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Oukka, Mohamed

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Oukka

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Mohamed

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Oukka, Mohamed
Author's Publications: search.filters.isAuthorOfPublication.bc365fa1-78cb-49e1-b175-0a4fa3d648ed

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    Adaptive Autoimmunity and Foxp3-Based Immunoregulation in Zebrafish
    (Public Library of Science, 2010) Quintana, Francisco; Iglesias, Antonio H.; Farez, Mauricio F.; Caccamo, Mario; Burns, Evan J.; Kassam, Nasim; Oukka, Mohamed; Weiner, Howard
    Background: Jawed vertebrates generate their immune-receptor repertoire by a recombinatorial mechanism that has the potential to produce harmful autoreactive lymphocytes. In mammals, peripheral tolerance to self-antigens is enforced by Foxp3+ regulatory T cells. Recombinatorial mechanisms also operate in teleosts, but active immunoregulation is thought to be a late incorporation to the vertebrate lineage. Methods/Principal Findings: Here we report the characterization of adaptive autoimmunity and Foxp3-based immunoregulation in the zebrafish. We found that zebrafish immunization with an homogenate of zebrafish central nervous system (zCNS) triggered CNS inflammation and specific antibodies. We cloned the zebrafish ortholog for mammalian Foxp3 (zFoxp3) which induced a regulatory phenotype on mouse T cells and controlled IL-17 production in zebrafish embryos. Conclusions/Significance: Our findings demonstrate the acquisition of active mechanisms of self-tolerance early in vertebrate evolution, suggesting that active regulatory mechanisms accompany the development of the molecular potential for adaptive autoimmunity. Moreover, they identify the zebrafish as a tool to study the molecular pathways controlling adaptive immunity.
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    Exogenous IFN-γ Ex Vivo Shapes the Alloreactive T-Cell Repertoire by Inhibition of Th17 Responses and Generation of Functional Foxp3+ Regulatory T Cells
    (WILEY-VCH Verlag, 2008) Feng, Gang; Gao, W; Strom, Terry B.; Oukka, Mohamed; Francis, Ross S; Wood, Kathryn J; Bushell, Andrew
    Interferon (IFN)-γ was originally characterized as a pro-inflammatory cytokine with T helper type 1-inducing activity, but subsequent work has demonstrated that mice deficient in IFN-γ or IFN-γ receptor show exacerbated inflammatory responses and accelerated allograft rejection, suggesting that IFN-γ also has important immunoregulatory functions. Here, we demonstrate that ex vivo IFN-γ conditioning of CD4 T cells driven by allogeneic immature dendritic cells (DC) results in the emergence of a Foxp3+ regulatory T-cell (Treg)- dominant population that can prevent allograft rejection. The development of this population involves conversion of non-Treg precursors, preferential induction of activation-induced cell death within the non-Treg population and suppression of Th2 and Th17 responses. The suppressive activity of IFN-γ is dependent on the transcription factor signal transducer and activator of transcription 1 and is mediated by induced nitric oxide. These data indicate not only how IFN-γ could be used to shape beneficial immune responses ex vivo for possible cell therapy but also provide some mechanistic insights that may be relevant to exacerbated inflammatory responses noted in several autoimmune and transplant models with IFN-γ deficiency.