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VAF347 is a low-molecular-weight compound, which activates the aryl hydrocarbon receptor (AhR). Herein, we report that oral administration of a water-soluble derivative of VAF347 (VAG539) IntroductionDendritic cells (DCs) induce and regulate adaptive immune responses by presenting antigens in an immunogenic or tolerogenic context. [1][2][3] The capacity of DCs to induce specific effector functions in naive T cells designates them as attractive means to stimulate beneficial and suppress detrimental immune responses. [4][5][6] However, specific in vivo modulation of DC function is a complex task because DCs encounter and respond to numerous stimuli, and may modify their function accordingly. 7 Various factors have been suggested to render DCs tolerogenic by enhancing their capacity to promote the induction and/or activation of regulatory T (Tr) cells. 3,6,8,9 Antigen presentation in the absence of costimulation can result in clonal deletion, or in the induction of an anergic and suppressive T-cell phenotype. 10 Indeed, both in human tissue culture and in mice, DCs have been shown to expand IL-10-producing type 1 (Tr1) regulatory T (Tr) cells. 5,11,12 Furthermore, specific DC subsets, such as plasmacytoid DCs and CD8 ϩ splenic DCs, have been shown to selectively expand CD4 ϩ CD25 ϩ Tr cells. [13][14][15][16] Recent evidence also suggests that LPS-activated mature DCs are capable of expanding CD4 ϩ CD25 ϩ Tr cells as well. 3,17 Conversely, in inflammatory conditions, DCs present antigens to effector T cells in the context of proinflammatory cytokines and costimulatory surface molecules, and initiate adaptive immune responses by promoting activation and proliferation of antigen-specific naive T cells. 1,4 In the context of organ transplantation, it has been demonstrated that activated DCs indeed initiate immune responses toward allogeneic antigens, which result in allograft rejection. 18 However, the nature of the maturation signal that activates DCs to initiate an allogeneic immune response remains unclear. 19,20 Several preclinical strategies for the prevention of allograft rejection target DCs, in an attempt to abrogate costimulation and T-cell activation, and to promote the expansion of alloantigenspecific Tr cells. [21][22][23] Islet transplantation offers patients with type 1 diabetes mellitus freedom from long-term insulin therapy and a degree of metabolic control that is far superior to injected insulin. 24 However, the therapeutic efficacy of this strategy is compromised by the necessity to use robust immunosuppressive regimens to prevent islet allograft rejection. 25,26 Therefore, a significant amount of research effort is presently dedicated to the development of novel strategies for the induction of islet donor-specific tolerance. 27 VAF347 is a low-molecular-weight compound that has been shown to modify immune responses through a dual mode of action, namely inhibition of DC-mediated T-cell proliferation and cytokine production and isotype-specific inhibition of IgE class switching by human B lymphocytes...

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Wiskott-Aldrich Syndrome (WAS) is a life-threatening X-linked disease characterized by immunodeficiency, thrombocytopenia, autoimmunity, and malignancies. Gene therapy could represent a therapeutic option for patients lacking a suitable bone marrow (BM) donor. In this study, we analyzed the long-term outcome of WAS gene therapy mediated by a clinically compatible lentiviral vector (LV) in a large cohort of was(null) mice. We demonstrated stable and full donor engraftment and Wiskott-Aldrich Syndrome protein (WASP) expression in various hematopoietic lineages, up to 12 months after gene therapy. Importantly, we observed a selective advantage for T and B lymphocytes expressing transgenic WASP. T-cell receptor (TCR)-driven T-cell activation, as well as B-cell's ability to migrate in response to CXCL13, was fully restored. Safety was evaluated throughout the long-term follow-up of primary and secondary recipients of WAS gene therapy. WAS gene therapy did not affect the lifespan of treated animals. Both hematopoietic and nonhematopoietic tumors arose, but we excluded the association with gene therapy in all cases. Demonstration of long-term efficacy and safety of WAS gene therapy mediated by a clinically applicable LV is a key step toward the implementation of a gene therapy clinical trial for WAS.