The Effect of Granulocyte Colony–Stimulating Factor on Immune-Modulatory Cytokines in the Bone Marrow Microenvironment and Mesenchymal Stem Cells of Healthy Donors

AbstractGranulocyte colony stimulating factor (G-CSF) is sometimes administered to donors before bone marrow (BM) harvest. G-CSF–primed (G-BM) and unprimed BM (U-BM)–derived mesenchymal stem cells (MSC) were obtained from 16 healthy donors and were expanded in vitro. Their proliferative characteristics, morphology, and differentiation capacity were examined. Supernatants of the second passage of MSCs were evaluated for transforming growth factor β1, hepatocyte growth factor, and prostaglandin E2 (PGE2) levels and compared with controls. The analyses of cytokines in the G-BM– and U-BM–derived MSCs supernatants revealed that PGE2 levels were significantly lower in the G-CSF–primed samples. These cytokines were also measured in BM plasma. The level of hepatocyte growth factor in G-BM plasma was significantly increased. The current study is the first to show the effects of G-CSF on the BM microenvironment of healthy human donors. The preliminary data suggest that G-BM– and U-BM–derived MSCs have similar morphologic/phenotypic properties and differentiation capacity but differ in their secretory capacity. Significant changes in cytokine levels of BM plasma in G-CSF–primed donors were also demonstrated. These findings suggest that BM MSCs and changes in the BM microenvironment may contribute to the effects of G-CSF on inflammation and immunomodulation

Hematopoietic Cell Transplantation Cures Adenosine Deaminase 2 Deficiency: Report on 30 Patients

PURPOSE: Deficiency of adenosine deaminase 2 (DADA2) is an inherited inborn error of immunity, characterized by autoinflammation (recurrent fever), vasculopathy (livedo racemosa, polyarteritis nodosa, lacunar ischemic strokes, and intracranial hemorrhages), immunodeficiency, lymphoproliferation, immune cytopenias, and bone marrow failure (BMF). Tumor necrosis factor (TNF-α) blockade is the treatment of choice for the vasculopathy, but often fails to reverse refractory cytopenia. We aimed to study the outcome of hematopoietic cell transplantation (HCT) in patients with DADA2. METHODS: We conducted a retrospective study on the outcome of HCT in patients with DADA2. The primary outcome was overall survival (OS). RESULTS: Thirty DADA2 patients from 12 countries received a total of 38 HCTs. The indications for HCT were BMF, immune cytopenia, malignancy, or immunodeficiency. Median age at HCT was 9 years (range: 2-28 years). The conditioning regimens for the final transplants were myeloablative (n = 20), reduced intensity (n = 8), or non-myeloablative (n = 2). Donors were HLA-matched related (n = 4), HLA-matched unrelated (n = 16), HLA-haploidentical (n = 2), or HLA-mismatched unrelated (n = 8). After a median follow-up of 2 years (range: 0.5-16 years), 2-year OS was 97%, and 2-year GvHD-free relapse-free survival was 73%. The hematological and immunological phenotypes resolved, and there were no new vascular events. Plasma ADA2 enzyme activity normalized in 16/17 patients tested. Six patients required more than one HCT. CONCLUSION: HCT was an effective treatment for DADA2, successfully reversing the refractory cytopenia, as well as the vasculopathy and immunodeficiency. CLINICAL IMPLICATIONS: HCT is a definitive cure for DADA2 with > 95% survival

Hematopoietic Cell Transplantation Cures Adenosine Deaminase 2 Deficiency : Report on 30 Patients

Correction; Early Access: ' DOI: 10.1007/s10875-022-01280-y Early Access: APR 2022Purpose Deficiency of adenosine deaminase 2 (DADA2) is an inherited inborn error of immunity, characterized by autoinflammation (recurrent fever), vasculopathy (livedo racemosa, polyarteritis nodosa, lacunar ischemic strokes, and intracranial hemorrhages), immunodeficiency, lymphoproliferation, immune cytopenias, and bone marrow failure (BMF). Tumor necrosis factor (TNF-alpha) blockade is the treatment of choice for the vasculopathy, but often fails to reverse refractory cytopenia. We aimed to study the outcome of hematopoietic cell transplantation (HCT) in patients with DADA2. Methods We conducted a retrospective study on the outcome of HCT in patients with DADA2. The primary outcome was overall survival (OS). Results Thirty DADA2 patients from 12 countries received a total of 38 HCTs. The indications for HCT were BMF, immune cytopenia, malignancy, or immunodeficiency. Median age at HCT was 9 years (range: 2-28 years). The conditioning regimens for the final transplants were myeloablative (n = 20), reduced intensity (n = 8), or non-myeloablative (n = 2). Donors were HLA-matched related (n = 4), HLA-matched unrelated (n = 16), HLA-haploidentical (n = 2), or HLA-mismatched unrelated (n = 8). After a median follow-up of 2 years (range: 0.5-16 years), 2-year OS was 97%, and 2-year GvHD-free relapse-free survival was 73%. The hematological and immunological phenotypes resolved, and there were no new vascular events. Plasma ADA2 enzyme activity normalized in 16/17 patients tested. Six patients required more than one HCT. Conclusion HCT was an effective treatment for DADA2, successfully reversing the refractory cytopenia, as well as the vasculopathy and immunodeficiency. Clinical Implications HCT is a definitive cure for DADA2 with > 95% survival.Peer reviewe

Correction to: Hematopoietic cell transplantation cures adenosine deaminase 2 deficiency: report on 30 patients

Correction to: Journal of Clinical Immunology (2021) 41:1633–164

Relationship Between the Levels of Holotranscobalamin and Vitamin B12 in Children.

The purpose of this study was to evaluate the relationship between the plasma holoTC and serum vitamin B12 in children and to identify a cutoff cobalamin values according to holoTC. One hundred and fifty-five children were enrolled into the study. All children were evaluated for hemoglobin, vitamin B12, folate, ferritin and holoTC levels. Children were grouped as with low vitamin B12 level (≤200 pg/mL, group I) and normal vitamin B12 (>200 pg/mL, group II). Serum vitamin B12, and holoTC levels were performed in each patient in the study. In 101 patients with low vitamin B12 (group I) the mean holoTC was 21.74 ± 1.14 pmol/L. In 54 children with normal vitamin B12 (group II) mean holoTC was 44.0 ± 2.7 pmol/L (p < 0.01). A ROC curve analysis was performed to delineate the optimum cut-off point for vitamin B12 level and it was found to be 165 pg/mL with a sensitivity of 70% and specificity of 74%; the area under curve was 0.783 (p < 0.01). Our study displayed a positive correlation between vitamin B12 and holoTC, and defined an optimum cutoff value for vitamin B12 as 165 pg/mL. Further studies using the markers both MMA, tHcy and holoTC to confirm the findings are needed

Severe Clinical Course in a Patient with Congenital Amegakaryocytic Thrombocytopenia Due to a Missense Mutation of the c-MPL Gene

Congenital amegakaryocytic thrombocytopenia (CAMT) generally begins at birth with severe thrombocytopenia and progresses to pancytopenia. It is caused by mutations in the thrombopoietin receptor gene, the myeloproliferative leukemia virus oncogene (c-MPL). The association between CAMT and c-MPL mutation type has been reported in the literature. Patients with CAMT have been categorized according to their clinical symptoms caused by different mutations. Missense mutations of c-MPL have been classified as type II and these patients have delayed onset of bone marrow failure compared to type I patients. Here we present a girl with severe clinical course of CAMT II having a missense mutation in exon 4 of the c-MPL gene who was admitted to our hospital with intracranial hemorrhage during the newborn period

Relationship Between the Levels of Holotranscobalamin and Vitamin B-12 in Children

The purpose of this study was to evaluate the relationship between the plasma holoTC and serum vitamin B-12 in children and to identify a cutoff cobalamin values according to holoTC. One hundred and fifty-five children were enrolled into the study. All children were evaluated for hemoglobin, vitamin B-12, folate, ferritin and holoTC levels. Children were grouped as with low vitamin B-12 level (<= 200 pg/mL, group I) and normal vitamin B-12 (> 200 pg/mL, group II). Serum vitamin B-12, and holoTC levels were performed in each patient in the study. In 101 patients with low vitamin B-12 (group I) the mean holoTC was 21.74 +/- 1.14 pmol/L. In 54 children with normal vitamin B-12 (group II) mean holoTC was 44.0 +/- 2.7 pmol/L (p < 0.01). A ROC curve analysis was performed to delineate the optimum cut-off point for vitamin B-12 level and it was found to be 165 pg/mL with a sensitivity of 70\% and specificity of 74\%; the area under curve was 0.783 (p < 0.01). Our study displayed a positive correlation between vitamin B-12 and holoTC, and defined an optimum cutoff value for vitamin B-12 as 165 pg/mL. Further studies using the markers both MMA, tHcy and holoTC to confirm the findings are needed

The Effect of Granulocyte Colony-Stimulating Factor on Immune-Modulatory Cytokines in the Bone Marrow Microenvironment and Mesenchymal Stem Cells of Healthy Donors

Granulocyte colony stimulating factor (G-CSF) is sometimes administered to donors before bone marrow (BM) harvest. G-CSF primed (G-BM) and unprimed BM (U-BM) derived mesenchymal stem cells (MSC) were obtained from 16 healthy donors and were expanded in vitro. Their proliferative characteristics, morphology, and differentiation capacity were examined. Supernatants of the second passage of MSCs were evaluated for transforming growth factor in, hepatocyte growth factor, and prostaglandin E2 (PGE2) levels and compared with controls. The analyses of cytokines in the G-BM and U-BM derived MSCs supernatants revealed that PGE2 levels were significantly lower in the G-CSF primed samples. These cytokines were also measured in BM plasma. The level of hepatocyte growth factor in G-BM plasma was significantly increased. The current study is the first to show the effects of G-CSF on the BM microenvironment of healthy human donors. The preliminary data suggest that G-BM and U-BM derived MSCs have similar morphologic/ phenotypic properties and differentiation capacity but differ in their secretory capacity. Significant changes in cytokine levels of BM plasma in G-CSF primed donors were also demonstrated. These findings suggest that BM MSCs and changes in the BM microenvironment may contribute to the effects of G-CSF on inflammation and immunomodulation. (C) 2015 American Society for Blood and Marrow Transplantation.WoSScopu

Role of a second transplantation for children with acute leukemia following posttransplantation relapse: a study by the Turkish Bone Marrow Transplantation Study Group

KILIC, SUAR CAKI/0000-0001-7489-2054; UNAL, Ekrem/0000-0002-2691-4826; Ileri, Talia/0000-0002-0244-353X; Aksu, Tekin/0000-0003-4968-109XWOS: 000513301500001PubMed: 32037917We examined outcomes of 51 pediatric patients with relapsed acute leukemia (AL) who underwent a second allogeneic hematopoietic stem cell transplantation (alloHSCT). After a median follow-up of 941 days (range, 69-2842 days), leukemia-free survival (LFS) and overall survival (OS) at 3 years were 26.6% and 25.6%, respectively. the nonrelapse mortality rate (NMR) and cumulative incidence of relapse (CIR) were 36.4% and 42.4%, respectively. the Cox regression analysis demonstrated that the risk factors at second transplantation for predicting limited LFS were active disease (hazard ratio (HR) = 5.1), reduced intensity conditioning (RIC) (HR = 5.0), matched unrelated donor (MUD) (HR = 3.4) and performance score <80 (HR = 3.2). Pediatric patients with AL who relapsed after their first alloHSCT may survive with a second alloHSCT. Disease status, conditioning intensity, donor type, and performance score at the second transplantation are the relevant risk factors. A score based on these factors may predict the results of the second transplantation