Tolerogenic Dendritic Cells and T-Regulatory Cells at the Clinical Trials Crossroad for the Treatment of Autoimmune Disease; Emphasis on Type 1 Diabetes Therapy

Brett Eugene Phillips, Yesica Garciafigueroa, Carl Engman, Massimo Trucco, Nick Giannoukakis, Brett Eugene Phillips, Yesica Garciafigueroa, Carl Engman, Massimo Trucco, Nick Giannoukakis

Abstract

Tolerogenic dendritic cells and T-regulatory cells are two immune cell populations with the potential to prevent the onset of clinical stage type 1 diabetes, and manage the beginning of underlying autoimmunity, at the time-at-onset and onwards. Initial phase I trials demonstrated that the administration of a number of these cell populations, generated ex vivo from peripheral blood leukocytes, was safe. Outcomes of some of these trials also suggested some level of autoimmunity regulation, by the increase in the numbers of regulatory cells at different points in a network of immune regulation in vivo. As these cell populations come to the cusp of pivotal phase II efficacy trials, a number of questions still need to be addressed. At least one mechanism of action needs to be verified as operational, and through this mechanism biomarkers predictive of the underlying autoimmunity need to be identified. Efficacy in the regulation of the underlying autoimmunity also need to be monitored. At the same time, the absence of a common phenotype core among the different dendritic cell and T-regulatory cell populations, that have completed phase I and early phase II trials, necessitates a better understanding of what makes these cells tolerogenic, especially if a uniform phenotypic core cannot be identified. Finally, the inter-relationship of tolerogenic dendritic cells and T-regulatory cells for survival, induction, and maintenance of a tolerogenic state that manages the underlying diabetes autoimmunity, raises the possibility to co-administer, or even to serially-administer tolerogenic dendritic cells together with T-regulatory cells as a cellular co-therapy, enabling the best possible outcome. This is currently a knowledge gap that this review aims to address.

Trial registration: ClinicalTrials.gov NCT00445913 NCT02354911.

Keywords: T-regulatory cells; autoimmunity; clinical trials; immunotherapy; tolerogenic dendritic cells; type 1 diabetes.

Figures

Figure 1
Figure 1
A simplified schematic of DC and Treg interactions. (A) immature mDC secrete anti-inflammatory cytokines inhibiting Teff activation and driving Th2 differentiation. Pattern recognition receptor (PPR)-dependent maturation of mDC increase expression of *-labeled molecules required for Teff primary and secondary activation. Changes in cytokine expression profiles further drive Teff activation and tip the Th balance toward Th1 cells. (B) treg can block Teff activation directly or through indirect interactions with mature DC. Treg also preferential sequester the T-cell proliferation factor IL-2 due to high constitutive IL-2R (CD25) expression. (C) pDC/Treg interactions stabilize and convert Teff to Treg populations in lymph nodes under steady state conditions.

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