intestinal Mucosa/chemistry
- Intestinal Mucosa/pathology
- Intestinal Mucosa/physiology
- Intestine, Large/chemistry
- Intestine, Large/pathology
- Intestine, Large/physiology
- Intestine, Small/chemistry
- Intestine, Small/pathology
- Intestine, Small/physiology
- Male
- Mice
- Mice, Knockout
- Muscle, Smooth/chemistry
- Phenotype
- Polymerase Chain Reaction
- Signal Transduction/physiology
- Smad3 Protein/genetics
- Smad3 Protein/physiology
- Smad7 Protein/analysis
- Transforming Growth Factor beta/analysis
- Transforming Growth Factor beta/physiology
- Transforming Growth Factor beta1
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Laguila Visentainer JE, Lieber SR, Lopes Persoli LB, Dutra Marques SB, Vigorito AC, Penteado Aranha FJ, de Brito Eid KA, Oliveira GB, Martins Miranda EC, Bragotto L, de Souza CA. Relationship between cytokine gene polymorphisms and graft-versus-host disease after allogeneic stem cell transplantation in a Brazilian population. Cytokine 2005; 32:171-7. [PMID: 16243534 DOI: 10.1016/j.cyto.2005.09.002] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2005] [Revised: 07/28/2005] [Accepted: 09/09/2005] [Indexed: 10/25/2022]
Abstract
Graft-versus-host disease (GVHD) is the major complication of allogeneic hematopoietic stem cell transplantation (HSCT), and cytokines are recognized as important mediators of GVHD. Polymorphisms in the regulatory regions of several cytokine genes have been associated with a number of immune diseases as well as organ transplant complications. In this study we have investigated the role of tumor necrosis factor-alpha(-308), interleukin (IL)-6(-174), IL-10(-1082, -819, -592), Interferon-gamma(-874), and transforming growth factor-beta1(+869, +915) polymorphisms on HSCT outcome. Donor/recipient genotypes were analyzed by polymerase chain reaction with sequence specific primers (PCR-SSP). Although we have found a small number of low IL-6, a polymorphism at position -174 of the recipient and donor IL-6 gene was associated with the increased incidence of chronic GVHD. Therefore, this study emphasizes the probable potential role of genetic variability of donor and recipient in determining outcome after transplantation.
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45
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Okamoto M, Okano A, Akamatsu S, Ashihara E, Inaba T, Takenaka H, Katoh N, Kishimoto S, Shimazaki C. Rituximab is effective for steroid-refractory sclerodermatous chronic graft-versus-host disease. Leukemia 2005; 20:172-3. [PMID: 16239908 DOI: 10.1038/sj.leu.2403996] [Citation(s) in RCA: 76] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
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Abstract
Transforming growth factor beta (TGF-beta) is a ubiquitous and essential regulator of cellular and physiologic processes including proliferation, differentiation, migration, cell survival, angiogenesis, and immunosurveillance. Alterations in the TGF-beta signaling pathway, including mutation or deletion of members of the signaling pathway and resistance to TGF-beta-mediated inhibition of proliferation are frequently observed in human cancers. Although these alterations define a tumor suppressor role for the TGF-beta pathway in human cancer, TGF-beta also mediates tumor-promoting effects, either through differential effects on tumor and stromal cells or through a fundamental alteration in the TGF-beta responsiveness of the tumor cells themselves. TGF-beta and members of the TGF-beta signaling pathway are being evaluated as prognostic or predictive markers for cancer patients. Ongoing advances in understanding the TGF-beta signaling pathway will enable targeting of this pathway for the chemoprevention and treatment of human cancers.
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Affiliation(s)
- Rebecca L Elliott
- Department of Medicine and Pharmacology and Cancer Biology, Duke University Medical Center, 221 BMSRB Research Drive, Box 2631 DUMC, Durham, NC 27710, USA
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47
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Abstract
Despite improvements in the practice of allogeneic hematopoietic stem cell transplantation (HCT) over the last 25 years, chronic graft-versus-host disease (GVHD) remains a substantial problem with little change in the incidence, morbidity, and mortality of this complication. In fact, with increased use of peripheral blood, transplantation of older patients, and less immediate transplantation-related mortality, the prevalence of chronic GVHD may increase. One of the difficulties in combating chronic GVHD is a lack of understanding about the pathophysiology of the syndrome. Inherent difficulties in conducting human clinical trials also contribute to the lack of meaningful progress. This review covers potential new approaches to the prevention and treatment of chronic GVHD.
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Affiliation(s)
- Stephanie J Lee
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
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48
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Clark FJ, Gregg R, Piper K, Dunnion D, Freeman L, Griffiths M, Begum G, Mahendra P, Craddock C, Moss P, Chakraverty R. Chronic graft-versus-host disease is associated with increased numbers of peripheral blood CD4+CD25high regulatory T cells. Blood 2004; 103:2410-6. [PMID: 14604970 DOI: 10.1182/blood-2003-06-2073] [Citation(s) in RCA: 163] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Abstract
Chronic graft-versus-host disease (cGVHD) is characterized by a state of profound immunodeficiency in association with alloreactive and autoimmune phenomena. These observations indicate an impairment of immunologic tolerance that could involve both central and peripheral mechanisms. Defective thymic function may contribute to dysregulation of central tolerance, but few studies have addressed peripheral tolerance. Recently a population of CD4+CD25+ T cells (Treg cells) has been characterized, which controls immunologic reactivity in vivo and which on transfer can prevent experimental acute GVHD. We investigated the number and function of peripheral blood CD4+CD25high T cells in patients more than 100 days after allogeneic hematopoietic stem cell transplantation. Patients with cGVHD had markedly elevated numbers of CD4+CD25high T cells as compared to patients without GVHD. CD4+CD25high T cells derived from patients in both groups were of donor origin, lacked markers of recent activation, and expressed intracellular CD152. In contrast to controls, CD4+CD25high T cells derived from patients with cGVHD were characterized by lower surface CD62L expression. In vitro, CD4+CD25high T cells were hyporesponsive to polyclonal stimulation and suppressed the proliferation and cytokine synthesis of CD4+CD25- cells, an effect that was independent of interleukin 10. These results indicate that chronic graft-versus-host injury does not occur as a result of Treg cell deficiency.
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Affiliation(s)
- Fiona J Clark
- Department of hematology, Institute of Cancer Studies, University of Birmingham, Edgbaston, United Kingdom
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49
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Remberger M, Jaksch M, Uzunel M, Mattsson J. Serum levels of cytokines correlate to donor chimerism and acute graft-vs.-host disease after haematopoietic stem cell transplantation. Eur J Haematol 2003; 70:384-91. [PMID: 12756021 DOI: 10.1034/j.1600-0609.2003.00078.x] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
BACKGROUND Some patients become full donor chimeras (DC) early after stem-cell transplantation (SCT), while others remain mixed chimeras for a longer time. Little is known about the mechanism behind these phenomena. METHODS Serum cytokine levels during conditioning and during the first month after SCT were analysed in 30 patients. Of the 21 patients who became full T-cell DC from the first analysed sample, 12 developed grade II-IV acute graft-vs.-host disease (GVHD) and the other nine, mild or no acute GVHD. Another nine patients were T-cell mixed chimeras (MC). All MC patients had no or mild acute GVHD. RESULTS During the pretransplant conditioning, DC patients had higher levels of tumour necrosis factor (TNF)-alpha and lower levels of transforming growth factor (TGF)-beta and interleukin (IL)-10, compared with MC patients. During the first week after SCT, lower levels of TGF-beta and IL-10 and higher levels of soluble Fas (sFas) were found in DC patients compared with MC patients. During the second and third weeks after SCT, increased levels of TNF-alpha, interferon (IFN)-gamma and sFas were found among DC patients compared with MC patients. Patients who developed moderate-to-severe acute GVHD had higher levels of TNF-alpha, IFN-gamma, IL-10 and sFas at 2 weeks post-SCT than in those with less GVHD. Patients homozygous for the TNFd microsatellite alleles 3 or 4 had significantly higher TNF-alpha levels during conditioning and more often developed acute GVHD grades II-IV. CONCLUSION These results indicate that an imbalance between pro-inflammatory and immune- modulating cytokines are involved in the development of chimerism and acute GVHD after allo-SCT. The Fas/FasL pathway is probably involved in the elimination of recipient cells leading to full donor chimerism.
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Affiliation(s)
- Mats Remberger
- Department of Clinical Immunology and Centre for Allogeneic Stem Cell Transplantation, Huddinge University Hospital, Stockholm, Sweden.
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Abstract
Chronic graft-versus-host disease (GVHD) remains a vexing and dangerous complication of allogeneic stem cell transplantation. Mild forms of chronic GVHD are often manageable with local or low-dose systemic immunosuppression and do not affect long-term survival. In contrast, more severe forms of chronic GVHD require intensive medical management and adversely affect survival. This report reviews current concepts of the pathogenesis, clinical risk factors, classification systems, organ manifestations, and available treatments for chronic GVHD. It also provides a comprehensive listing of the published clinical trials aimed at prevention and primary treatment of chronic GVHD.
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Affiliation(s)
- Stephanie J Lee
- Department of Adult Oncology, Dana-Farber Cancer Institute, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
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