Tolerising cellular therapies: what is their promise for autoimmune disease?

Abstract

The current management of autoimmunity involves the administration of immunosuppressive drugs coupled to symptomatic and functional interventions such as anti-inflammatory therapies and hormone replacement. Given the chronic nature of autoimmunity, however, the ideal therapeutic strategy would be to reinduce self-tolerance before significant tissue damage has accrued. Defects in, or defective regulation of, key immune cells such as regulatory T cells have been documented in several types of human autoimmunity. Consequently, it has been suggested that the administration of ex vivo generated, tolerogenic immune cell populations could provide a tractable therapeutic strategy. Several potentially tolerogenic cellular therapies have been developed in recent years; concurrent advances in cell manufacturing technologies promise scalable, affordable interventions if safety and efficacy can be demonstrated. These therapies include mesenchymal stromal cells, tolerogenic dendritic cells and regulatory T cells. Each has advantages and disadvantages, particularly in terms of the requirement for a bespoke versus an 'off-the-shelf' treatment but also their suitability in particular clinical scenarios. In this review, we examine the current evidence for these three types of cellular therapy, in the context of a broader discussion around potential development pathway(s) and their likely future role. A brief overview of preclinical data is followed by a comprehensive discussion of human data.

Keywords: Cellular therapies; Crohn’s disease; TR1 cells; autoimmune thyroiditis; graft versus host disease; mesenchymal stromal cells; multiple sclerosis; myasthenia gravis; regulatory T-cells; rheumatoid arthritis; systemic lupus erythematosus; tolerogenic dendritic cells; type 1 diabetes.

Figure 1

A schematic representation of the mechanisms of action of tolerogenic cells. MSCs promote the differentiation and survival of Tregs and tolDC. Tregs and tolDC, on the other hand, enjoy a mutual bidirectional positive interaction with each other. Tregs and MSCs inhibit the actions of B cells, effector T cells, macrophages and neutrophils through cell-cell contact (eg, Fas:Fas Ligand (FasL) mediated deletion), and various soluble factors such as TGF-β, IDO, PGE2, IL-10, IL-6, and sHLA-G5. MSCs also act through extracellular vesicles. TolDC directly inhibit effector T cells through various mechanisms. These include: cell-cell ligand-receptor mediated deletion, for example, Fas: FASL, PD-L1 and PD-L2 on tolDC and PD-1 receptors on effector T cells; effector T cell anergy secondary to low expression of co-stimulatory molecules CD80/CD86, CD40 and pro-inflammatory cytokines (TNF, IL-12, IL-21 and IL-16) by tolDC. Other mechanisms include soluble anti-inflammatory cytokines such as IL-10, IL-4 and TGF-β.TolDC directly promote Tregs and so indirectly inhibit other immunogenic cells through Tregs. Mechanisms include soluble factors such as IL-10, IDO, TGF-β and TSLP and cell-cell interaction between CTLA-4 and CD80/86. This interaction, in turn, leads to transendocytosis of CD80/86 and further tolerogenic phenotypic ‘reinforcement’ of tolDC. Tregs also promote tolDC via IL-10 and TGF-β. CTLA-4, cytotoxic T-lymphocyte associated protein 4; IDO, indoleamine-2,3-dioxygenase; IL, interleukin; MSCs, mesenchymal stromal cells; PDL, programmed death ligand; PGE2, prostaglandin E2; sHLA, soluble human leucocyte antigen; TGF-β, transforming growth factor beta; tolDC, tolerogenic dendritic cells; TSLP, thymic stromal lymphopoietin.

Figure 2

Preparation and administration of tolerogenic cellular therapies. This figure describes the process of cellular therapy manufacture and administration. Sources of substrate cells include autologous or allogeneic umbilical cord tissue, bone marrow aspirate and lipo-aspirate for mesenchymal stromal cells and autologous whole blood for expanded regulatory T cells and tolerogenic dendritic cells. Mononuclear cells are usually extracted by density gradient centrifugation of whole blood, bone marrow aspirate and digested tissue (lipo-aspirate and umbilical cord tissue) or by leukapheresis (whole blood). Mononuclear cells are then cultured in the appropriate media and culture conditions for the requisite duration or number of passages. Harvested cells can be administered immediately through various routes (subcutaneous, intravenous, intralesional and intrathecal) or cryopreserved for future use.