Approaches to Establishing Tolerance in Immune Mediated Diseases

Abstract

The development of rational approaches to restore immune tolerance requires an iterative approach that builds on past success and utilizes new mechanistic insights into immune-mediated pathologies. This article will review concepts that have evolved from the clinical trial experience of the Immune Tolerance Network, with an emphasis on lessons learned from the innovative mechanistic studies conducted for these trials and new strategies under development for induction of tolerance.

Keywords: allergy; autoimmunity; clinical trial; immune tolerance; immunomodulation; immunosuppression; transplantation.

Figure 1

Conceptual parallels between the approach to autoimmunity and allergy tolerance trials, using examples from T1D and from peanut allergy. Identification of early at-risk children allows for prevention strategies that rely on antigen exposure in the context of immune deviation or anergy. After initial antigen sensitization, however, additional measures are required to blunt effector responses to inhibit immune amplification events. Failing this, determinant spreading elicits robust immunity that recruits additional effector pathways and conditions inflammatory innate tissue responses, now requiring combinations of targeted therapeutics to ‘reset’ the immunological threshold and enable an opportunity to reestablish homeostatic balance between regulatory and effector pathways. Recognition of these differences requires appropriate staging and monitoring in order to select therapeutic options with tolerogenic potential.

Figure 2

A conceptual framework for induction and maintenance of immune tolerance. Tolerogenic therapies that focus on boosting regulatory immune responses face daunting hurdles in the form of established immunological memory and robust redundant effector activation pathways, involving both adaptive and innate immunity. Creating a host environment conducive to regulation is augmented by first inducing clinical remission and decreasing tissue inflammation. This concept creates a practical platform for combination therapies in which short-term immunosuppressive or immunomodulatory interventions are first employed, followed by emphasis on restoration of immune regulation.