Therapeutic potential of tolerogenic dendritic cells in IBD: from animal models to clinical application

Abstract

The gut mucosa undergoes continuous antigenic exposure from food antigens, commensal flora derived ligands, and pathogens. This constant stimulation results in controlled inflammatory responses that are effectively suppressed by multiple factors. This tight regulation, necessary to maintain intestinal homeostasis, is affected during inflammatory bowel diseases (IBD) resulting in altered immune responses to harmless microorganisms. Dendritic cells (DCs) are sentinels of immunity, located in peripheral and lymphoid tissues, which are essential for homeostasis of T cell-dependent immune responses. The expression of a particular set of pathogen recognition receptors allows DCs to initiate immune responses. However, in the absence of danger signals, different DC subsets can induce active tolerance by inducing regulatory T cells (Treg), inhibiting inflammatory T helper cell responses, or both. Interestingly, several protocols to generate clinical grade tolerogenic DC (tol-DCs) in vitro have been described, opening the possibility to restore the intestinal homeostasis to bacterial flora by cellular therapy. In this review, we discuss different DC subsets and their role in IBD. Additionally, we will review preclinical studies performed in animal models while describing recent characterization of tol-DCs from Crohn's disease patients for clinical application.

Figure 1

Summary of different mechanisms to induce tolerance by DCs; Treg and Tr1 cells generation, suppression of T effector cells, inhibition of proliferation, apoptosis induction, T cell anergy, and hyporesponsiveness.

Figure 2

General scheme: dendritic cell therapy for Crohn's disease patients. Isolated monocytes are cultured and differentiated into DCs by adding IL-4 and GM-CSF to the media. At day 3, addition of dexamethasone induces the tolerogenic profile, and at day 6, addition of the maturation cytokine cocktail potentiates the tolerogenic properties.