Deficient CD4+ CD25+ FOXP3+ T regulatory cells in acquired aplastic anemia

Solomou, Elena E.; Rezvani, Katayoun; Mielke, Stephan; Malide, Daniela; Keyvanfar, Keyvan; Visconte, Valeria; Kajigaya, Sachiko; Barrett, A. John; Young, Neal S.

doi:10.1182/blood-2007-01-066258

Cited by 193 publications

(165 citation statements)

References 22 publications

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“…The above data along with T reg kinetics in stable and progressive disease and after reduction of tumor burden by chemotherapy would suggest that alterations in the dynamics and function of T regs could be a parameter determining disease progression; study of more patients will be needed to establish whether this indeed is the case. Analogous to our findings in E-MDS patients, T reg deficiency has also been reported in idiopathic aplastic anemia, 48 further supporting a shared and overlapping pathogenesis between the two disorders. In addition, as in L-MDS, an expansion of functionally normal T regs is observed in patients with acute leukemia, 35 providing further evidence for a link between T reg -mediated immunomodulation and malignant hematopoiesis.…”

Section: Discussionsupporting

confidence: 74%

Kinetics, function and bone marrow trafficking of CD4+CD25+FOXP3+ regulatory T cells in myelodysplastic syndromes (MDS)

et al. 2008

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CD4 þ CD25 þ FOXP3 þ T regulatory cells (T regs ) prevent autoimmunity by restricting overexuberant immune responses, but the same subpopulation can incur detrimental effects on antitumor responses. In both cases, the suppressor potential of T regs appears to be strongly influenced by their compartmentalization. In myelodysplastic syndromes (MDS), immune deregulation and autoimmunity in the early stages might lead to ineffective hematopoiesis and bone marrow (BM) failure, whereas late-stage disease is characterized by the immune escape of the malignant clone. We show that these two stages of MDS are associated with differential T reg activity. Specifically, we found that in early stage MDS, compared with normal hematopoiesis and late stage MDS, T regs are dysfunctional and their BM homing through the CXCL12/CXCR4 axis is seriously impaired as a result of CXCR4 downregulation. Conversely, in late stage MDS, T regs are systemically and locally expanded and retain their function and migratory capacity. Moreover, T reg levels follow the disease course and are significantly reduced in treatment responding patients. Our findings indicate T reg involvement in the pathophysiology of MDS; defective suppressor function and BM trafficking of T regs may be important in the autoimmune process of early MDS, but increased T reg activity could favor leukemic clone progression in late stage disease.

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Section: Discussionsupporting

confidence: 74%

Kinetics, function and bone marrow trafficking of CD4+CD25+FOXP3+ regulatory T cells in myelodysplastic syndromes (MDS)

et al. 2008

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“…It has been shown that a T-lymphocyte subpopulation, Treg, is involved as in many other autoimmune diseases. Solomou et al (12) have shown that the number of Treg was decreased in patients with aplastic anemia. More recently, Sutton et al (16) demonstrated that Treg were a good prognostic factor for response and severity of aplastic anemia.…”

Section: Application To New Patientsmentioning

confidence: 99%

“…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

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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.

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“…A fourcolour protocol was used. ) /TCRa/b+ populations were identified by using the appropriate gates (Solomou et al, 2007).…”

Section: Foxp3 Enumeration and Dn-t-cell Enumerationmentioning

confidence: 99%

Double‐negative regulatory T cells induce allotolerance when expanded after allogeneic haematopoietic stem cell transplantation

McIver¹,

Serio²,

Dunbar³

et al. 2008

Br J Haematol

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SummaryDouble-negative (DN) regulatory T cells (Tregs) are specialized T lymphocytes involved in the down-modulation of immune responses, resulting in allotolerance after allogeneic haematopoietic stem cell transplantation (HSCT). Most of the properties of DN Tregs were identified in murine models, including the unique ability to suppress alloreactive syngeneic effector T cells in an antigen-specific manner via Fas/ Fas-ligand interactions. We investigated the behaviour of DN Tregs following human allogeneic HSCT with regard to occurrence of graft-versus-host disease (GvHD) and restoration of T-cell receptor repertoire in a cohort of 40 patients. The frequency of DN Tregs and CD4/CD8 TCR repertoire was measured serially and at the time of diagnosis of GvHD by flow cytometry. Analysis demonstrated a positive correlation between degree of alloreactivity, as measured by grade of GvHD, and the number of variable beta chain (Vb) family expansions in both T-cell populations. We also found that a deficiency of DN Tregs was associated with an increased number of Vb family expansions, and most importantly, with the occurrence of GvHD. All individuals who demonstrated more than 1% DN Tregs did not develop GvHD, providing evidence that DN Tregs participate in peripheral tolerance to prevent GvHD when expanded after allogeneic HSCT.

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Deficient CD4+ CD25+ FOXP3+ T regulatory cells in acquired aplastic anemia

Cited by 193 publications

References 22 publications

Kinetics, function and bone marrow trafficking of CD4+CD25+FOXP3+ regulatory T cells in myelodysplastic syndromes (MDS)

Kinetics, function and bone marrow trafficking of CD4+CD25+FOXP3+ regulatory T cells in myelodysplastic syndromes (MDS)

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

Double‐negative regulatory T cells induce allotolerance when expanded after allogeneic haematopoietic stem cell transplantation

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