References of "Humblet, Stéphanie"
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See detailLoss of T cell microRNA provides systemic protection against autoimmune pathology in mice
Tian, L.; De Hertogh, G.; Fedeli, M. et al

in Journal of Autoimmunity (2012)

With an increasing number of studies demonstrating alterations in T cell microRNA expression during autoimmune disease, modulation of the T cell microRNA network is considered a potential therapeutic ... [more ▼]

With an increasing number of studies demonstrating alterations in T cell microRNA expression during autoimmune disease, modulation of the T cell microRNA network is considered a potential therapeutic strategy. Due to the complex and often opposing interactions of individual microRNA, prioritization of therapeutic targets first requires dissecting the dominant effects of the T cell microRNA network. Initial results utilizing a unidirectional screen suggested that the tolerogenic functions were dominanat, with spontaneous colitis resulting from T cell-specific excision of Dicer. Here we performed a bidirectional screen for microRNA function by removing Dicer from the T cells of both wildtype mice and Transforming Growth Factor β (TGFβ) receptor-deficient mice. This allowed the impact of microRNA loss on T cell activation, effector T cell differentiation and autoimmune pathology to be systematically assessed. This bidirectional screen revealed a dominant immunogenic functionfor T cell microRNA, with potent suppression of T cell activation, IFNγ production and autoimmune pathology in all targeted organs except the colon, where Dicer-dependent microRNA demonstrated a dominant tolerogenic function. These results reverse the original conclusions of microRNA function in T cells by revealing a systemic pro-autoimmune function. [less ▲]

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See detailRegulatory T cells fulfil their promise ?
Humblet, Stéphanie ULg; Baron, Frédéric ULg; Liston, Adrian

in Immunology & Cell Biology (2011)

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See detailDevelopment of B-lineage predominant lentiviral vectors for use in genetic therapies for B cell disorders
Sather, B. D.; Ryu, B. Y.; Stirling, B. V. et al

in Molecular Therapy : The Journal of the American Society of Gene Therapy (2011), 19(3), 515-25

Sustained, targeted, high-level transgene expression in primary B lymphocytes may be useful for gene therapy in B cell disorders. We developed several candidate B-lineage predominant self-inactivating ... [more ▼]

Sustained, targeted, high-level transgene expression in primary B lymphocytes may be useful for gene therapy in B cell disorders. We developed several candidate B-lineage predominant self-inactivating lentiviral vectors (LC) containing alternative enhancer/promoter elements including : the immunoglobulin β (Igβ) promoter combined with the immunoglobulin µ enhancer (EµB29); and the endogenous BTK promoter with or without Eµ (EµBtkp or Btkp). LV-driven enhanced green fluorescent protein (eGFP) reporter expression was evaluated in cell lines and primary cells derived from human or murine hematopoietic stem cells (HSC). In murine primary cells, eµB29 and EµBtkp LV-mediated high-level expression in immature and mature B cells compared with all other lineages. Expression increased with B cell maturation and was maintained in peripheral subsets. Expression in T and myeloid cells was much lower in percentage and intensity. Similarly, both EµB29 and EµBtkp LV exhibited high-level activity in human primary B cells. In contrast to EµB29, Btkp and EµBtkp LV also exhibited modest actiity in myeloid cells, consistent with the expression profile of endogenous Bruton's tyrosine kinase (Btk). Notably, EµB29 end EµBtkp activity was superior in all expression models to an alternative, B-lineage targeted vector containing the EµS.CD19 enhancer/promoter. In summary, EµB29 and EµBtkp LV comprise efficient delivery platforms for gene expression in B-lineage cells. [less ▲]

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See detailB cell-specific lentiviral gene therapy leads to sustained B-cell functional recovery in a murine model of X-linked agammaglobulinemia
Kerns, H. M.; Ryu, B. Y.; Stirling, B. V. et al

in Blood (2010), 115(11), 2146-55

The immunodeficiency disorder, X-linked agammaglobulinemia (XLA), results from mutations in the gene encoding Bruton tyrosine kinase (Btk). Btk is required for pre-B cell clonal expansion and B-cell ... [more ▼]

The immunodeficiency disorder, X-linked agammaglobulinemia (XLA), results from mutations in the gene encoding Bruton tyrosine kinase (Btk). Btk is required for pre-B cell clonal expansion and B-cell antigen receptor signaling. XLA patients lack mature B cells and immunoglobulin and experience recurrent bacterial infections only partially mitigated by life-long antibody replacement therapy. In pursuit of definitive therapy for XLA, we tested ex vivo gene therapy using a lentiviral vector (LV) containing the immunoglobulin enhancer (Eµ) and IgB (B29) minimal promoter to drive B lineage-specific human Btk expression in Btk/Teck-/- mice, a strain that reproduces the features of human XLA. After transplantation of EµB29-Btk-LV-transduced stem cells, treated mice showed significant, albeit incomplete, rescue of mature B cells in the bone marrow, peripheral blood, spleen, and peritoneal cavity, and improved responses to T-independent and T-dependent antigens. LV-teated B cells exhibited enhanced B-cell antigen receptor signaling and an in vivo selective advantage in the peripheral versus central B-cell compartment. Secondary transplantation showed sustained Btk expression, viral integration, and partial functional responses, consistent with long-term stem cell marking; and serial transplantation revealed no evidence for cellular or systemic toxicity. These findings strongly support pursuit of B lineage-targeted LV gene therapy in human XLA. [less ▲]

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See detailWiskott-Aldrich syndrome protein deficiency in B cells results in impaired peripheral homeostasis
Meyer-Bahlburg, A.; Becker-Herman, S.; Humblet, Stéphanie ULg et al

in Blood (2008), 112(10), 4158-69

To more precisely identify the B-cell phenotype in Wiskott-Aldrich syndrome (WAS), we used 3 distinct murine in vivo models to define the cell intrinsic requirements for WAS protein (WASp) in central ... [more ▼]

To more precisely identify the B-cell phenotype in Wiskott-Aldrich syndrome (WAS), we used 3 distinct murine in vivo models to define the cell intrinsic requirements for WAS protein (WASp) in central versus peripheral B-cell development. Whereas WASp is dispensable for early bone marrow B-cell development, WASp deficiency results in a marked reduction in each of the major mature peripheral B-cell subsets, exerting the greatest impact on marginal zone and B1a B cells. Using in vivo bromodeoxyuridine labeling and in vitro funtcional assays, we show that these dificits reflect altered peripheral homeostasis, partially resulting from an impairment in integrin function, rather than a developmental defect. Consistent with these observations, we also show that : (1) WASp expression levels increase with cell maturaity, peaking in those subsets exhibiting the greatest sensitivity to WASp deficiency; (2) WASp+ murine B cells exhibit a marked selective advantage beginning at the late transitional B-cell stage; and (3) a similar in vivo selective advantage is manifest by mature WASp+ human B cells. Together, our data provide a better understanding of the clinical phenotype of WAS and suggest that gene therapy might be a useful approach to rescue altered B-cell homeostasis in this disease. [less ▲]

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See detailWiskott-Aldrich syndrome protein is required for regulatory T cell homeostasis
Humblet, Stéphanie ULg; Sather, B.; Anover, S. et al

in Journal of Clinical Investigation (2007), 117(2), 407-18

Wiskott-Aldrich syndrome protein (WASp) is essential for optimal T cell activation. Patients with WAS exhibit both immunodeficiency and a marked susceptibility to systemic autoimmunity. We investigated ... [more ▼]

Wiskott-Aldrich syndrome protein (WASp) is essential for optimal T cell activation. Patients with WAS exhibit both immunodeficiency and a marked susceptibility to systemic autoimmunity. We investigated whether alterations in Treg function might explain these paradoxial observations. While WASp-deficient (WASp-/-) mice exibited normal thymic Treg generation, the competitive fitness of peripheral Tregs was severely compromised. The total percentage of forkhead box P3-positive (Foxp3+) Tregs among CD4+T cells was reduced, and WASp-/- Tregs were rapidly outcompeted by WASp+ Tregs in vivo. These findings correlated with reduced expression of markers associated with self-antigen-driven peripheral Treg activation and homing to inflamed tissue. Consistent with these findings, WASp-/- Tregs showed a reduced ability to control aberrant T cell activation and autoimmune pathology in Foxp3-/- Scurfy (sf) mice. Finally, WASp+ Treg exhibited a marked selective advantage in vivo in a WAS patient with a spontaneous revertant mutation, indicating that altered Treg fitness likely explains the autoimmune features in human WAS. [less ▲]

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See detailSustained correction of B-cell development and function in a murine model of X-linked agammaglobulinemia (XLA) using retroviral-mediated gene transfer
Yu, P. W.; Tabuchi, R. S.; Kato, R. M. et al

in Blood (2004), 104(5), 1281-90

X-linked agammaglobulinemia (XLA) is a human immunodeficiency caused by mutations in Bruton tyrosine kinase (Btk) and characterized by an arrest in early B-cell development, near absence of serum ... [more ▼]

X-linked agammaglobulinemia (XLA) is a human immunodeficiency caused by mutations in Bruton tyrosine kinase (Btk) and characterized by an arrest in early B-cell development, near absence of serum immunoglobulin, and recurrent bacteria infections. Using Btk- and Tec-deficient mice (BtkTec-/-) as a model for XLA, we determined if Btk gene therapy could correct this disorder. Bone marrow (BM) from 5-fluorouracil (5FU)-treated BtkTec-/- mice was transduced with a retroviral vector expressing human Btk and transplanted into BtkTec-/- recipients. Mice engrafted with transduced hematopoietic cells exhibited rescue of both primary and peripheral B-lineage development, revocery of peritoneal B1 B cells, and correction of serum immunoglobulin M (IgM) and IgG3 levels. Gene transfer also restored T-independent type II immune responses, and B-cell antigen receptor (BCR) proliferative responses. B-cell progenitors derived from Btk-transduced stem cells exhibited higher levels of Btk expression than non-B cells; and marking studies demonstrated a selective advantage for Btk-transduced B-lineage cells. BM derived from primary recipients also rescued Btk-dependent function in secondary hosts that had received a transplant. Together, these data demonstrate that gene transfer into hematopoietic stem cells can reconstitute Btk-dependent B-cell development and function in vivo, and strongly support the feasibility of pursuing Btk gene transfer for XLA. [less ▲]

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