Role of Cytokines in the Pathophysiology of Acute Graft-Versus-Host Disease (GVHD)– Are Serum/Plasma Cytokines Potential Biomarkers for Diagnosis of Acute GVHD Following Allogeneic Hematopoietic Cell Transplantation (Allo-HCT)?

2012 ◽  
Vol 7 (3) ◽  
pp. 229-239 ◽  
Author(s):  
Tomomi Toubai ◽  
Junji Tanaka ◽  
Sophie Paczesny ◽  
Yusuke Shono ◽  
Pavan Reddy ◽  
...  
Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2227-2227
Author(s):  
Marcello Rotta ◽  
Barry E Storer ◽  
Rainer F Storb ◽  
Paul J Martin ◽  
Shelly Heimfeld ◽  
...  

Abstract Abstract 2227 Poster Board II-204 Acute graft-versus-host disease (GVHD) contributes to morbidity and mortality after allogeneic hematopoietic cell transplantation (HCT) and more effective prevention and treatment strategies are needed. The 3-hydroxy-3-methylglutaryl coenzyme A-reductase inhibitors (statins) have been shown to possess immunomodulatory properties in vitro and in vivo. To determine whether donor or recipient statin use may affect the risk of GVHD, we retrospectively analyzed outcomes among 567 patients with hematologic malignancies who had hematopoietic cell transplantation from HLA-matched related donors at a single institution between 2001 and 2007. Compared to allografts where neither the donor nor recipient was treated with a statin at the time of transplant (n=464), statin use by the donor and not the recipient (n=75) was associated with a profoundly decreased risk of grade 3-4 acute GVHD (multivariate hazard ratio [HR], 0.28; 95= confidence interval [CI], 0.1-0.9; p=0.03) (Table). Statin use by both donor and recipient (n=12) was suggestively associated with a decreased risk of grade 3-4 acute GVHD (HR, 0.00; 95= CI, undefined; p=0.06), while statin use by the recipient and not the donor (n=16) did not confer GVHD-protection. Risks of chronic GVHD, recurrent malignancy, non-relapse mortality and overall mortality were not significantly affected by donor or recipient statin exposure. Statin-associated GVHD-protection was restricted to recipients with cyclosporine-based postgrafting immunosuppression (n=417; 74=) and was not observed among those given tacrolimus (significance of effect modification: cyclosporine vs. tacrolimus, p=0.009). These results suggest that donor statin treatment may be a promising strategy for preventing severe acute GVHD without compromising immunologic control of the underlying malignancy. Disclosures: No relevant conflicts of interest to declare.


Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2553-2553
Author(s):  
Rebecca Nelson ◽  
Janelle Perkins ◽  
Jamie Shapiro ◽  
Jongphil Kim ◽  
Binglin Yue ◽  
...  

Abstract Background: Sirolimus, an inhibitor of the mammalian target of rapamycin (mTOR), is used in combination with tacrolimus as prophylaxis for acute graft-versus-host-disease (GVHD). Two published randomized trials (one single institution and a multicenter one) failed to demonstrate a survival advantage of sirolimus plus tacrolimus (SIR-TAC) vis-à-vis methotrexate plus tacrolimus (MTX-TAC) when used for acute GVHD prophylaxis in HLA-matched related or unrelated allogeneic hematopoietic cell transplantation. No data exists comparing these two regimens when combined with antithymocyte globulin (ATG) in mismatched unrelated donor (MMUD) allografting. This study aims at comparing the efficacy of SIR-TAC-ATG vs. MTX-TAC-ATG in MMUD allografting. Patients and methods: We retrospectively analyzed 122 patients allografted between 01/2006 and 08/2013 after acute GVHD prophylaxis using SIR-TAC-ATG (n=28) or MTX-TAC-ATG (n=94). All patients received 7.5 mg/kg of rabbit ATG. Conditioning regimens were myeloablative (n=94) or reduced-intensity (n=28). Patient-, disease-, and treatment-related characteristics are summarized in Table 1. Results: Patients receiving SIR-TAC-ATG were older (54 vs. 47 years, p=0.015). The median follow-up from day of cell infusion for all patients was 11.2 (0.5-84.4) months; and for patients in the sirolimus-group or methotrexate-group were 11.5 (1.8-54.9) months and 10.4 (0.5-84.4) months, respectively. The 1-year survival was superior in patients who received SIR-TAC-ATG (83% vs. 57%, p=0.012). The 100-day cumulative incidences of grade 2-4 acute GVHD were 57% in the sirolimus- and 71% in the methotrexate-group, p=0.14. Patients who received methotrexate had over two-fold higher cumulative incidence of NRM (3-year), albeit not statistically significant (37% vs. 16%, p=0.1). There were no difference in median relapse-free survival (RFS) (MTX-TAC-ATG=17.8 months vs. SIR-TAC-ATG=not reached, p=0.21) or cumulative incidence of relapse at 1-year (MTX-TAC-ATG =19% vs. 19%, p= 0.94). Use of rituximab for preemptive treatment of EBV reactivation was higher in the group treated with sirolimus (79% vs. 51%, p= 0.01). Multivariate analyses using Cox proportional-hazard model identified use of sirolimus (HR=0.28 (95%CI=0.10, 0.78), p=0.015) and low CIBMTR disease risk (Hazard ratio (HR) =0.49 (95%CI=0.27, 0.88), p=0.018) as favorable predictors of overall survival (OS); but only low CIBMTR disease risk (HR=0.47 (95%CI=0.22, 0.98), p=0.045) as predictor for lower NRM. Conclusion: This study suggests that combining SIR-TAC-ATG results in improved OS in MMUD allogeneic hematopoietic cell transplantation when compared to MTX-TAC-ATG. These findings need to be confirmed in a prospective randomized controlled trial. Table 1. Variables Sirolimus-based Methotrexate-based p-value Recipient median (range) age (years) 54 (24-67) 47(20-69) 0.015 Recipient gender Male (M) Female (F) M=46% F=54% M=63% F=37% 0.13 Conditioning regimen MAC RIC MAC=75% RIC=25% MAC=78% RIC=22% 0.80 Recipient CMVserology seropositive 75% 70% 0.81 Primary disease Myeloid Lymphoid Others 68% 11% 21% 55% 17% 28% 0.55 CIBMTR disease risk High=18% Int=36% Low=47% High=23% Int=33% Low=44% 0.78 Median CD34 cell dose (x106/kg) 8.5 (3.2-23) 8.6 (1.8-25) 0.53 Rituximab Yes 79% 51% 0.01 MAC regimens: FLU-BU (AUC5300); RIC regimens: FLU-BU (AUC3500), FLU-CY, FLU-MEL, FLU-2GyTBI; Myeloid: AML, CML, MDS; Lymphoid: ALL, CLL Disclosures Off Label Use: sirolimus for prophylaxis for acute Graft-versus-host disease; Antithymocyte globulin for prophylaxis for acute Graft-versus-host disease.


Blood ◽  
2005 ◽  
Vol 106 (12) ◽  
pp. 3995-4001 ◽  
Author(s):  
Ming-Tseh Lin ◽  
Barry Storer ◽  
Paul J. Martin ◽  
Li-Hui Tseng ◽  
Bryan Grogan ◽  
...  

We have previously shown that the interleukin 10 (IL-10)/-592*A allele of the recipient is associated with less severe acute graft-versus-host disease (GVHD) and a lower risk of nonrelapse mortality after hematopoietic cell transplantation (HCT) from an HLA-identical sibling. In the present study, we examined variation in the IL-10 receptor β gene as a further test of the hypothesis that the IL-10 pathway regulates the risk of acute GVHD. A single nucleotide polymorphism (A/G) at cDNA position 238 of the IL-10 receptor β gene (IL10RB/c238) was genotyped in 953 HC transplant recipients and their HLA-identical sibling donors. IL-10/-592 and IL10RB/c238 genotypes were tested for association with GVHD by multivariable analysis. The IL-10/-592*A allele of the recipient and IL10RB/c238*G allele of the donor were significantly associated with a lower risk of grades III-IV acute GVHD (trend P < .001 and P = .02, respectively). The donor IL10RB/c238*G allele provided protection among patients with the IL-10/-592 A/C or A/A genotypes but not among patients with the high-risk IL-10/-592 C/C genotype. These data suggest an interaction of the patient IL-10/-592 and donor IL10RB/c238 genotypes on risk of GVHD, further supporting the hypothesis that the IL-10 pathway plays an important role in controlling the severity of acute GVHD.


2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Enrique Mir ◽  
Marta Palomo ◽  
Enric Carreras ◽  
Maribel Diaz-Ricart ◽  
Montse Rovira ◽  
...  

Acute Graft-Versus-Host Disease (aGVHD) is the most common early complication after allogeneic Hematopoietic Cell Transplantation (allo-HCT). We demonstrated endothelial dysfunction (ED) in association with allo-HCT. According to this data, aGVHD has been linked to an inflammatory process that may affect the endothelium. To investigate the differential degree of endothelial damage in patients developing or not aGVHD, to identify potential biomarkers, and to explore the protective effect of defibrotide (DF) in this scenario. DF has orphan designation for GVHD prevention. Patients blood samples were collected before allo-HCT, at day 0, and every week till day 28 after HCT. Plasma proteins (sTNFR1, sVCAM-1, VWF and ADAMTS-13) were measured as biomarkers of ED in individual samples from patients developing (GVHD, n=24), or not (NoGVHD, n=13), aGVHD. In in vitro assays, endothelial cells (EC) in culture were exposed to media containing pooled sera from patients to evaluate changes in the: a) expression of VCAM-1 and ICAM-1 on cell surfaces; b) presence of VWF on the extracellular matrix (ECM) and c) reactivity of the ECM towards platelets, under flow. The effect of DF was explored in the in vitro experiments by previous exposure of the EC (for 24h) followed by continuous incubation (100 μg/ml, added every 24h). Levels of sTNFRI, sVCAM-1 and VWF in samples from group GVHD were significantly higher than in NoGVHD (increases of 100, 37 and 150% respectively, at diagnose, p<0.01). ADAMTS-13 activity and VWF levels were inversely related. In in vitro studies, cell surface expression of VCAM-1 and ICAM-1, presence of VWF and platelet adhesion on the ECM in response to GVHD samples were always superior (increases vs NoGVHD of 80, 40, 100 and 21%, respectively, at diagnose). In vitro exposure of EC to DF attenuated signs of endothelial injury reducing significantly (p<0.05) the expression of VCAM-1, ICAM-1 and VWF (reductions of 22, 30 and 30%, respectively) in the GVHD condition. Our results demonstrate endothelial damage in association with aGVHD, as evidenced by elevated plasma levels of several biomarkers. The in vitro approach showed a marked proinflammatory and prothrombotic phenotype in association with aGVHD, which could be significantly prevented by defibrotide.


2022 ◽  
pp. 106002802110681
Author(s):  
Rémi Tilmont ◽  
Ibrahim Yakoub-Agha ◽  
Nassima Ramdane ◽  
Micha Srour ◽  
Valérie Coiteux ◽  
...  

Background Defibrotide is indicated for patients who develop severe sinusoidal obstructive syndrome following allogeneic hematopoietic cell transplantation (allo-HCT). Preclinical data suggested that defibrotide carries a prophylactic effect against acute graft-versus-host disease (aGVHD). Objective The purpose of this study was to investigate the effect of defibrotide on the incidence and severity of aGVHD. Methods This single-center retrospective study included all consecutive transplanted patients between January 2014 and December 2018. A propensity score based on 10 predefined confounders was used to estimate the effect of defibrotide on aGVHD via inverse probability of treatment weighting (IPTW). Results Of the 482 included patients, 64 received defibrotide (defibrotide group) and 418 did not (control group). Regarding main patient characteristics and transplantation modalities, the two groups were comparable, except for a predominance of men in the defibrotide group. The median age was 55 years (interquartile range [IQR]: 40-62). Patients received allo-HCT from HLA-matched related donor (28.6%), HLA-matched unrelated donor (50.8%), haplo-identical donor (13.4%), or mismatched unrelated donor (7.0%). Stem cell source was either bone marrow (49.6%) or peripheral blood (50.4%). After using IPTW, exposure to defibrotide was not significantly associated with occurrence of aGVHD (HR = 0.97; 95% CI 0.62-1.52; P = .9) or occurrence of severe aGVHD (HR = 1.89, 95% CI: 0.98-3.66; P = .058). Conclusion and Relevance Defibrotide does not seem to have a protective effect on aGVHD in patients undergoing allo-HCT. Based on what has been reported to date and on these results, defibrotide should not be considered for the prevention of aGVHD outside clinical trials.


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