scholarly journals Ophthalmic manifestations are associated with reduced tear lymphotoxin-α levels in chronic ocular graft-versus-host disease

2022 ◽  
Vol 22 (1) ◽  
Author(s):  
Jiao Ma ◽  
Chendi Li ◽  
Yinghan Zhao ◽  
Zhan Shen ◽  
Bohao Hu ◽  
...  
Keyword(s):  
Graft Versus Host Disease ◽  
Roc Analysis ◽  
Area Under The Curve ◽  
Cutoff Value ◽  
Host Disease ◽  
Commercial Test ◽  
Test Strips ◽  
Graft Versus Host ◽  
Ophthalmic Manifestations ◽  
Lymphotoxin Α

Abstract Purpose To determine the role tear lymphotoxin-α (LT-α) in chronic ocular graft-versus-host disease (oGVHD). Methods Twenty-two chronic oGVHD and 17 control tear samples were collected, and commercial test strips were used to detect LT-α concentrations. Concentration differences between patients with and without oGVHD were determined via Mann-Whitney U test. The correlation between LT-α levels and ophthalmic parameters was analyzed using Spearman’s test. Results The concentration of LT-α was significantly lower in oGVHD patients than in controls. LT-α levels were significantly correlated with OSDI, NIH eye score, T-BUT, and CFS among all participants. ROC analysis revealed that the area under the curve of LT-α was 0.847, and the cutoff value for chronic oGVHD diagnosis was 0.203 ng/mL. Conclusion Our study revealed the significant decrease of tear LT-α in oGVHD, and suggested LT-α as a promising marker for chronic oGVHD diagnosis.

scholarly journals Expression of Serum Micrornas Are Dysregulated during Acute Graft Versus Host Disease

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5715-5715
Author(s):  
Rachel E Crossland ◽  
Jean Norden ◽  
Mateja Kralj Juric ◽  
Kile Green ◽  
Kim F Pearce ◽  
...  
Keyword(s):  
Graft Versus Host Disease ◽  
Roc Analysis ◽  
Microrna Expression ◽  
Haematopoietic Stem Cell ◽  
Cell Transplant ◽  
Diagnostic Ability ◽  
Host Disease ◽  
Graft Versus Host ◽  
Acute Graft ◽  
Independent Cohort

Abstract Introduction MicroRNAs are expressed in body fluids and have recently been associated with the etiology of acute graft versus host disease (GvHD), but global expression profiling in a haematopoietic stem cell transplant (HSCT) setting is lacking. An improved understanding of the molecular pathogenesis of aGvHD may allow for improved therapeutic options, or guide personalised prophylactic protocols. Methods Mature microRNA serum expression (n=799) was assessed using nCounter technology (NanoString) in a training cohort of diagnostic aGvHD samples (n=12). Analysis assessed for microRNAs that were dysregulated in patients who developed aGvHD compared to no aGvHD. Signature microRNAs were validated in an independent cohort of serum samples taken at aGvHD diagnosis (n=42) and prior to disease onset (day 14 (D14) post-HSCT, n=47). Results NanoString profiling identified 61 microRNAs that were differentially expressed at aGvHD onset, of which n=27 were downregulated (fold change (FC) -6.94 - -1.75; p<0.01 - p=0.048) in aGvHD while n=34 were upregulated (FC 1.35 - 5.41; p<0.01 - p=0.046). 10 microRNAs (miR-146a, miR-30b, miR-374, miR-20a, miR-15a, miR-181a, miR-18a, miR-19a, miR-19b and miR-451a) were selected for further assessment in an independent diagnostic cohort (n=42), based on high FC or those reported in the literature to be implicated in GvHD, T-cell function or the inflammatory response. MiR-146a (p=0.03), miR-30b-5p (p=0.007), miR-374-5p (p=0.02) and miR-181a (p=0.03) were significantly downregulated, whilst miR-20a (p=0.03) and miR-15a (p=0.03) were significantly upregulated in aGvHD. MiR-30b (AUC=0.75, p=0.007), miR-374-5p (AUC=0.74, p=0.01) and miR-15a (AUC=0.70, p=0.04) had diagnostic ability for aGvHD as assessed by receiver operator characteristic (ROC) analysis, whilst miR-181 (AUC=0.68, p=0.06), miR-146a (AUC=0.66, p=0.09) and miR-20a (AUC=0.68, p=0.06) were approaching significance. There was no significant difference in microRNA expression between clinical factors including transplant relationship, patient gender or conditioning regimen, indicating the effect to be related to aGvHD incidence. MicroRNA expression was also assessed at D14 post-HSCT in an independent cohort (n=47) to investigate their prognostic marker potential. MiR-146a (p=0.01), miR-20a (p=0.03), miR-18a (p=0.03), miR-19a (p=0.03), miR-19b (p=0.02) and miR-451 (p=0.01) were expressed at significantly higher levels in patients who developed aGvHD vs. no aGvHD. In ROC analysis, miR-146a (A=0.68, p=0.03), miR-19b (A=0.70, p=0.02) and miR-451 (A=0.69, p=0.03) had diagnostic ability with regards to aGvHD incidence, whilst miR-18a (A=0.65, p=0.09), miR-19a (A=0.65, p=0.08) and miR-20a (A=0.67, p=0.06) were approaching significance. Conclusions Circulating microRNAs have the capacity to act as prognostic and diagnostic biomarkers for aGvHD and might assist in developing personalised therapeutic approaches. Their dysregulated expression suggests a role in aGvHD pathology, which warrants further investigation. Disclosures No relevant conflicts of interest to declare.

scholarly journals Area-under-the-Curve-Based Mycophenolate Mofetil Dosage May Contribute to Decrease the Incidence of Graft-versus-Host Disease after Allogeneic Hematopoietic Cell Transplantation in Pediatric Patients

2021 ◽  
Vol 10 (3) ◽  
pp. 406
Author(s):  
Giorgia Carlone ◽  
Roberto Simeone ◽  
Massimo Baraldo ◽  
Alessandra Maestro ◽  
Davide Zanon ◽  
...  
Keyword(s):  
Mycophenolate Mofetil ◽  
Cell Transplantation ◽  
Graft Versus Host Disease ◽  
Pediatric Patients ◽  
Chronic Gvhd ◽  
Area Under The Curve ◽  
Control Group ◽  
Study Group ◽  
Host Disease ◽  
Graft Versus Host

Acute graft-versus-host disease (GvHD) remains the second leading cause of death, after disease relapse, in patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). The medical records of 112 pediatric patients who underwent allo-HSCT from matched unrelated and haploidentical donors were analyzed. Patients were divided into two groups, according to the GvHD prophylactic regimen used. In the control group, GvHD prophylaxis consisted of cyclosporine A (CsA) and methotrexate (MTX) or CsA and mycophenolate mofetil (MMF) at a standard daily dose of 30 mg/kg. All subjects in the study group received tacrolimus (FK506) and MMF. In this group, MMF was subjected to therapeutic drug monitoring (TDM) through mycophenolic acid (MPA) area under the curve AUC0–12. We found a statistically significant difference in both overall acute GvHD (p < 0.0001) and overall chronic GvHD (p < 0.05) incidence between the study and the control group. The initial daily MMF dose and the age at transplant in the study group proved to be inversely correlated (r = −0.523, p < 0.0001). The children under six years of age required a significantly higher daily MMF dose (p < 0.008). This study showed that pharmacological monitoring of MPA AUC0–12 concentration allowed a reduction in the incidence of acute and chronic GvHD. MMF showed age-dependent pharmacokinetics due to greater drug clearance in younger children.

scholarly journals Serum and Extracellular Vesicle Micrornas MiR-423, MiR-199 and MiR-93* As Biomarkers for Acute Graft Versus Host Disease

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4545-4545
Author(s):  
Rachel E Crossland ◽  
Jean Norden ◽  
Kim F Pearce ◽  
Mateja Kralj Juric ◽  
Clare Lendrem ◽  
...  
Keyword(s):  
Graft Versus Host Disease ◽  
Roc Analysis ◽  
Rna Extraction ◽  
Cell Transplant ◽  
Diagnostic Ability ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Graft Versus Host ◽  
Qrt Pcr ◽  
Acute Graft

Abstract Introduction MicroRNAs are small, non-coding single-stranded RNAs and regulate approximately 50% of all genes by repressing translation. They are present in bodily fluids, where they are protected from RNase-mediated degradation by encapsulation into extracellular vesicles (EVs) and demonstrate a novel capacity to regulate the cellular differentiation of blood cells and immune function. Candidate microRNAs miR-377, miR-199, miR-93* and miR-423 have previously been associated with acute graft versus host disease (aGvHD) in post-hematopoietic stem cell transplant (HSCT) patient plasma. However, validation in independent cohorts is necessary, as well as further exploration to assess expression in the EV fraction of the blood. Methods MicroRNA expression was evaluated in early HSCT time point exploratory (n=34), validation (n=47) and diagnostic (n=65) serum cohorts by TaqMan qRT-PCR. Expression was also assessed in serum EVs (exploratory n=16 and validation n=47 cohorts) by EV isolation, RNA extraction and TaqMan qRT-PCR analysis. Results In sequential pre- and post-HSCT serum samples (n=34; pre-HSCT, Day0 (D0), D7, D14 & D28), miR-423 (p=0.03), miR-199 (p=0.06), miR-93* (p=0.04) and miR-377 (p=0.03) were upregulated at D14 in patients who developed aGvHD vs. no aGvHD. MiR-423 was also significantly upregulated at D0 (p=0.04), D7 (p=0.03) and D28 (p=0.03) in aGvHD patients. In relation to aGvHD severity, miR-423 (p=0.05), miR-199 (p=0.007) and miR-93* (p=0.09) were differentially expressed at D14 according to aGvHD grade. MiR-423 (p=0.02), miR-199 (p=0.07) and miR-93* (p=0.01) expression was validated at D14 in an independent cohort (n=47). When the exploratory and validation D14 samples were combined (n=81), miR-423 (p<0.001), miR-199 (p=0.04) and miR-93* (p<0.001) expression was upregulated in patients that developed aGvHD vs. no GvHD and ROC analysis identified miR-423 (p<0.001, AUC=0.75), miR-199 (p=0.09, AUC=0.62) and miR-93* (p<0.001, AUC=0.74) to have diagnostic ability. MiR-423 (p=0.001), miR-199 (p=0.01) and miR-93* (p<0.001) expression was higher in severe (III-IV) vs. no aGvHD, miR-423 (p=0.006) and miR-93* (p=0.01) were higher in mild (I-II) vs. no aGvHD and miR-199 was higher in severe (III-IV) vs. mild (I-II) aGvHD (p=0.002). All microRNAs demonstrated significant positive correlation (p<0.001), thus, principle component analysis (PCA) was performed. The PC1 composite score was used for ROC analysis and showed diagnostic ability for aGvHD incidence (p<0.001, AUC=0.73). In an independent diagnostic cohort (n=65), from a separate Institution, miR-423 (p=0.02), miR-199 (p=0.007) and miR-93* (p=0.004) expression was higher at aGvHD onset and showed diagnostic ability by ROC analysis (miR-423 p=0.03 AUC=0.66; miR-199 p=0.04 AUC=0.65; and miR-93* p=0.01 AUC=0.68). The three microRNAs had diagnostic ability with respect to aGvHD incidence based on composite ROC analysis of PC1 (p=0.019, AUC=0.68). MicroRNAs were also investigated within serum EVs (n=15). MiR-199 (p=0.008), miR-93* (p=0.001) and miR-423 (p=0.09) expression was lower at D14 in patients who developed aGvHD. Results were confirmed in a D14 validation cohort (n=47), with lower EV miR-423 (p=0.02) and miR-199 (p=0.04), but not miR-93* (p=0.15) expression in patients who developed aGvHD. MiR-423 and miR-199 had diagnostic ability based on composite PC1 ROC analysis (p=0.06, AUC=0.69). By D14, patients remaining aGvHD free had higher expression of miR-423 (p=0.03), miR-199 (p=0.05) and miR-93* (p<0.001) in the EV fraction compared to whole serum. Conclusions Results validate the capacity for circulating serum miR-423, miR-199 and miR-93* to act as diagnostic and prognostic biomarkers for aGvHD. Novel findings of differential expression between whole serum and the EV compartment prior to disease onset suggest a role for EV microRNAs in the biology of aGvHD, which warrants further investigation. Disclosures No relevant conflicts of interest to declare.

Allogeneic HSCT Patients Receiving More RBC Transfusions Are At Increased Risk For Development Of Grade 2-4 Acute Graft-Versus-Host Disease

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3298-3298
Author(s):  
Cynthia R. Giver ◽  
Zahir Ali ◽  
Sheilagh Barclay ◽  
Sakura Hosaba ◽  
Qunna Li ◽  
...  
Keyword(s):  
T Cells ◽  
Retrospective Analysis ◽  
Graft Versus Host Disease ◽  
Chronic Gvhd ◽  
Hematopoietic Stem ◽  
Cutoff Value ◽  
Host Disease ◽  
Graft Versus Host ◽  
Post Transplant ◽  
Rbc Transfusion

Abstract Background A critical barrier to progress in allogeneic hematopoietic stem cell transplantation (allo-HSCT) has been a lack in understanding regarding why some transplant recipients of HLA-matched transplant grafts develop severe graft-versus-host disease (GvHD) while other recipients have relapse of their cancer without GvHD. Patients who develop a modest degree of acute and/or chronic GvHD have less relapse and optimal survival after allogeneic BMT. Thus, a mechanistic understanding of regulation of donor T-cell activation after allo-HSCT is needed. Using mouse models, Desmarets et al. have shown that pre-transplant leukoreduced RBC transfusions can cause recipient immunization against minor histocompatibility antigens (miHA) and activation and expansion of recipient T-cells that recognize donor miHA, contributing to rejection of subsequent allo-HSCT (Blood. 2009; 114:2315). Preliminary data from our lab suggest that leukoreduced RBC transfusions given concurrently with allo-HSCT can also increase post-transplant activation and expansion of donor T-cells, an effect which may lead to increased GvHD after transplant. Here, we have conducted a retrospective study of post-transplant RBC transfusions and acute GvHD (aGvHD) in allo-HSCT patients. We hypothesized that increased numbers of transfusions during the 30-day post-transplant period would be correlated with increased severity of aGvHD in these patients. Methods We conducted a retrospective analysis of RBC transfusion records and aGvHD data collected for 181 adult allo-HSCT patients who received their transplants at Emory University Hospital (EUH) between 2004 and 2009. Nine patients were excluded who died < 50 days post-transplant without developing aGvHD, since this was too early to determine aGvHD occurrence. Of the remaining 172 patients studied (median age 48 yrs at time of transplant, range 18-72), 88 (49%) were male and 84 (51%) were female. Patients had received either matched related HSCT (n=69, 40%) or matched unrelated HSCT (n=103, 60%) for treatment of SAA (n=7), BAL (n=2), ALL (n=18), AML (n=69), hemolytic anemia (n=2), CLL (n=6), CML (n=8), HD (n=5), MDS (n=23), myelofibrosis (n=6), MM (n=7) or NHL (n=19). For pts who developed aGvHD, the onset time ranged from 1 to 139 days post-transplant, with a median of 30 days. No aGvHD (grade 0) was diagnosed in 58 pts (34%), while 37 pts (21%) developed grade 1 aGvHD and 77 pts (45%) developed grade 2-4 aGvHD. The number of ABO matched, irradiated RBC units transfused 0 - 30 days post-transplant was tallied for each patient, ranging from 0 (no transfusions, n=13, 7.6% of pts) to 26 units, with an average of 5.6 and median of 4 units. All transfusions during this timeframe were administered at EUH. The median follow up time was 22 months post-transplant (range, 1.1 – 96.1 months). Results Pts were assigned to two groups, those who developed grade 0-1 aGvHD (n=95, 55%) or grade 2-4 aGvHD (n=77, 45%) within 140 days post-transplant. This study did not include analysis of late-onset aGvHD or chronic GvHD past this time point. Patients with grade 2-4 aGvHD had a higher average number of transfusions 0 - 30 days post-transplant compared with patients having grade 0-1 aGvHD (6.5 vs. 4.9 units, p = 0.02). Receiver-operator characteristics (ROC) analysis showed that a cutoff value of > 4 transfusions 0 - 30 days post-transplant had 56% sensitivity and 65% specificity to predict development of grade 2-4 aGvHD. When tested by logistic regression in a multivariate model, this cutoff value had a highly significant correlation with grade 2-4 aGvHD, with an odds ratio of 2.83 and p value = 0.0024. Other covariates including patient age, gender, and type of transplant (related vs. unrelated) were not significantly associated with aGvHD outcome. Conclusion Our retrospective analysis identified a significant positive correlation between the number of post-transplant RBC transfusions and severity of aGvHD after allo-HSCT. Additional studies are planned to determine whether RBC transfusions 0 - 30 days post-transplant stimulate allo-reactive T-cells via allo-antigen presentation or by otherwise promoting inflammation, and if one or both of these mechanisms contribute to increased GvHD. If so, it may be possible to develop strategies for optimization of RBC transfusion practices to reduce the risk of severe aGvHD after allo-HSCT. Disclosures: No relevant conflicts of interest to declare.

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