Prospects for therapeutic tolerance in humans

Abstract

Purpose of review: To provide an overview of recent advances and future possibilities for therapeutic tolerance.

Recent findings: Allograft survival despite complete immunosuppressant withdrawal has been demonstrated in selected renal-transplant recipients with haematopoietic chimerism. Early clinical trials of mesenchymal stromal cell therapy have shown promising results in several autoimmune diseases. Regulatory T cells show potential benefit in graft versus host disease, although challenges to ex-vivo expansion remain. Targeted modulation of T-cell function in vivo with monoclonal antibodies has shown beneficial effects in phase II/III trials of multiple sclerosis (alemtuzumab) and type I diabetes mellitus (teplizumab, otelixizumab). Emerging data from animal models suggest an important role for the commensal microbiome in the maintenance and disruption of immune tolerance with parallels in human studies.

Summary: After years of slow progress, recent research has reduced the translational gap between animal models and clinical therapeutic tolerance. Early detection of autoimmunity, potentially at preclinical stages, offers a window of opportunity for tolerogenic therapy. Reliable biomarkers of tolerance are urgently needed to provide objective measurements of the effectiveness of tolerogenic therapies, and to allow intelligent immunosuppressant withdrawal in patients whose autoimmune disease is stable.

Video abstract available: See the Video Supplementary Digital Content 1 (http://links.lww.com/COR/A8).

Figure 1

Overview of central and peripheral tolerance mechanisms. Thymocytes are produced by the bone marrow from early foetal life and travel to the thymus for maturation. In the thymus, promiscuous expression of self-antigens from a range of tissue types (mediated by the AIRE gene) and affinity-based mechanisms result in deletion of autoreactive T cells and the generation of regulatory T-cells. In the periphery, further deletion and anergy can occur if T cells encounter antigen in the absence of sufficient co-stimulatory “danger” signals. Furthermore, unwanted autoreactivity can be directly suppressed by regulatory T-cells (dominant regulation).

Figure 2

Approaches to therapeutic tolerance induction.