Activation of the aryl hydrocarbon receptor promotes allograft-specific tolerance through direct and dendritic cell–mediated effects on regulatory T cells

Abstract

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...

Harnessing Nanoparticles for Immune Modulation

“…Using similar particles, although loaded with PLP 139-151 , the authors also showed that subcutaneous injection could reduce the incidence of EAE; however, unlike intravenous infusion, protection was not 100% [5,94]. Another strategy that focuses on altering DC phenotype is the administration of NPs that agonize the ligand-activated transcription factor aryl hydrocarbon receptor [7,[95][96][97]. The activation of aryl hydrocarbon receptor on DCs supports their differentiation into tolerogenic APCs, which supports the expansion of Tregs [95][96][97].…”

“…Another strategy that focuses on altering DC phenotype is the administration of NPs that agonize the ligand-activated transcription factor aryl hydrocarbon receptor [7,[95][96][97]. The activation of aryl hydrocarbon receptor on DCs supports their differentiation into tolerogenic APCs, which supports the expansion of Tregs [95][96][97]. Using the MOG or PLP EAE model, pegylated gold NPs loaded with the aryl hydrocarbon receptor agonist 2-(1′H-indole-3′-carbonyl)-thiazole-4-carboxylic acid methyl ester and MOG or PLP were tested for their ability to ameliorate disease [7].…”

Nanoparticle-mediated codelivery of myelin antigen and a tolerogenic small molecule suppresses experimental autoimmune encephalomyelitis

“…AhR activation with the nontoxic mucosal ligand 2-(1′H-indole-3′-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE) expands Tregs and suppresses EAE (11). We (11) and others (13)(14)(15) showed that the generation of Tregs by AhR ligands involves the induction of tolerogenic dendritic cells (DCs). Indeed, the activation of AhR signaling in DCs by ITE or other ligands induces DCs that promote FoxP3 + Treg differentiation (11,(13)(14)(15).…”

Impact of environmental factors on alloimmunity and transplant fate

“…TCDD administration also prolonged graft survival in a fully allogeneic MHC-mismatched cardiac transplant model (89). In a murine islet cell transplant model, oral administration of VAG539, a pro-agent that is converted to the AHR ligand VAF347, led to long-term graft acceptance in 69% of recipients (90). Furthermore, VAG539-induced tolerance was transferable by the adoptive transfer of CD11c + cells isolated from treated recipients.…”