Dominant Role for SDF-1 in the Vasculo-Angiogenesis Phenotype in Children with Sickle Cell Disease.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1432-1432
Author(s):  
Beatrice E Gee ◽  
Jerry M Manlove-Simmons ◽  
Yao Huang ◽  
Nana Wilson ◽  
Jonathan Stiles ◽  
...  
Keyword(s):  
Growth Factors ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Vascular Injury ◽  
Peripheral Blood ◽  
Plasma Concentrations ◽  
Control Group ◽  
Cell Disease ◽  
Angiogenic Growth Factors ◽  
Colony Number

Abstract BACKGROUND: Vasculogenesis is critically important to restoring and maintaining vascular homeostasis in patients who have sickle cell disease. Emerging evidence indicates vasculo-angiogenesis is a complex process involving recruitment of endothelial progenitor cells (EPCs) from the bone marrow and homing of EPCs to sites of vascular injury. Both recruitment and homing of EPCs are intimately regulated by cytokines and growth factors that are released in response to vascular insult. Hitherto, the phenotype of growth factors and cytokines intimately involved in EPC recruitment and homing in patients who have sickle cell disease remains poorly understood. METHODS: A total of 50 children aged 6–18 years were studied, 30 with Hemoglobin SS, including 11 on chronic red blood cell transfusions, and 20 with normal hemoglobin. We measured plasma concentrations of angiogenesis growth factors/cytokines using a multiplex assay, which permitted analysis of nine factors concurrently, and determined the number and phenotype of EPC colonies derived from peripheral blood samples. RESULTS: Plasma concentrations of stromal derived growth factor (SDF-1, 1.7-fold), angiopoietin-2 (Ang-2, 2-fold) and erythropoietin (7-fold) were significantly elevated (p<0.001) in children with sickle cell disease compared to control subjects. On the contrary, plasma leptin was significantly lower (2-fold, p<0.001) in the sickle cell disease group, while no significant differences were found for several other angiogenic growth factors including VEGF, HGF, IL-8, PGF and PDGF between children with sickle cell disease and the control group. Peripheral blood-derived EPC colonies were significantly higher (almost 3-fold) in patients who have sickle cell disease compared to the control group. Interestingly, EPC colony number was lower in sickle cell patients on chronic transfusion therapy compared to those who were not on chronic transfusion. There were significant correlations between EPC colony number and plasma concentrations of SDF-1 (r=0.65, p<0.001) and Ang-2 (r=0.36, p<0.05), but no correlation between EPC colony number and plasma erythropoietin and leptin. CONCLUSION: These data demonstrate for the first time enhanced vasculogenic potential in patients with sickle cell disease at steady-state. SDF-1 enhances the homing of EPCs and is highly expressed in ischemic tissues. The association of elevated SDF-1 and Ang-2 levels with EPC colony number is consistent with the hypothesis that sickle cell disease causes ongoing ischemic vascular injury. SDF-1 may be potentially used as a marker for vascular injury and a therapeutic target that can be developed to augment vascular repair in sickle cell disease.

Increased Levels and Activities of Matrix Metalloproteinases in Sickle Cell Disease.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1220-1220
Author(s):  
Carla F. Franco-Penteado ◽  
Stephen Hyslop ◽  
Nicola Conran ◽  
Sara T.O. Saad ◽  
Fernando F. Costa
Keyword(s):  
Sickle Cell Disease ◽  
Matrix Metalloproteinases ◽  
Sickle Cell ◽  
Plasma Concentrations ◽  
Gelatin Zymography ◽  
Control Group ◽  
Cell Disease ◽  
Cell Counts ◽  
Significant Difference ◽  
Leukocyte Counts

Abstract Sickle cell disease is characterized by a chronic inflammatory state, however, the mechanism underlying this inflammation is unclear. Elevated basal leukocyte counts, endothelial activation, altered availability of vaso-active factors, increased adhesion molecule expression and cytokines are found in this disease. Matrix metalloproteinases (MMPs) play an important role in physiological and pathological processes, participating in the extracellular matrix turnover as well as tissue degradation, repair mechanisms and cell migration. Since MMPs are important modulators of inflammation and the activity of cytokines and chemokines, our aim was to compare MMP and tissue inhibitor of matrix metalloproteinases (TIMP; inhibitors of MMP) levels and the activities of MMPs in the plasma of healthy subjects and in SCD patients on or off HU therapy (20–30 mg/kg/day, 3 month minimum duration). Gelatin zymography was used to measure MMP-2 and MMP-9 activities and ELISA was used for MMPs and TIMPs determination. After densitometric analysis of zymograms, a significant increase (p=0.03) in the activity of pro-MMP-9 was observed in the plasma of SCD patients (27.09 ± 1.99 average pixel, n=30) compared with the control group (20.96 ± 1.35 average pixel, n=29). Pro-MMP-9 activity in the plasma of SCD patients on HU (SCDHU) was greater (27.2 ± 1.35 average pixel, n=17); however this difference was not quite significant (p=0.07). With regard to MMP-2 activity, no significant difference (P>0.05, data not shown) between groups of patients and control individuals was observed. MMP-9 levels were significantly increased in the plasma of SCD patients (20.99 ± 1.52, n=32) compared to healthy controls (13.96 ± 1.64, n=16, p=0.02), although no effect of HU therapy on these augmented levels was observed (SCDHU; 23.66 ± 2.93, n=22, P>0.05). MMP-9 levels correlated significantly with total WBC counts (r=0.4221, p=0.01) in SCD patients (on and off HU), as well as with neutrophil counts (r=0.4436, p<0.001), but not with mononuclear cell counts. TIMP-1 and TIMP-2 levels were significantly (p<0.0001) higher in SCD patients not on HU therapy (83.69 ± 6.73, n=15; 95.49 ± 4.99, n=14, respectively) compared to control individuals (41.26 ± 3.75, n=11; 62.84 ± 3.43, n=10, respectively). HU therapy had no significant effect on increased TIMP-1 levels (84.14 ± 4.69, n=12, p>0.05) when compared to SCD patients not on HU. TIMP-2 levels were higher in SCD patients treated with HU (87.62 ± 9.39, n=12) than those observed in control subjects, however this difference was not quite significant (p=0.059). In contrast, MMP-2 and MMP-8 plasma concentrations were not significantly different in SCD individuals compared to controls (P>0.05). Data demonstrate, for the first time, that the level and activity of plasma MMP-9 are significantly increased in SCD, and that these levels are not affected by HU therapy. Importantly, MMP-9 levels correlate with leukocyte counts in SCD, indicating that MMP-9 may be a useful marker for inflammation in SCD.

Th17/Treg Imbalance in Sickle Cell Disease and Hydroxyurea Therapy

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1050-1050
Author(s):  
Simone Gilli ◽  
Fernando V Pericole ◽  
Luis Gustavo Fernandes ◽  
Karina A. R. Ribeiro ◽  
Lilian Castilho ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Peripheral Blood ◽  
Conflicts Of Interest ◽  
Th2 Cells ◽  
Control Group ◽  
Healthy Controls ◽  
Cell Disease ◽  
T Cell Dysfunction ◽  
Th17 Differentiation

Abstract Abstract 1050 Background: Tregs and proinflammatory Th17 cells have been described as two distinct subsets from Th1 and Th2 cells and have opposite effects in autoimmunity and inflammation. Th17/Treg balance controls inflammation and is important in the pathogenesis of autoimmune, infectious and chronic diseases. In view of growing evidence linking sickle cell disease (SS) and chronic inflammation and the potential anti-inflammatory role of Tregs cells, we hypothesized that SS is associated with decreased Treg subpopulation and consequent T cell dysfunction. Furthermore, the effects of hydroxyurea (HU) in this balance are not understood. To assess whether the Th17/Treg balance is impaired in patients with sickle cell disease, we investigated the peripheral blood Th17 and Treg frequencies and the expression of TGFβ1 and RORγT, a master regulator of Th17 differentiation, in sickle cell patients under HU therapy (SS-HU) and without HU (SSw/oHU). Methods. Thirty-eight patients with steady-state sickle cell disease (mean age 43 ± 10.5 yo; range 19–57 yo; 21 female/17 male), 19 SS-HU, 19 SSw/oHU and 20 healthy blood donors were evaluated. Tregs and Th17 quantification was performed by flow cytometry analysis and the expression of TGFβ1 and RORγT by q-PCR. Results. We found significant decrease in the Treg frequency (Foxp3+CD25+CD4+ population) comparing total SS patients and healthy controls (p=0.001) and this difference was more expressive between SS-HU and healthy controls (P=0.0006). Moreover, we found statistically increase of Th17 in SS-HU (p=0.02) and in SSw/oHU (p=0.01), comparing both with healthy controls. The TGFβ1 expression was increased in SS-HU (p=0.04) and SSw/oHU patients (p=0.01) when compared to control group. Interestingly, RORγT expression was significantly elevated only in SSw/oHU vs controls (p=0.03). Conclusion: Our results demonstrated a numerical imbalance of Th17/Treg in the peripheral blood of patients with SS disease. HU has no role mediating Th17/Treg plasticity and even SS patients under HU therapy remains Treg depleted. However, HU is able to modulated RORγT, corroborating the importance of other regulating factors during Th17 differentiation. Moreover, the higher expression of TGFβ1 may be an important positive instructive signal for Th17 differentiation. Th17/Treg imbalance might impact the disease presentation and phenotype and HU therapy may be involved in this issue. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Is there a role for selective vasodilation in the management of sickle cell disease?

Blood ◽  
1988 ◽  
Vol 71 (3) ◽  
pp. 597-602 ◽  
Author(s):  
GP Rodgers ◽  
MS Roy ◽  
CT Noguchi ◽  
AN Schechter
Keyword(s):  
Blood Flow ◽  
Steady State ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Microvascular Obstruction ◽  
Controlled Study ◽  
Control Group ◽  
Cell Disease ◽  
Retinal Arteriolar

Abstract To test the hypothesis that microvascular obstruction to blood flow at the level of the arteriole may be significant in individuals with sickle cell anemia, the ophthalmologic effects of orally administered nifedipine were monitored in 11 steady-state patients. Three patients with evidence of acute peripheral retinal arteriolar occlusion displayed a prompt reperfusion of the involved segment. Two other patients showed fading of retroequatorial red retinal lesions. Color vision performance was improved in six of the nine patients tested. The majority of patients also demonstrated a significant decrease in the amount of blanching of the conjunctiva which reflects improved blood flow to this frequently involved area. Such improvements were not observable in a control group of untreated stable sickle cell subjects. These findings support the hypothesis that inappropriate vasoconstriction or frank vasospasm may be a significant factor in the pathogenesis of the microvascular lesions of sickle cell disease and, further, that selective microvascular entrapment inhibition may offer an additional strategy to the management of this disorder. We believe a larger, placebo-controlled study with nifedipine and similar agents is warranted.

scholarly journals Early Myeloid Derived Suppressor Cells (eMDSCs) Are Associated With High Donor Myeloid Chimerism Following Haploidentical HSCT for Sickle Cell Disease

2021 ◽  
Vol 12 ◽  
Author(s):  
Deepali K. Bhat ◽  
Purevdorj B. Olkhanud ◽  
Arunakumar Gangaplara ◽  
Fayaz Seifuddin ◽  
Mehdi Pirooznia ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Graft Rejection ◽  
Immune Cell ◽  
Plasma Concentrations ◽  
Suppressor Cells ◽  
Suppressor Cell ◽  
Cell Disease ◽  
Hematopoietic Stem ◽  
Post Transplant

Haploidentical hematopoietic stem cell transplantation (haplo-HSCT) is a widely available curative option for patients with sickle cell disease (SCD). Our original non-myeloablative haplo-HSCT trial employing post-transplant (PT) cyclophosphamide had a low incidence of GVHD but had high rejection rates. Here, we aimed to evaluate immune reconstitution following haplo-HSCT and identify cytokines and cells associated with graft rejection/engraftment. 50 cytokines and 10 immune cell subsets were screened using multiplex-ELISA and flow cytometry, respectively, at baseline and PT-Days 30, 60, 100, and 180. We observed the most significant differences in cytokine levels between the engrafted and rejected groups at PT-Day 60, corresponding with clinical findings of secondary graft rejection. Of the 44 cytokines evaluated, plasma concentrations of 19 cytokines were different between the two groups at PT-Day 60. Factor analysis suggested two independent factors. The first factor (IL-17A, IL-10, IL-7, G-CSF, IL-2, MIP-1a, VEGF, and TGFb1 contributed significantly) was strongly associated with engraftment with OR = 2.7 (95%CI of 1.4 to 5.4), whereas the second factor (GROa and IL-18 contributed significantly) was not significantly associated with engraftment. Sufficient donor myeloid chimerism (DMC) is critical for the success of HSCT; here, we evaluated immune cells among high (H) DMC (DMC≥20%) and low (L) DMC (DMC<20%) groups along with engrafted and rejected groups. We found that early myeloid-derived suppressor cell (eMDSC) frequencies were elevated in engrafted patients and patients with HDMC at PT-Day 30 (P< 0.04 & P< 0.003, respectively). 9 of 20 patients were evaluated for the source of eMDSCs. The HDMC group had high mixed chimeric eMDSCs as compared to the LDMC group (P< 0.00001). We found a positive correlation between the frequencies of eMDSCs and Tregs at PT-Day 100 (r=0.72, P <0.0007); eMDSCs at BSL and Tregs at PT-Day 100 (r=0.63, P <0.004). Of 10 immune regulatory cells and 50 cytokines, we observed mixed chimeric eMDSCs and IL-17A, IL-10, IL-7, G-CSF, IL-2, MIP-1a, VEGF, TGFb1 as potential hits which could serve as prognostic markers in predicting allograft outcome towards engraftment following haploidentical HSCT employing post-transplant cyclophosphamide. The current findings need to be replicated and further explored in a larger cohort.

scholarly journals Data on eNOS T786 and G894T polymorphisms and peripheral blood eNOS mRNA levels in Sickle Cell Disease

Data in Brief ◽  
2017 ◽  
Vol 10 ◽  
pp. 192-197 ◽  
Author(s):  
Iakovos Armenis ◽  
Vassiliki Kalotychou ◽  
Revekka Tzanetea ◽  
Panagoula Kollia ◽  
Zoi Kontogeorgiou ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Peripheral Blood ◽  
Mrna Levels ◽  
Cell Disease ◽  
Enos Mrna

scholarly journals TheCCR5Δ32Polymorphism in Brazilian Patients with Sickle Cell Disease

2014 ◽  
Vol 2014 ◽  
pp. 1-4 ◽  
Author(s):  
Mariana Pezzute Lopes ◽  
Magnun Nueldo Nunes Santos ◽  
Eliel Wagner Faber ◽  
Marcos André Cavalcanti Bezerra ◽  
Betânia Lucena Domingues Hatzlhofer ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Statistical Significance ◽  
Population Sample ◽  
Selective Advantage ◽  
Northeastern Brazil ◽  
Control Group ◽  
Cell Disease ◽  
Specific Pcr

Background. Previous studies on the role of inflammation in the pathophysiology of sickle cell disease (SCD) suggested that theCCR5Δ32allele, which is responsible for the production of truncated C-C chemokine receptor type 5 (CCR5), could confer a selective advantage on patients with SCD because it leads to a less efficient Th1 response. We determined the frequency of theCCR5Δ32polymorphism in 795 Afro-Brazilian SCD patients followed up at the Pernambuco Hematology and Hemotherapy Center, in Northeastern Brazil, divided into a pediatric group (3 months–17 years,n=483) and an adult group (18–70 years,n=312). The adult patients were also compared to a healthy control group (blood donors, 18–61 years,n=247).Methods. TheCCR5/CCR5Δ32polymorphism was determined by allele-specific PCR.Results. No homozygous patient for theCCR5Δ32allele was detected. The frequency of heterozygotes in the study population (patients and controls) was 5.8%, in the total SCD patients 5.1%, in the children 5.4%, in the adults with SCD 4.8%, and in the adult controls 8.1%. These differences did not reach statistical significance.Conclusions. Our findings failed to demonstrate an important role of theCCR5Δ32allele in the population sample studied here.

Genomic Instability in Sickle Cell Disease Patients Using Hydroxyurea Assessed by Micronucleus Assay.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3801-3801
Author(s):  
Joao R. Friedrisch ◽  
Sharbel W. Maluf ◽  
Christina M. Bittar ◽  
Maria A. Silva ◽  
Lucia M. Silla
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Micronucleus Assay ◽  
Myeloproliferative Disorders ◽  
Peripheral Blood Lymphocytes ◽  
Control Group ◽  
Cell Disease ◽  
Carcinogenic Potential ◽  
Increased Risk

Abstract Hydroxyurea (HU) is an antineoplastic drug, which also plays an important role in treatment of sickle cell disease patients (SCD). Short-term HU toxicities primarily include transient myelosuppression, but long-term HU risks have not been defined. The mutagenic and carcinogenic potential of HU is not established, although HU has been associated with an increased risk of leukemia in some patients with myeloproliferative disorders. In the present study we analyzed the presence of DNA damage in patients with SCD treated with HU, in peripheral blood lymphocytes, using micronucleus assay. We analyzed 36 patients with SCD (16 males and 20 females), aged 2–59 years (mean 25,75 ± 14,5), received oral HU median dose of 26,5 mg/Kg/day, for a period of 0.6– 11,8 years (mean 5,01). The control group was composed of 34 healthy individuals (16 males and 18 females), aged 4–52 years (mean 26,61 ± 7,20). The results revealed that frequency of micronucleus was significantly higher in SCD patients using HU than in controls(p=0,0182). This study indicates a possible genotoxicity of the HU, although further works are necessary to evaluate its mutagenicity.

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