scholarly journals Glucagon-like peptide 2 for intestinal stem cell and Paneth cell repair during graft-versus-host disease in mice and humans

Blood ◽  
2020 ◽  
Vol 136 (12) ◽  
pp. 1442-1455 ◽  
Author(s):  
Johana Norona ◽  
Petya Apostolova ◽  
Dominik Schmidt ◽  
Rebekka Ihlemann ◽  
Nadine Reischmann ◽  
...  
Keyword(s):  
Graft Versus Host Disease ◽  
Acute Gvhd ◽  
Hematopoietic Cell Transplantation ◽  
De Novo ◽  
Paneth Cell ◽  
Host Disease ◽  
Graft Versus Host ◽  
L Cells ◽  
Enhanced Production ◽  
Glucagon Like Peptide

Abstract Acute graft-versus-host disease (GVHD) is a life-threatening complication after allogeneic hematopoietic cell transplantation (allo-HCT). Although currently used GVHD treatment regimens target the donor immune system, we explored here an approach that aims at protecting and regenerating Paneth cells (PCs) and intestinal stem cells (ISCs). Glucagon-like-peptide-2 (GLP-2) is an enteroendocrine tissue hormone produced by intestinal L cells. We observed that acute GVHD reduced intestinal GLP-2 levels in mice and patients developing GVHD. Treatment with the GLP-2 agonist, teduglutide, reduced de novo acute GVHD and steroid-refractory GVHD, without compromising graft-versus-leukemia (GVL) effects in multiple mouse models. Mechanistically GLP-2 substitution promoted regeneration of PCs and ISCs, which enhanced production of antimicrobial peptides and caused microbiome changes. GLP-2 expanded intestinal organoids and reduced expression of apoptosis-related genes. Low numbers of L cells in intestinal biopsies and high serum levels of GLP-2 were associated with a higher incidence of nonrelapse mortality in patients undergoing allo-HCT. Our findings indicate that L cells are a target of GVHD and that GLP-2–based treatment of acute GVHD restores intestinal homeostasis via an increase of ISCs and PCs without impairing GVL effects. Teduglutide could become a novel combination partner for immunosuppressive GVHD therapy to be tested in clinical trials.

Graft Versus Host Disease Prophylaxis with Everolimus and Tacrolimus in Patients with Myelodysplastic Syndromes (MDS) and Acute Myeloid Leukaemia (AML) Receiving Allogeneic Peripheral Blood Stem Cell Transplantation (PBSCT).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2886-2886 ◽  
Author(s):  
Uwe Platzbecker ◽  
Caroline Pabst ◽  
Alexander Kiani ◽  
Johannes Schetelig ◽  
Martin Wermke ◽  
...  
Keyword(s):  
Graft Versus Host Disease ◽  
Peripheral Blood ◽  
Acute Gvhd ◽  
De Novo ◽  
Chronic Gvhd ◽  
Clinical Signs ◽  
Unrelated Donor ◽  
Peripheral Blood Stem Cells ◽  
Host Disease ◽  
Graft Versus Host

Abstract Introduction: The use of a calcineurin-inhibitor in combination with methotrexate is the current standard in the prophylaxis of graft versus host disease (GVHD). Everolimus is a newly developed m-TOR inhibitor, which, besides a potent immunosuppressive action including the stimulation of regulatory CD4+foxp3+ T-cells (Tregs), seems to mediate anti-neoplastic effects in MDS and AML. Methods: We report results of a prospective study investigating for the first time a combination of everolimus (days 0–56) with tacrolimus (starting day 0) in 16 patients with MDS (RCMD n=3, RAEB-1 n=3, RAEB-2 n=3, CMMOL-1 n=1, CMMOL-2 n=1, MDS/AML n=1) or de novo AML (n=4) undergoing allogeneic myeloablative conditioning (busulfan 16 mg/kg over 4 days, fludarabine 120 mg/m² over 4 days) followed by a median of 7.0 x 106/kg CD34+ peripheral blood stem cells (PBSC) from related (n=2) or unrelated donors (n=14). It is of note that 5 unrelated donor/recipient pairs displayed one allel-mismatch whereas all others were matched in 10 out 10 HLA characters. The median age of the patients was 61 years (range 47–69) and the majority (n=7) of MDS patients were classified INT-2 or HIGH according to IPSS. Results: All patients engrafted a median of 14 days (platelets) and 17 days (neutrophils) after transplant. On day 21 and 56 after PBSCT the median number of CD4+foxp3+ cells in the blood was not significantly different from normal donors (patients, n=5: 3.2 and 2.3 x 104/ul, controls n=4: 3.7 x 104/ul) Nevertheless, the rate of acute GVHD was moderate with five patients (31 %) developing acute GVHD grade II and only one patient experiencing grade IV GVHD after cessation of immunosuppression due to thrombotic-thrombocytopenic purpura (TTP). Decrease of thrombocytes together clinical signs of TTP were seen in two additional patients while four patients developed VOD of the liver, which was fatal in one case. Extensive chronic GVHD was seen in 50 % of evaluable patients. Mucositis CTC grade III was observed in 5 patients only. The total day 100 mortality rate was 19 % and currently eleven out of sixteen patients (69%) are alive and in remission. Conclusion: Everolimus and tacrolimus are highly efficient in preventing GVHD after unrelated PBSCT in older patients with MDS and AML, which seems not to be mediated by an increase in Tregs. Nevertheless, side effects associated with thrombotic microangiopathy might be more prevalent compared to other regimens.

Serious Acute or Chronic Graft-Versus-Host Disease after Hematopoietic Cell Transplantation: A Comparison of Myeloablative and Non-Myeloablative Conditioning Regimens.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 755-755
Author(s):  
Olga Sala-Torra ◽  
Paul J. Martin ◽  
Barry Storer ◽  
Mohamed Sorror ◽  
Rainer F. Storb ◽  
...  
Keyword(s):  
Cell Transplantation ◽  
Graft Versus Host Disease ◽  
Acute Gvhd ◽  
Hematopoietic Cell Transplantation ◽  
Chronic Gvhd ◽  
Univariate Analysis ◽  
Hematopoietic Cell ◽  
Host Disease ◽  
Graft Versus Host ◽  
Co Morbidity

Abstract We have previously described serious graft-versus-host disease (GVHD) as a highly undesirable outcome after allogeneic hematopoietic cell transplantation (HCT). Serious GVHD encompasses death, lengthy hospitalization, major disability, or recurrent major infections related to either acute or chronic GVHD. In a previous study, we found a 25% incidence of serious GVHD among 171 consecutive patients who had HCT after non-myeloablative (NMA) conditioning between January 1998 and May 2002. To put this observation into perspective, we applied the same criteria for serious GVHD in a cohort of 264 consecutive patients who had HCT after myeloablative (MA) conditioning during the same period of time and compared results with those of the previous study. The overall incidence of serious GVHD was 17% (44/264) in the MA group, compared to 25% (43/171) in the NMA group. There were no statistically significant differences in the incidence of grades III–IV GVHD, extensive chronic GVHD or nonrelapse mortality between the two groups (Table). Patients in the NMA group were older and had higher comorbidity scores than those in the MA group. In the univariate analysis, the hazard ratio (HR) of serious GVHD for the NMA group compared to the MA group was 1.71 (95% C.I., 1.1–2.6) (p = 0.01). After adjusting for patient age, patient and donor gender, donor type, HLA-mismatch, aggressive versus indolent malignancy at HCT, remission versus relapse at HCT, myeloid versus non–myeloid malignancy, HCT co–morbidity index, and prior donor lymphocyte infusion, the HR of serious GVHD was 1.50 (95% C.I., 0.8–2.7) (p = 0.17). After censoring for recurrent or progressive malignancy after HCT, the cumulative incidence of serious GVHD at 3 years was 21% for the NMA group and 14% for the MA group, and the HR was 1.33 (95% C.I., 0.7–2.6) (p = 0.40). Reasons for categorization of GVHD as serious (i.e., death, lengthy hospitalization, major disability, or recurrent major infections) were similar between the MA and NMA cohorts. Among the 44 patients with serious GVHD in the MA group, 19 (43%) had serious acute GVHD, and 25 (57%) had serious chronic GVHD. Among the 43 patients with serious GVHD in the NMA group, 20 (46%) had serious acute GVHD, and 30 (70%) had serious chronic GVHD. Among the 264 MA patients, 28 (11%) had grade III–IV acute GVHD and 147 (56%) had extensive chronic GVHD that did not meet the criteria for serious GVHD, compared to 7 (4%) and 84 (49%) of the 171 NMA patients, respectively. We conclude that the type of pretransplant conditioning regimen does not have a large effect on the incidence of serious GVHD after HCT. Assessment of serious GVHD provides additional useful information to acute GVHD grades and the classification of limited and extensive chronic GVHD in describing overall GVHD-related outcomes after HCT. MA NMA Outcome, n (%) n = 264 n = 171 Serious GVHD 44 (17) 43 (25) Grades III–IV acute GVHD 54 (20) 27 (16) Extensive chronic GVHD 174 (66) 114 (68) 2-year nonrelapse mortality 66 (25) 43 (25)

scholarly journals Comparative analysis of risk factors for acute graft-versus-host disease and for chronic graft-versus-host disease according to National Institutes of Health consensus criteria

Blood ◽  
2011 ◽  
Vol 117 (11) ◽  
pp. 3214-3219 ◽  
Author(s):  
Mary E. D. Flowers ◽  
Yoshihiro Inamoto ◽  
Paul A. Carpenter ◽  
Stephanie J. Lee ◽  
Hans-Peter Kiem ◽  
...  
Keyword(s):  
Risk Factors ◽  
Graft Versus Host Disease ◽  
Acute Gvhd ◽  
Hematopoietic Cell Transplantation ◽  
Chronic Gvhd ◽  
Human Leukocyte ◽  
National Institutes Of Health ◽  
Host Disease ◽  
Graft Versus Host ◽  
Acute Graft

Abstract Risk factors for grades 2-4 acute graft-versus-host disease (GVHD) and for chronic GVHD as defined by National Institutes of Health consensus criteria were evaluated and compared in 2941 recipients of first allogeneic hematopoietic cell transplantation at our center. In multivariate analyses, the profiles of risk factors for acute and chronic GVHD were similar, with some notable differences. Recipient human leukocyte antigen (HLA) mismatching and the use of unrelated donors had a greater effect on the risk of acute GVHD than on chronic GVHD, whereas the use of female donors for male recipients had a greater effect on the risk of chronic GVHD than on acute GVHD. Total body irradiation was strongly associated with acute GVHD, but had no statistically significant association with chronic GVHD, whereas grafting with mobilized blood cells was strongly associated with chronic GVHD but not with acute GVHD. Older patient age was associated with chronic GVHD, but had no effect on acute GVHD. For all risk factors associated with chronic GVHD, point estimates and confidence intervals were not significantly changed after adjustment for prior acute GVHD. These results suggest that the mechanisms involved in acute and chronic GVHD are not entirely congruent and that chronic GVHD is not simply the end stage of acute GVHD.

Association of IL-10 and IL-10 Receptor Gene Polymorphisms and Graft-Versus-Host Disease Following Hematopoietic Cell Transplantation.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 421-421 ◽  
Author(s):  
Li-Hui Tseng ◽  
Ming-Tseh Lin ◽  
Barry Storer ◽  
Paul J. Martin ◽  
Bryan Grogan ◽  
...  
Keyword(s):  
Cell Transplantation ◽  
Graft Versus Host Disease ◽  
Lower Risk ◽  
Acute Gvhd ◽  
Hematopoietic Cell Transplantation ◽  
Multivariable Analysis ◽  
Hematopoietic Cell ◽  
P Value ◽  
Host Disease ◽  
Graft Versus Host

Abstract Polymorphisms in cytokine genes can influence immune responses and may affect the outcome of hematopoietic cell transplantation (HCT). We have shown that the IL-10/-592*A allele of the recipient is a marker for less severe acute graft-versus-host disease (GVHD) and a lower risk of non-relapse mortality (NRM) after HCT from an HLA-identical sibling (N Engl J Med, 2003). To further test the hypothesis that IL-10 pathway is important in the intensity of acute GVHD, we undertook a study of variation in the IL-10 receptor β gene. A single nucleotide polymorphism (A/G) at cDNA position 238 of the IL-10 receptor β gene (IL-10RB/1304) was genotyped in 953 HCT recipients and their HLA-identical sibling donors. IL-10/-592 and IL-10RB alleles and genotypes were tested for association with GVHD by multivariable analysis. The IL-10/-592*A allele of the recipient and IL-10RB/238*G allele of the donor were significantly associated with a lower risk of acute grades III-IV GVHD (trend p value 0.0008 and 0.02, respectively). None of the 16 cases with a patient IL-10 A/A genotype and donor IL-10RB G/G genotype developed grades III-IV acute GVHD (HR = 0.0 and p value = 0.007), compared to pairs with a patient IL-10 C/C genotype and donor IL-10RB A/A genotype. The hazard ratios were 0.4–0.6 among pairs with a patient IL-10 A/A genotype and donor IL-10RB A/G or A/A genotype and among pairs with a patient IL-10 A/C genotype and donor IL-10RB G/G or A/G genotype. The effect of donor IL-10RB genotype on GVHD was observed only among pairs with a patient IL-10 A/C or A/A genotype (trend p value = 0.005 and 0.06 respectively), but not among pairs with a patient IL-10 C/C genotype (trend p value = 0.82). These data suggest an interaction in the effect of the patient IL-10/-592 and donor IL-10RB/1304 genotypes on GVHD, further supporting the hypothesis that the IL-10 pathway plays an important role in controlling the severity of acute GVHD.

scholarly journals Cyclosporine or Cyclosporine Plus Methylprednisolone for Prophylaxis of Graft-Versus-Host Disease: A Prospective, Randomized Trial

Blood ◽  
1997 ◽  
Vol 89 (10) ◽  
pp. 3880-3887 ◽  
Author(s):  
H. Joachim Deeg ◽  
Danyu Lin ◽  
Wendy Leisenring ◽  
Michael Boeckh ◽  
Claudio Anasetti ◽  
...  
Keyword(s):  
Graft Versus Host Disease ◽  
Acute Gvhd ◽  
De Novo ◽  
Chronic Gvhd ◽  
Single Agent ◽  
Incidence Rates ◽  
Host Disease ◽  
Graft Versus Host ◽  
Gvhd Prophylaxis ◽  
To Receive

Patients with a lymphohematopoietic malignancy considered to be at high risk for posttransplant relapse were enrolled in a study to compare the use of cyclosporine (CSP) as a single agent with a combination of methylprednisolone (MP) and CSP for graft-versus-host disease (GVHD) prophylaxis after marrow transplantation from an HLA-identical sibling donor. Sixty patients were randomized to receive CSP only and 62 were randomized to receive CSP plus MP. Daily CSP was started on day −1 (5 mg/kg/d intravenously) and administered at gradually reduced doses until day 180. MP was started on day 7 at 0.5 mg/kg/d, increased to 1.0 mg/kg/d on day 15, started on a taper schedule on day 29, and discontinued on day 72. All 104 evaluable patients (surviving ≥28 days) had sustained engraftment. The incidence rates of grades II-IV acute GVHD were 73% and 60% for patients receiving CSP and CSP plus MP, respectively (P = .01). No difference was seen for grades III-IV GVHD. However, chronic GVHD occurred somewhat more frequently in patients receiving CSP plus MP (44%) than in patients receiving only CSP (21%; P = .02). The incidence of de novo chronic GVHD was marginally higher in patients receiving CSP plus MP (P = .08). No significant differences in the risk of infections were observed. There was a suggestion that the risk of relapse was lower in patients receiving CSP plus MP (P = .10) and, although the overall survival in the two groups was not different (P = .44), there was a slight advantage in favor of CSP plus MP-treated patients for relapse-free survival (P = .07). These results suggest that prophylactic MP, when combined with CSP, has only limited efficacy in acute GVHD prevention and may increase the probability of chronic GVHD.

scholarly journals Regenerating Islet-Derived 3-alpha is a Prognostic Biomarker for Gastrointestinal Chronic Graft-Versus-Host Disease

2022 ◽  
Author(s):  
Brittany Paige DePriest ◽  
Hong Li ◽  
Alan Bidgoli ◽  
Lynn Onstad ◽  
Daniel R. Couriel ◽  
...  
Keyword(s):  
Graft Versus Host Disease ◽  
Acute Gvhd ◽  
Hematopoietic Cell Transplantation ◽  
Cox Regression ◽  
Prognostic Biomarker ◽  
Plasma Concentrations ◽  
Gi Tract ◽  
Host Disease ◽  
Graft Versus Host ◽  
Biomarker Validation

Prognostic biomarkers used to identify likelihood of disease progression have not been identified for chronic graft-versus-host disease (cGVHD), the leading cause of late non-relapse mortality (NRM) in survivors of allogenic hematopoietic cell transplantation. Gastrointestinal cGVHD (GI-cGVHD) has been particularly challenging to classify. Here, we analyzed three proteomics markers [Regenerating-islet-derived-3-alpha (Reg3α), C-X-C-motif-ligand (CXCL9) and Stimulation-2 (ST2)] in two independent cohorts of patients with cGVHD totaling 289 patients. Plasma concentrations of Reg3α were significantly increased in patients with GI-cGVHD compared to those without (p=0.0012, p=0.01 respectively), CXCL9 and ST2 were not. Patients with high Reg3α (≥72ng/mL) vs. low Reg3α had higher NRM (23% vs. 11%, p=0.015). Since Reg3α has been identified as a lower GI-tract marker in acute GVHD, we correlated Reg3α with lower acute-like GI-cGVHD vs. classical fibrotic-like esophageal manifestations and found Reg3a did not differ between the subtypes. No difference was observed between upper and lower subtypes. Patients with extremely high Reg3α (≥180 ng/mL) had higher GI-scores but not higher lower-GI-scores. In multivariate Cox regression model, patients with high Reg3α were 1.9 times more likely to die without relapse. Our findings demonstrate the utility of Reg3α as a prognostic marker for GI-cGVHD. These data warrant prospective biomarker validation studies.

scholarly journals Cyclosporine or Cyclosporine Plus Methylprednisolone for Prophylaxis of Graft-Versus-Host Disease: A Prospective, Randomized Trial

Blood ◽  
1997 ◽  
Vol 89 (10) ◽  
pp. 3880-3887 ◽  
Author(s):  
H. Joachim Deeg ◽  
Danyu Lin ◽  
Wendy Leisenring ◽  
Michael Boeckh ◽  
Claudio Anasetti ◽  
...  
Keyword(s):  
Graft Versus Host Disease ◽  
Acute Gvhd ◽  
De Novo ◽  
Chronic Gvhd ◽  
Single Agent ◽  
Incidence Rates ◽  
Host Disease ◽  
Graft Versus Host ◽  
Gvhd Prophylaxis ◽  
To Receive

Abstract Patients with a lymphohematopoietic malignancy considered to be at high risk for posttransplant relapse were enrolled in a study to compare the use of cyclosporine (CSP) as a single agent with a combination of methylprednisolone (MP) and CSP for graft-versus-host disease (GVHD) prophylaxis after marrow transplantation from an HLA-identical sibling donor. Sixty patients were randomized to receive CSP only and 62 were randomized to receive CSP plus MP. Daily CSP was started on day −1 (5 mg/kg/d intravenously) and administered at gradually reduced doses until day 180. MP was started on day 7 at 0.5 mg/kg/d, increased to 1.0 mg/kg/d on day 15, started on a taper schedule on day 29, and discontinued on day 72. All 104 evaluable patients (surviving ≥28 days) had sustained engraftment. The incidence rates of grades II-IV acute GVHD were 73% and 60% for patients receiving CSP and CSP plus MP, respectively (P = .01). No difference was seen for grades III-IV GVHD. However, chronic GVHD occurred somewhat more frequently in patients receiving CSP plus MP (44%) than in patients receiving only CSP (21%; P = .02). The incidence of de novo chronic GVHD was marginally higher in patients receiving CSP plus MP (P = .08). No significant differences in the risk of infections were observed. There was a suggestion that the risk of relapse was lower in patients receiving CSP plus MP (P = .10) and, although the overall survival in the two groups was not different (P = .44), there was a slight advantage in favor of CSP plus MP-treated patients for relapse-free survival (P = .07). These results suggest that prophylactic MP, when combined with CSP, has only limited efficacy in acute GVHD prevention and may increase the probability of chronic GVHD.

scholarly journals Biomarkers in acute graft-versus-host disease: new insights

2019 ◽  
Vol 10 ◽  
pp. 204062071989135 ◽  
Author(s):  
Hrishikesh K. Srinagesh ◽  
John E. Levine ◽  
James L.M. Ferrara
Keyword(s):  
Graft Versus Host Disease ◽  
Acute Gvhd ◽  
Hematopoietic Cell Transplantation ◽  
The United States ◽  
Response To Treatment ◽  
Gi Tract ◽  
Potential Measurement ◽  
Host Disease ◽  
Curative Therapy ◽  
Graft Versus Host

Hematopoietic cell transplantation (HCT) is a potentially curative therapy for hematologic malignancies that relies on the graft- versus-leukemia (GVL) effect to eradicate malignant cells. GVL is tightly linked to graft- versus-host disease (GVHD) however, in which donor T cells damage healthy host tissues. Acute GVHD occurs in nearly 50% of patients receiving HCT, and damages the skin, liver, and gastrointestinal (GI) tract. The organ stages are totaled in an overall grade (I–IV), and severe (grade III/IV) GVHD has a high mortality rate (50–70%). In the past decade, serum biomarkers have emerged as an additional potential measurement of acute GVHD severity. The discovery and validation of GVHD biomarkers is a principal objective of the Mount Sinai Acute GVHD International Consortium (MAGIC), a group of 25 HCT centers conducting GVHD research. MAGIC has validated an algorithm that combines two GI biomarkers (ST2 and REG3α) into a single value that estimates the probability of 6 month nonrelapse mortality (NRM) for individual patients, known as the MAGIC algorithm probability (MAP). The MAP reflects GI crypt damage and serves as a ‘liquid biopsy’ of the lower GI tract; it also predicts response to treatment and maximum GVHD severity and is now commercially available and widely used among scores of centers in clinical practice. The MAP is the focus of this review, with consideration of the categorization of types of biomarkers as defined by the United States National Institutes of Health (NIH) and Food and Drug Administration (FDA).

Re-Evaluation of Chronic Graft-Versus-Host Disease Using National Institute of Health Consensus Criteria.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2239-2239
Author(s):  
Dae-Young Kim ◽  
Je-Hwan Lee ◽  
Jung-Hee Lee ◽  
Se Hyung Kim ◽  
Sung-nam Lim ◽  
...  
Keyword(s):  
Graft Versus Host Disease ◽  
Scoring System ◽  
Acute Gvhd ◽  
Hematopoietic Cell Transplantation ◽  
Late Onset ◽  
Chronic Gvhd ◽  
Prognostic Significance ◽  
P Value ◽  
Host Disease ◽  
Graft Versus Host

Abstract Background: The National Institutes of Health (NIH) proposed new consensus criteria for the diagnosis and scoring of chronic graft-versus-host disease (cGVHD). Using the new system, we re-evaluated the patients with cGVHD that was diagnosed by classic criteria. Methods: Of 618 patients who underwent allogeneic hematopoietic cell transplantation (HCT) from December 1994 to April 2008 at the Asan Medical Center, Seoul, Korea, we retrieved 236 patients who had cGVHD by classic criteria from the AMC BMT Registry. Among 236 patients, 20 patients with liver-only involvement could not be diagnosed as cGVHD by the NIH criteria, thus we reclassified and graded 216 patients according to the NIH criteria. We also evaluated the ability of the NIH criteria to stratify and predict the risk of cGVHD patients, as assessed by GVHD-specific survival (GSS). Results: Twenty patients (9.3%) were reclassified as acute GVHD by NIH criteria (‘classic acute’ in 7 and ‘persistent, recurrent, or late-onset acute’ in 13) and 196 patients (90.7%) remained as chronic GVHD (‘classic chronic’ [Cl-Ch] in 170 and ‘overlap syndrome’ [Ov-Sy] in 26). Median age of 196 patients with cGVHD by NIH criteria, 119 males and 77 females, was 35.5 years (range, 15 to 57). Acute GVHD preceded cGVHD in 70 patients (35.7%). The probability of GSS at 5 years was 86.2% with 22 cGVHD-related deaths. The GSS was significantly different between two subtypes of cGVHD by NIH criteria: 88.6% for Cl-Ch vs 70.2% for Ov-Sy (p=0.002). NIH global scoring system stratified risk of cGVHD patients better than stage by classic criteria at both onset and peak of cGVHD (Table 1). We evaluated 12 variables at onset of cGVHD to determine their prognostic significance for GSS. Multivariate analysis demonstrated that NIH global score at onset (mild vs moderate, HR 6.1, p=0.027; mild vs. severe, HR 7.0, p=0.015), preceding aGVHD (no vs. yes, HR 6.2, p=0.001), and number of HLA ABDR mismatch (0 vs. 1, HR 2.0, p=0.555; 0 vs 2, HR 200.4, p=0.009) were independent predictors for GSS. Conclusion: Our results indicate that a new NIH system can provide a proper risk-stratification of patients with cGVHD and global scoring system at onset of cGVHD can predict the prognosis of patients. Table 1. GVHD-specific survival according to NIH global scoring system or stage by classic criteria Onset of cGVHD Peak of cGVHD Pt. No. GSS (5-y) P-value Pt. No. GSS (5-y) P-value NIH criteria mild 70 95.2% 0.022 36 100% 0.004 moderate 64 82.8% 42 92.2% severe 62 79.7% 118 79.6 Classic criteria limited 86 90.1% 0.305 45 97.8% 0.039 extensive 110 83.7% 151 83.0%

scholarly journals Genetic variation in the IL-10 pathway modulates severity of acute graft-versus-host disease following hematopoietic cell transplantation: synergism between IL-10 genotype of patient and IL-10 receptor β genotype of donor

Blood ◽  
2005 ◽  
Vol 106 (12) ◽  
pp. 3995-4001 ◽  
Author(s):  
Ming-Tseh Lin ◽  
Barry Storer ◽  
Paul J. Martin ◽  
Li-Hui Tseng ◽  
Bryan Grogan ◽  
...  
Keyword(s):  
Cell Transplantation ◽  
Graft Versus Host Disease ◽  
Lower Risk ◽  
Acute Gvhd ◽  
Hematopoietic Cell Transplantation ◽  
Multivariable Analysis ◽  
Hematopoietic Cell ◽  
Host Disease ◽  
Graft Versus Host ◽  
Acute Graft

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.

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