Clinical significance of anti-endothelial cell antibody in allogeneic hematopoietic stem cell transplantation recipients with graft-versus-host disease

Anti-endothelial cell antibody (AECA) is well known to reflect endothelial injury. Graft-versus-host disease (GVHD), a major complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT), is also closely associated with endothelial injury. We hypothesized that AECA may be associated with GVHD. To investigate the clinical significance of AECA in allo-HSCT recipients with GVHD, we detected AECA by cyto-enzyme-linked immunosorbent assay (cyto-ELISA) in allo-HSCT recipients with acute and/or chronic GVHD (aGVHD and cGVHD). Incidences of anti-HMEC-1 AECA (anti-HMEC) and anti-EA.hy926 AECA (anti-EAHY) were significantly higher in patients with grade II–IV than grade 0–I aGVHD (P = 0.049, P = 0.011, respectively). There was no difference in the incidence of AECA between patients with and without cGVHD. Patients with anti-EAHY positive in the early stage post-transplant demonstrated a higher incidence of cGVHD (P = 0.044). In patients with grade 0–I aGVHD, AECA-positive patients had higher overall survival and disease-free survival (P < 0.05), and tended to have lower incidences of relapse and transplant-related mortality. Our data suggest that AECA plays an important role in the pathogenesis of GVHD.     

Risk factors for chronic graft-versus-host disease after allogeneic stem cell transplantation in children

We analyzed the incidence and risk factors for chronic graft-versus-host disease (GVHD) in 265 children undergoing allogeneic stem cell transplantation (SCT) who survived longer than 3 months post SCT. Patients transplanted from HLA-mismatched related donors and matched unrelated donors were included. Fifty-five patients developed chronic GVHD between 1 and 25 months after SCT, and the 5-year cumulative incidence of chronic GVHD was 22%. By multivariate analysis, acute GVHD (P = 0.004), malignant disease (P = 0.004), recipient age (> or =10 years) (P = 0.01) and a female donor to male recipient (P = 0.035) were significant risk factors for chronic GVHD. When acute GVHD was excluded from the multivariate analysis, malignant disease (P = 0.002) and older recipient age (P = 0.007) were identified. The incidence of chronic GVHD in this childhood study was lower than that observed in adults, and recipient age was an important factor in childhood SCT. The high incidence associated with malignant disease may be affected by changes in GVHD prophylaxis in order to ensure graft-versus-tumor effects.     

Chronic graft-versus-host disease after allogeneic blood stem cell transplantation

The incidence, characteristics, risk factors for, and impact of chronic graft-vs-host disease (GVHD) were evaluated in a consecutive series of 116 evaluable HLA-identical blood stem cell transplant recipients. Minimum follow-up was 18 months. Limited chronic GVHD occurred in 6% (95% confidence interval [CI], 0%-13%), and clinical extensive chronic GVHD in 71% (95% CI, 61%-80%). The cumulative incidence was 57% (95% CI, 48%-66%). In univariate analyses, GVHD prophylaxis other than tacrolimus and methotrexate, prior grades 2 to 4 acute GVHD, use of corticosteroids on day 100, and total nucleated cell dose were significant risk factors for clinical extensive chronic GVHD. On multivariate analysis, GVHD prophylaxis with tacrolimus and methotrexate was associated with a reduced risk of chronic GVHD (hazard ratio [HR], 0.35; P =.001), whereas the risk was increased with prior acute GVHD (HR, 1.67; P =.046). When adjusted for disease status at the time of transplantation, high-risk chronic GVHD had an adverse impact on overall mortality (HR, 6.6; P <.001) and treatment failure (HR, 5.2; P <.001) at 18 months. It was concluded that there is a substantial rate of chronic GVHD after HLA-identical allogeneic blood stem cell transplantation, that clinical factors may alter the risk of chronic GVHD, and that high-risk chronic GVHD adversely affects outcome.     

Nephrotic syndrome associated with chronic graft-versus-host disease after allogeneic hematopoietic stem cell transplantation

Chronic graft-versus-host disease (cGVHD) is the most common late complication of allogeneic hematopoietic cell transplantation (HCT) causing significant morbidity and mortality. The kidneys are not considered a target organ for cGVHD in humans, although animal models show renal damage. Renal involvement in patients with cGVHD, presenting as nephrotic syndrome (NS), has rarely been reported in patients who received allogeneic transplantation. Herein we describe, by far, the largest series of nine patients with NS associated with cGVHD, including two patients who received a reduced-intensity regimen. Pathological features of membranous nephropathy were the most common finding on renal biopsy. The clinical course of the NS was temporally associated with the classical features of cGVHD in all but one of the nine cases. The clinicopathologic features of NS in our series as well as reports in the literature demonstrate an immunopathologic process typical of antibody-mediated damage consistent with cGVHD. Treatment directed against antibody-mediated damage, such as anti-B-cell antibody may play an important role in ameliorating NS associated with cGVHD.     

Postmortem examination of the kidney in allogeneic hematopoietic stem cell transplantation recipients: possible involvement of graft-versus-host disease

To investigate the association between graft-versus-host disease (GVHD) and renal injury after allogeneic stem cell transplantation (allo-SCT), we compared autopsy findings of 26 consecutive allo-SCT recipients with two control groups: patients with hematologic malignancies who received cytotoxic chemotherapy alone (Control 1, n = 21) and those with non-hematologic diseases (Control 2, n = 12). We evaluated the following renal pathology; renal tubulitis, allograft glomerulitis, intimal arteritis, allograft nephropathy, and peritubular capillaritis. These changes were found in 11 allo-SCT recipients and 10 patients in Control 1, but none in Control 2. While overall frequency of renal impairments was similar between allo-SCT recipients and Control 1 (3/26 vs. 1/21), allo-SCT recipients were more likely to have renal tubulitis and peritubular capillaritis compared to Control 1 (5/26 vs. 1/21), but less likely to present with glomerulitis (1/26 vs. 6/21). Grade III–IV acute or extensive-type chronic GVHD were seen in all of the three patients with renal tubulitis and four of the five patients with peritubular capillaritis. Allo-SCT recipients with severe GVHD tended to have tubulitis and peritubular capillaritis. These findings have implications of some renal impairment attributable to GVHD.     

Association between acute and chronic graft-versus-host disease and bronchiolitis obliterans organizing pneumonia in recipients of hematopoietic stem cell transplants

Bronchiolitis obliterans organizing pneumonia (BOOP) has been reported following hematopoietic stem cell (HSC) transplantation, but the clinical features and risk factors for this disorder have not been well characterized. This case-control study of 49 patients with histologic BOOP and 161 control subjects matched by age and year of transplantation describes the clinical features and analyzes the risk factors for BOOP following HSC transplantation. Data on clinical features and outcome were collected by chart review. Odds ratios, estimating the relative risk of BOOP in allogeneic HSC recipients, were calculated by conditional logistic regression with adjustment for potential confounding factors. Clinical features of BOOP in this population were similar to idiopathic BOOP and BOOP occurring in other disease settings. There was an association between acute and chronic graft-versus-host disease (GVHD) and the subsequent development of BOOP (odds ratios, 3.8 [95% CI, 1.2 to 12.3] and 3.1 [95% CI, 1.1 to 9.2], respectively). Patients with BOOP were more likely to have acute GVHD involving the skin (odds ratio, 4.6; P =.005) and chronic GVHD involving the gut (odds ratio, 6.6; P =.018) and oral cavity (odds ratio, 5.9; P =.026). This study shows that histologic BOOP following HSC transplantation has clinical features that resemble idiopathic BOOP and is strongly associated with prior acute and chronic GVHD. These results have important implications for the care of patients who develop respiratory symptoms after HSC transplantation and may help elucidate the pathogenesis of idiopathic BOOP.     

An association between human leucocyte antigen alleles and acute and chronic graft-versus-host disease after allogeneic haematopoietic stem cell transplantation

The association between various human leucocyte antigen (HLA) alleles and the occurrence of acute and chronic graft-versus-host disease (GVHD) was evaluated in 493 haematopoietic stem-cell transplant (HSCT) patients with HLA identical sibling donors. There were 307 men and 186 women with a median age of 30 years (0.2-77). Most of the patients had a haematological malignancy and received total body irradiation or busulphan combined with cyclophosphamide as conditioning before transplantation. GVHD prophylaxis consisted of monotherapy with methotrexate (MTX) or cyclosporin (CsA) in 118 patients, MTX + CsA in 323, T-cell depletion in 28 and other combinations in 24. In total, 84 patients (17%) received a peripheral blood stem-cell graft, whereas the rest received bone marrow. The cumulative incidence of acute GVHD grades II-IV was 20%, and chronic GVHD 46%. In the multivariate analysis, HLA-A10 (OR 2.14, CI 1.04-4.41, P = 0.03) and HLA-B7 (OR 1.80, CI 1.04-3.12, P = 0.03) correlated with an increased risk of acute GVHD grades II-IV. We also found an association between HLA-B27 (RR 0.60, CI 0.37-0.95, P = 0.04) and a lower incidence of chronic GVHD. These HLA alleles were independent of other known risk factors for acute or chronic GVHD, as shown by multivariate analysis. These results show that major histocompatibility comlex (MHC) alleles may influence the incidence of GVHD in HSCT with HLA identical sibling donors.     

Association between BMI-1 expression, acute graft-versus-host disease, and outcome following allogeneic stem cell transplantation from HLA-identical siblings in chronic myeloid leukemia

Expression of CD7, ELA-2, PR-3, and the polycomb group gene BMI-1 reflects the intrinsic heterogeneity and predicts prognosis of patients with chronic myeloid leukemia (CML) who were not treated with allogeneic stem cell transplantation (allo-SCT). This study investigated whether expression of these genes determined outcome following allo-SCT in a cohort of 84 patients with chronic-phase (CP) CML. We found that patients expressing BMI-1 at a "high" level before allo-SCT had an improved overall survival (P = .005) related to a reduced transplantation-related mortality. In multivariate analysis, when adjusted for the European Group for Blood and Marrow Transplantation (EBMT)-Gratwohl score and other prog-nostic factors, there was an independent association between BMI-1 expression and grades 2 to 4 acute graft-versus-host disease (relative risk [RR] = 2.85; 95% confidence interval [CI], 1.3-6.4; P = .011), suggesting that BMI-1 measured prior to allo-SCT can serve as a biomarker for predicting outcome in patients with CP-CML receiving allo-SCT, and may thus contribute to better therapeutic decisions.     

血清脂联素水平与冠心病严重程度的关系

目的探讨血清脂联素（APN）水平与冠心病及其病变严重程度的相关性。方法选取135例行冠状动脉造影的患者,分别按Gensini积分、冠状动脉病变数目及临床诊断分组,进行血清APN测定。结果Gensini积分0分组（74.53±30.76ng/mL）和〈20分组（62.99±26.51ng/mL）APN水平分别显著高于20～40分组（44.06±15.18ng/mL）和〉40分组（28.96±11.87ng/mL）,P均〈0.01。20～40分组APN水平高于〉40分组（P〈0.05）。APN水平与Gensini积分的对数呈负相关（r=-0.556,P〈0.001）。对照组APN水平显著高于单支、双支和三支病变组（74.14±29.48ng/mL比55.29±23.40ng/mL、49.31±25.61ng/mL和38.39±15.57ng/mL,P均〈0.01）,单支病变组APN水平显著高于三支病变组（P〈0.01）。急性冠状动脉综合征组APN水平显著低于非冠心病组和稳定型心绞痛组（47.59±23.57ng/mL比67.05±31.53ng/mL、62.29±26.62ng/mL,P〈0.01和P〈0.05）。结论APN与冠状动脉狭窄程度、范围以及稳定性显著相关,有助于临床评价冠心病病变程度及其进展。     

Sclerodermatous chronic graft-versus-host disease after allogeneic hematopoietic stem cell transplantation: incidence, predictors and outcome

Scleroderma may be one of the most severe forms of chronic graft-versus-host disease (GVHD). We retrospectively evaluated its incidence, predictor variables and outcome in 133 patients who survived at least 4 months after allogeneic hematopoietic stem cell transplantation. The 5-year cumulative incidence was 15.5% in patients with chronic GVHD. The generalized form had a progressive course despite immunosuppressive therapy. Eosinophilia, autoimmune markers, and previous skin involvement by chronic GVHD with disorders of pigmentation were significantly associated with an increased probability of developing scleroderma.     

Squamous cell carcinoma of the tongue complicating chronic oral mucosal graft-versus-host disease after allogeneic hematopoietic stem cell transplantation

Two patients underwent allogeneic hematopoietic stem cell transplantation (HSCT) for acute myeloid leukemia. Chronic graft-versus-host disease (GVHD) developed, with persistent symptomatic oral lesions. At 2 and 6 years post-HSCT, both patients developed squamous cell carcinoma (SCC) of the tongue in areas previously involved by chronic GVHD. None had any known risk factor for SCC. Histologically, moderate to severe dysplasia was present in noncancerous oral mucosa. Oral SCC is rarely described after HSCT, and a review of the reported cases showed chronic GVHD to be a common risk, suggesting that the chronic inflammation associated with GVHD might be of pathogenetic significance.     

Increased serum levels of matrix metalloproteinase-9 in acute graft-versus-host disease after allogeneic haematopoietic stem cell transplantation

Matrix metalloproteinases (MMPs) have been implicated in a variety of normal and pathological conditions that involve matrix degradation and remodelling. We investigated the role of MMPs in acute graft-versus-host disease (aGVHD) in 29 patients who had undergone allogeneic haematopoietic stem cell transplantation. The present study showed that the serum levels of MMP-9, but not those of MMP-2, significantly correlated with the occurrence and severity of aGVHD. Moreover, immunohistochemical analysis of the cutaneous lesions of patients with aGVHD revealed an increased number of inflammatory cells positive for MMP-9. These results suggest that MMP-9 might play an important role in the pathogenesis of aGVHD.     

Thalidomide after allogeneic haematopoietic stem cell transplantation: activity in chronic but not in acute graft-versus-host disease

Thalidomide was used to treat acute (n=21) or chronic (n=59) graft-vs-host disease (GVHD) in 80 haematopoietic stem cell allograft recipients after failure to respond to the combination of cyclosporine and corticosteroids with or without other agents. The median time to onset of acute GVHD was 11 days, and thalidomide was started at a median of 48 days post transplant. In addition to corticosteroids and cyclosporine, 13 patients had also received other agents before thalidomide. None of the patients responded and all died of acute GVHD. For chronic GVHD (limited in 13, extensive in 46), thalidomide was started at a median of 385 days post transplant. In addition to corticosteroids and cyclosporine, 34 patients received azathioprine concomitantly. In all patients, thalidomide was added to the ongoing immunosuppressive regimen. The median duration of therapy with thalidomide was 60 days (range, 11-1210; <2 weeks in 11). In total, 13 patients (22%) had complete response, eight (14%) partial response and 38 (64%) no response. Response rates were comparable for limited (39%) and extensive (33%) chronic GVHD. At a median of 53 months, 19 patients are alive, 13 without evidence of chronic GVHD. Survival was significantly better in patients who responded to thalidomide. The principal causes of death were progressive chronic GVHD (n=29) and relapsed leukaemia (n=7). In conclusion, thalidomide has no activity in acute GVHD, but has some activity in chronic GVHD in combination with other agents.     

Plasma level of lipopolysaccharide-binding protein is indicative of acute graft-versus-host disease following allogeneic hematopoietic stem cell transplantation

Acute graft-versus-host disease (aGVHD) is the major cause of non-relapse mortality following allogeneic hematopoietic stem cell transplantation. To date, there are no consensus specific plasma biomarkers for aGVHD. We recently identified several candidates differentially expressed in aGVHD patients. Here, we have validated one such candidate: lipopolysaccharide-binding protein (LBP). We detected plasma LBP level by ELISA in 73 patients and performed correlation analysis with the progression and severity of aGVHD. We found that plasma LBP level increased during the period of aGVHD and decreased markedly as aGVHD was resolved. LBP level in patients with moderate aGVHD (25-50 % skin rash area of grade 1 and grade 2) was higher than in patients with no, little (skin rash area <25 % of grade 1), or severe aGVHD (grade 3-4). Higher LBP level indicated higher probability of aGVHD. Multivariate analysis showed that LBP level above 15000 ng/ml was significantly associated with an increased risk of aGVHD (HR 2.43; 95 % CI 1.29-4.58; P = 0.006). If LBP level exceeded 15000 ng/ml at d7 and d14 after HSCT, the subsequent probability of aGVHD increased markedly, especially at the time point of d14. There was no correlation between LBP level and the site of aGVHD. In conclusion, our study demonstrated that an elevated LBP level of >15000 ng/ml may serve as a biomarker for the prediction and monitoring of aGVHD.     

Serum albumin level predicts survival of patients with gastrointestinal acute graft-versus-host disease after allogeneic stem cell transplantation

In a retrospective single-centre study, we analysed the prognostic impact of factors identifiable at initial diagnosis of acute GVHD (aGVHD). We retrospectively analysed 495 adult patients of whom 308 (62 %) developed acute GVHD (I–IV) and were included in further analysis. Gut aGVHD was diagnosed in 163/308 cases (53 %). Conditioning was myeloablative conditioning (MAC) in 123 (39.9 %) and reduced intensity (RIC) in 185 (60.1 %) patients. Median serum albumin level at diagnosis of aGVHD was 34 g/l, which was used as cut-off for low vs. normal albumin levels. In patients with gut aGVHD, low albumin level at the time of diagnosis of aGVHD was associated with poorer overall survival (OS) which was 52 vs. 67 % at 1 year and 40 vs. 61 % at 3 years, p?=?0.015. In patients with only skin aGVHD, 1- and 3-year OS of patients with low vs. normal albumin levels were 72 vs. 72 % and 59 vs. 57 %, respectively, p?=?0.69. In multivariate analysis of patients with gut aGVHD, low serum albumin level ≤34 g/l (relative risk (RR) 2.13, p?=?0.003), gut aGVHD grades 3–4 (RR 2.70, p?=?0.001), RIC (RR 1.84, p?=?0.024), matched unrelated donor (RR 1.86, p?=?0.18) and mismatched unrelated donor (RR 2.76, p?=?0.03) retained negative impact on OS. Subgroup analysis revealed that impact of albumin was restricted to patients with gut aGVHD after RIC. Low serum albumin levels are associated with poorer OS in patients with gut but not skin aGVHD after RIC but not MAC allogeneic stem cell transplantation.     

Proteomic patterns predict acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation

Acute graft-versus-host disease (aGvHD) contributes significantly to morbidity and mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Diagnosis of GvHD is mainly based on clinical features and tissue biopsies. A noninvasive, unbiased laboratory test for GvHD diagnosis does not exist. Here we describe the application of capillary electrophoresis coupled online with mass spectrometry (CE-MS) to 13 samples from 10 patients with aGvHD of grade II or more and 50 control samples from 23 patients without GvHD. About 170 GvHD-specific polypeptides were detected and a tentatively aGvHD-specific model consisting of 31 polypeptides was chosen, allowing correct classification of 13 of 13 (sensitivity 100.0% [95% confidence interval {CI} 75.1 to 100.0]) aGvHD samples and 49 of 50 (specificity 98.0% [95% CI 89.3 to 99.7]) control samples of the training set. The subsequent blinded evaluation of 599 samples enabled diagnosis of aGvHD greater than grade II, even prior to clinical diagnosis, with a sensitivity of 83.1% (95% CI 73.1 to 87.9) and a specificity of 75.6% (95% CI 71.6 to 79.4). Thus, high-resolution proteome analysis represents an unbiased laboratory-based screening method, enabling diagnosis, and possibly enabling preemptive therapy.