Functional characterization of CD4+ T cells in aplastic anemia

Kordasti, Shahram; Marsh, Judith; Al-Khan, Sufyan; Jiang, Jie; Smith, Alexander E.; Mohamedali, Azim; Abellan, Pilar Perez; Veen, Caroline; Costantini, Benedetta; Kulasekararaj, Austin; Benson-Quarm, Nana; Seidl, Thomas; Mian, Syed A; Farzaneh, Farzin; Mufti, Ghulam J.

doi:10.1182/blood-2011-08-368308

Cited by 147 publications

(139 citation statements)

References 46 publications

Supporting

Mentioning

125

Contrasting

Unclassified

Order By: Relevance

“…Total RNA was isolated from total mononuclear cells, using a combination of TriZOL reagent (Invitrogen, Carlsbad, CA, USA) to lyse the cells and RNAeasy Mini prep (Qiagen, Venlo, The Netherlands) to purify the RNA, as previously described (Kordasti et al, 2012). The quantity and integrity of RNA was evaluated by measuring the absorbance at 260 nm with a Nanodrop ND8000 (Labtech, Uckfield, Sussex, UK) and bioanalyser (Agilent, Santa Clara, CA, USA).…”

Section: Rna Isolation and Quantitative Real-time Pcrmentioning

confidence: 99%

TP53 mutations in myelodysplastic syndrome are strongly correlated with aberrations of chromosome 5, and correlate with adverse prognosis

et al. 2013

Self Cite

View full text Add to dashboard Cite

SummaryThis study aimed to determine the incidence/prognostic impact of TP53 mutation in 318 myelodysplastic syndrome (MDS) patients, and to correlate the changes to cytogenetics, single nucleotide polymorphism array karyotyping and clinical outcome. The median age was 65 years (17-89 years) and median follow-up was 45 months [95% confidence interval (CI) 27-62 months]. TP53 mutations occurred in 30 (9Á4%) patients, exclusively in isolated del5q (19%) and complex karyotype (CK) with -5/5q-(72%), correlated with International Prognostic Scoring System intermediate-2/high, TP53 protein expression, higher blast count and leukaemic progression. Patients with mutant TP53 had a paucity of mutations in other genes implicated in myeloid malignancies. Median overall survival of patients with TP53 mutation was shorter than wild-type (9 versus 66 months, P < 0Á001) and it retained significance in multivariable model (Hazard Ratio 3Á8, 95% CI 2Á3-6Á3,P < 0Á001). None of the sequentially analysed samples showed a disappearance of the mutant clone or emergence of new clones, suggesting an early occurrence of TP53 mutations. A reduction in mutant clone correlated with response to 5-azacitidine, however clones increased in nonresponders and persisted at relapse. The adverse impact of TP53 persists after adjustment for cytogenetic risk and is of practical importance in evaluating prognosis. The relatively common occurrence of these mutations in two different prognostic spectrums of MDS, i.e. isolated 5q-and CK with -5/5q-, possibly implies two different mechanistic roles for TP53 protein.

show abstract

Section: Rna Isolation and Quantitative Real-time Pcrmentioning

confidence: 99%

TP53 mutations in myelodysplastic syndrome are strongly correlated with aberrations of chromosome 5, and correlate with adverse prognosis

et al. 2013

Self Cite

View full text Add to dashboard Cite

show abstract

“…The response to IST suggests an autoimmune mechanism (11), with the involvement of deficient regulatory T cells (Treg). Recently, it has been shown that Treg counts are reduced at diagnosis (12)(13)(14)(15). Furthermore, Treg have been suggested as a prognostic factor for response to IST (16).…”

Section: Introductionmentioning

confidence: 99%

Model-Based Determination of Effective Blood Concentrations of Cyclosporine for Neutrophil Response in the Treatment of Severe Aplastic Anemia in Children

Philippe

Hénin

Bertrand

et al. 2015

AAPS J

View full text Add to dashboard Cite

Abstract. Optimal immunosuppressive therapy in acquired severe aplastic anemia (SAA) remains to be refined, especially cyclosporine (CsA) use. Current recommendations state that CsA trough blood concentrations (TBC) should be maintained between 200 and 400 ng/mL despite the lack of supporting data. This study aimed at quantifying relationships between CsA exposure and neutrophil response and determining an effective range for CsA TBC. Twenty-three SAA patients treated with CsA were retrospectively analyzed. Nonlinear mixed effect modeling approaches were used to develop a pharmacokinetic-pharmacodynamic model. The pharmacokinetic model described the relationships between CsA doses and TBC. The pharmacodynamic model allowed to estimate boundaries for optimal CsA effects, neutrophils being used as biomarker of response. A time-to-event model linked effective concentration to time-to-therapeutic success. CsA TBC were adequately described by a twocompartment model with first-order absorption, a lag time, and a linear elimination. The efficient range of CsA TBC was estimated between 87 and 120 ng/mL. Model-based simulations and external validation in three additional patients confirmed these results. This original modeling approach was successful in describing the relationship between CsA TBC and neutrophil response in SAA patients. Although further evaluation of the model is necessary, this work suggests that an optimal CsA TBC target of 100 ng/mL would be associated with a better neutrophil response in children with SAA.

show abstract

“…2 In acquired SAA, there is absolute and functional deficiency of regulatory T cells. 3,4 The best evidence for an immune pathogenesis is provided by the response to immune suppressive therapy (IST) with antithymocyte globulin (ATG) and cyclosporine. IST with ATG and cyclosporine is currently used as first-line treatment for children with SAA who do not have a matched sibling donor for bone-marrow transplantation.…”

mentioning

confidence: 99%

Immune suppression for childhood acquired aplastic anemia and myelodysplastic syndrome: where next?

2014

View full text Add to dashboard Cite

Functional characterization of CD4+ T cells in aplastic anemia

Cited by 147 publications

References 46 publications

TP53 mutations in myelodysplastic syndrome are strongly correlated with aberrations of chromosome 5, and correlate with adverse prognosis

TP53 mutations in myelodysplastic syndrome are strongly correlated with aberrations of chromosome 5, and correlate with adverse prognosis

Model-Based Determination of Effective Blood Concentrations of Cyclosporine for Neutrophil Response in the Treatment of Severe Aplastic Anemia in Children

Immune suppression for childhood acquired aplastic anemia and myelodysplastic syndrome: where next?

Contact Info

Product

Resources

About