Induction of Antigen-Specific Tolerance in T Cell Mediated Diseases

Abstract

The development of novel approaches to control unwanted immune responses represents an ambitious goal in the management of a number of clinical conditions, including autoimmunity, autoinflammatory diseases, allergies and replacement therapies, in which the T cell response to self or non-harmful antigens threatens the physiological function of tissues and organs. Current treatments for these conditions rely on the use of non-specific immunosuppressive agents and supportive therapies, which may efficiently dampen inflammation and compensate for organ dysfunction, but they require lifelong treatments not devoid of side effects. These limitations induced researchers to undertake the development of definitive and specific solutions to these disorders: the underlying principle of the novel approaches relies on the idea that empowering the tolerogenic arm of the immune system would restore the immune homeostasis and control the disease. Researchers effort resulted in the development of cell-free strategies, including gene vaccination, protein-based approaches and nanoparticles, and an increasing number of clinical trials tested the ability of adoptive transfer of regulatory cells, including T and myeloid cells. Here we will provide an overview of the most promising approaches currently under development, and we will discuss their potential advantages and limitations. The field is teaching us that the success of these strategies depends primarily on our ability to dampen antigen-specific responses without impairing protective immunity, and to manipulate directly or indirectly the immunomodulatory properties of antigen presenting cells, the ultimate in vivo mediators of tolerance.

Keywords: antigen-specific; autoimmunity; cell therapy; dendritic cells; immunomodulation; tolerance.

Figure 1

Strategies to induce Ag-specific tolerance in T cell mediated diseases. Approaches under development include: inverse vaccination with autoantigen-encoding DNA or viral vectors; in vivo administration of whole Ags, unmodified peptides or altered peptide ligads (APLs); autoantigen-loaded vehicles; transfer of polyclonal or Ag-specific Tregs or of tolerogenic DC loaded with disease-relevant Ags.

Figure 2

Mechanism of DC-mediated tolerance. Tolerogenic (Tol)DC promote deletion or modulate Teff cells via Fas/FasL interaction [1], starvation of Teff cells via IDO production that degrades tryptophan (L-Trp) into kynurenine (Kyn) [2]. IDO is induced by the interaction between CD80/CD86 on tolDC and CTLA-4 on regulatory T cell (FOXP3 Treg), which concur to the suppression of Teff cells [3]. The interaction of inhibitory molecules on tolDC and Teff cells in the presence of IL-10 secretion promotes T cell anergy [4]. TolDC favor the activation and expansion of pre-existing Tregs [5] of de novo induction of FOXP3 Treg of Tr1 cells [6]. Finally, surface expression of inhibitory molecules and secretion of regulatory mediators promote the conversion of resident APCs into tolerogenic APCs, which sustain tolerance [7]. Teff, effector T cells; CTLA-4, cytotoxic T-lymphocyte antigen-4; IDO, indoleamine 2,3-dioxygenase; L-Trp, L-tryptophan, Kyn, kynurenins; Fas, first apoptosis signal; FasL, Fas ligand.