scholarly journals Transforming-Growth Factor Beta Pathway Components Is Down Regulated in Patients with Chronic Graft Versus Host Disease

2017 ◽  
Vol 23 (3) ◽  
pp. S362
Author(s):  
Marcos Paulo Colella ◽  
Beatriz Corey Morini ◽  
Matheus Rodrigues Lopes ◽  
Francisco J.P. Aranha ◽  
Afonso C. Vigorito ◽  
...  
Keyword(s):  
Growth Factor ◽  
Graft Versus Host Disease ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Host Disease ◽  
Graft Versus Host ◽  
Growth Factor Beta

Efficacy of Imatinib Mesylate in the Treatment of Refractory Sclerodermatous Chronic Graft-Versus-Host Disease.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2141-2141
Author(s):  
Ibrahim YakoubAgha ◽  
Leonardo Magro ◽  
Benoit Catteau ◽  
Christophe Willekens ◽  
Valerie Coiteux ◽  
...  
Keyword(s):  
Growth Factor ◽  
Imatinib Mesylate ◽  
Graft Versus Host Disease ◽  
Transforming Growth Factor ◽  
Dermal Fibroblasts ◽  
In Vivo Studies ◽  
Background Information ◽  
Skin Damage ◽  
Host Disease ◽  
Graft Versus Host

Abstract Outcomes in the treatment of sclerodermatous chronic graft-versus-host disease (cGVHD) are generally disappointing. Imatinib mesylate enables selective, dual inhibition of the transforming growth factor beta (TGFβ) and platelet-derived growth factor (PDGF) pathways. Recently, the drug’s effects on fibroblasts have been reported in both in vitro and in vivo studies. Inhibiting fibroblast growth (and thus decreasing collagen production in dermal fibroblasts) is thus a logical therapeutic approach. Here, we report on our experience with 12 patients who received imatinib mesylate for refractory sclerodermatous cGVHD following allogeneic stem cell transplantation (allo-SCT). The patients’ characteristics were as follows: median age, 35 years (range: 15–59); 7 male recipients, 6 female donors; 4 cases of CML, 4 MDS, 2 ALL and 2 Hodgkin’s lymphoma. The patients had received either myelo-ablative conditioning with standard GVHD prophylaxis based on cyclosporine and short-course MTX (n=9) or nonmyelo-ablative conditioning with cyclosporine and MMF. Seven patients received a marrow graft and 5 received a peripheral blood graft. All displayed refractory, chronic, sclerodermatous GHVD with at least 3 lines (range 3–6) of prior immunosuppressive therapy. The modified Rodnan skin score was used to assess the extent of skin damage. Glivec was initiated at a dose of 400 mg/day between 16 and 119 months post-transplantation (median: 44). Despite an imatinib dose reduction and the administration of various symptomatic treatments, 4 patients (33%) had to discontinue their treatment soon after its initiation (range: 16–64 days) because of intolerance (especially muscle cramps) and were not evaluable in terms of the efficacy criterion. Other side effects reported were parenthesis, diarrhea and edema. In the remaining patients, the scleroderma symptoms improved within three months of treatment initiation. At the time of this report, all patients were alive and those who tolerated imatinib mesylate have experienced a complete or near-complete response (n=4) or partial response (n=4). All responders (except for one who discontinued the drug 157 days after initiation, due to cramps) were still on the treatment, after a median time period of 216 days (range: 80–2053). This retrospective report shows that when imatinib mesylate is well tolerated, it is effective in patients with refractory sclerodermatous cGVHD and is thus a promising candidate for the treatment of this complication. This study should provide useful background information for building prospective, multicenter studies.

Single Nucleotide Polymorphism (SNP) Approach of Multiple Candidate Pathways Predicting the Risk of Acute / Chronic Graft-Versus-Host Disease or Transplant Outcomes Following Allogeneic Hematopoietic Stem Cell Transplantation: Potential Involvement of Nuclear Factor Kappa-B (NFKB), Platelet-Derived Growth Factor (PDGF) and Transforming Growth Factor-Beta (TGF-β) Pathway with Chronic Graft-Versus-Host Disease Graft-Versus-Host Disease.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2221-2221
Author(s):  
Dong Hwan (Dennis) Kim ◽  
Jina Yun ◽  
Jee Hyun Kong ◽  
Chul Won Jung ◽  
Ahmed Galal ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Growth Factor ◽  
Graft Versus Host Disease ◽  
Acute Gvhd ◽  
Transforming Growth Factor ◽  
Chronic Gvhd ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Graft Versus Host ◽  
Cytokine Activation

Abstract Abstract 2221 Poster Board II-198 Background: Acute graft-versus-host disease (GVHD) was known to be involved in the Th1 cytokine activation and alloreactive T-cell cytotoxicity, while the pathogenesis of chronic GVHD is yet revealed fully although in which Th2 cytokine activation or transforming growth factor (TGF) mediated pathway was suggested to be involved. The current study is a hypothesis generating study in order to identify potential predictive surrogate associated with the risk of acute or chronic GVHD in addition with transplant outcomes after allogeneic hematopoietic stem cell transplantation (HSCT). Methods: The current study was performed to identify genetic surrogates predicting the risk of acute / chronic GVHD, relapse free survival, non-relapse mortality and overall survival in 394 pairs transplanted at the Princess Margaret Hospital, Toronto, ON, Canada. In addition, the predictive markers for organ specific incidence of acute / chronic GVHD were also evaluated (i.e. for skin/liver/gut acute GVHD or skin, eye, oral, lung or liver chronic GVHD). Total of 261 single nucleotide polymorphisms (SNPs) in 56 genes were determined for donor/recipients' genotypes using MALDI-TOF based platform, involving in the pathways of 1) cytokines (i.e. IL1A, IL1B and its receptor, IL1R1, IL2 & IL2RA, IL4 & IL4R, IL6 & IL6R, IL8, IL10 & IL10RA, RB, IL12A/BandIL12RB1, IFNG & IFNGR1/2, TNFTI/II/II), 2) NFKB (NFKB1/2/A, NFKBIA/B, IKB, IKK1, IKBKB, RelB), 3) apoptosis (FAS, TRAIL & TRAILR1), 4) endothelium nitric oxide regulation (EDN1, NOS1/2A/3), 5) PDGF (PDGFB/C/D & PDGFRA/B), 6) TGF-β (TGFB1/2 & TGFBR1/2/3, TGFRB1), 7) Toll-like receptor (TLR4/5), 8) NOD2/CARD15 and 9) prostaglandin-endoperoxide synthase (PTGS1/2). The candidate genotypes have been selected by choosing the SNPs in non-synonymous SNPs in exon region with minor allele frequency of > 0.05 to 0.1. Results: Followings are the lists of recipients' and donors' genotypes with p-value<0.05 thus associating with clinical outcomes following allogeneic HSCT: In summary, the risk of chronic GVHD was significantly associated with SNP of the genes involved in the pathway of NFKB, PDGF, TGF-β, and some of cytokines (esp. type II, IL6 & IL4), while that of acute GVHD associates with the genotypes in the pathway of TNF and apoptosis. In addition, survival after allogeneic transplantation was associated with the genotypes in NOS (nitric oxide synthase, endothelial nitric oxide synthesis pathway), IL-2 and TGF pathway. Conclusion: Because of complex nature of GVHD pathogenesis, multiple candidate pathway SNPs has been explored targeting SNPs in the pathway of cytokines, NFKB, apoptosis, endothelium nitric oxide regulation, NOD2/CARD15, PDGF, PTGS1/2, TGF-β and TLR. Different involvements were noted of TGF-β, PDGF or NFKB with chronic GVHD versus TNF and apoptosis-associated SNPs with acute GVHD. Further study will help us to reach more clear conclusion which genotype is the predictor of the risk of GVHD. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Tirosin Kinase Inhibitors in Chronic Graft versus Host Disease: From Bench to Bedside

2011 ◽  
Vol 11 ◽  
pp. 1908-1931 ◽  
Author(s):  
Jacopo Olivieri ◽  
Sabrina Coluzzi ◽  
Imma Attolico ◽  
Attilio Olivieri
Keyword(s):  
Growth Factor ◽  
Graft Versus Host Disease ◽  
Kinase Inhibitors ◽  
Transforming Growth Factor ◽  
Toxicity Profile ◽  
Term Outcome ◽  
Long Term Outcome ◽  
Host Disease ◽  
Graft Versus Host

Chronic Graft Versus Host Disease (cGVHD) is a major complication of allogeneic stem-cell transplantation (SCT). In many inflammatory fibrotic diseases, such as Systemic Scleroderma (SSc) and cGVHD with fibrotic features, an abnormal activation of transforming growth factor (TGFβ) and platelet-derived growth factor receptor (PDGF-R) pathways have been observed. Tyrosin Kinase Inhibitors (TKIs), which are currently used for treatment of patients with Chronic Myeloid Leukemia (CML), share potent antifibrotic and antiinflammatory properties, being powerful dual inhibitors of both PDGF-R and TGFβpathways. Moreover accumulating in vitro data confirm that TKIs, interacting with the TCR and other signalling molecules, carry potent immunomodulatory effects, being involved in both T-cell and B-cell response. Translation to the clinical setting revealed that treatment with Imatinib can achieve encouraging responses in patients with autoimmune diseases and steroid-refractory cGVHD, showing a favourable toxicity profile. While the exact mechanisms leading to such efficacy are still under investigation, use of TKIs in the context of clinical trials should be promoted, aiming to evaluate the biological changes induced in vivo by TKIs and to assess the long term outcome of these patients. Second-generation TKIs, with more favourable toxicity profile are under evaluation in the same setting.

Transforming growth factor-beta gene polymorphisms and acute graft-versus-host disease.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e18013-e18013
Author(s):  
Sivadasan Kanangat ◽  
Sanjib Basu ◽  
Ina Kurbecovic ◽  
Michele Prod ◽  
John Joseph Maciejewski ◽  
...  
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor Beta ◽  
Gene Polymorphisms ◽  
Acute Gvhd ◽  
Transforming Growth Factor ◽  
Unrelated Donor ◽  
Cytokine Gene ◽  
Graft Versus Host ◽  
Cytokine Gene Polymorphisms ◽  
Growth Factor Beta

e18013 Background: Despite allele level HLA matching, graft-versus-host disease (GVHD) remains a major complication of allogeneic hematopoietic cell transplantation (HCT). Differences in minor histocompatibility antigens impact GVHD and HCT outcome via activation of donor T cells that also mediate a graft-versus-leukemia (GVL) effect. Non-HLA determinants, such as immunomodulatory cytokines can promote or protect against GVHD. Certain cytokine gene polymorphisms have been associated with acute GVHD in related and unrelated donor HCT. Methods: 17 patients (pts) who underwent related or unrelated donor HCT for hematologic malignancies and their donors were retrospectively analyzed for polymorphisms in gene sequences for interleukin (IL)-6, IL-10, tumor necrosis factor-alpha (TNF-α), transforming growth factor-beta (TGF-β) and interferon gamma (IFN-γ) using SSP-PCR reagents from One Lambda Inc. (Canaga Park, CA, USA). Pts and donors were categorized into low, intermediate or high producers of respective cytokines based on single nucleotide polymorphisms (SNPs) identified by sequence specific primers as per manufacturer’s instructions. Conditioning regimens included tacrolimus/sirolimus or alemtuzumab/cyclosporine. Results: A marginal association was found between development of acute GVHD and donor intermediate producers of TGF-β (p=0.056). None of the other cytokine gene polymorphisms tested showed significant relationships to either acute or chronic GVHD. Of seven pts tested who received alemtuzumab conditioning, only one pt developed GVHD; both pt and donor were high producers of all five cytokine genes tested. Conclusions: These results suggest that TGF-β gene polymorphisms may affect risk of developing acute GVHD following allogeneic HCT. Further study is warranted in larger cohorts with measurement of low, intermediate, and high cytokine producers, as well as evaluation of the interplay of cytokines and alemtuzumab in GVHD.

Sign in / Sign up

Export Citation Format

Share Document