Adoptive Transfer of Regulatory Immune Cells in Organ Transplantation

Abstract

Chronic graft rejection remains a significant barrier to solid organ transplantation as a treatment for end-organ failure. Patients receiving organ transplants typically require systemic immunosuppression in the form of pharmacological immunosuppressants for the duration of their lives, leaving these patients vulnerable to opportunistic infections, malignancies, and other use-restricting side-effects. In recent years, a substantial amount of research has focused on the use of cell-based therapies for the induction of graft tolerance. Inducing or adoptively transferring regulatory cell types, including regulatory T cells, myeloid-derived suppressor cells, and IL-10 secreting B cells, has the potential to produce graft-specific tolerance in transplant recipients. Significant progress has been made in the optimization of these cell-based therapeutic strategies as our understanding of their underlying mechanisms increases and new immunoengineering technologies become more widely available. Still, many questions remain to be answered regarding optimal cell types to use, appropriate dosage and timing, and adjuvant therapies. In this review, we summarize what is known about the cellular mechanisms that underly the current cell-based therapies being developed for the prevention of allograft rejection, the different strategies being explored to optimize these therapies, and all of the completed and ongoing clinical trials involving these therapies.

Keywords: IL-10-producing B cells Bregs; chimeric antigen receptor; graft rejection; immunoengineering; myeloid derived suppressive cells; regulatory T cells; solid organ transplant; transplantation.

Figure 1

The immune environment surrounding a transplanted organ. 1) CTLA-4-CD80/86 interaction between Tregs and APCs resulting in increased tryptophan metabolism by APCs via IDO-dependent pathway. 2) LAG-3 and TIGIT on Tregs directing APCs towards a more tolerogenic phenotype. 3) Treg consumption of IL-2. 4) CD39 and CD73 acting as ectonucleotidases to break down ATP and 5’AMP to adenosine. 5) Tregs suppressing effector T cells via CTLA-4-CD80/86 interaction. 6) Tregs secreting anti-inflammatory cytokines to reduce the pro-inflammatory response, induce apoptosis of effector T cells, and promote the expansion of regulatory cell types. 7) MDSCs suppressing effector T cell, B cell, and NK cell proliferation via consumption of L-arginine in an iNOS dependent pathway. This mechanism is enhanced but upregulation of Arg-1 and HO-1 by MDSCs. 8) IL-10 and TGF-b secreted by MDSCs promoting the activation of Tregs. 9) CCL5 secreted by MDSCs establishing a graft-to-periphery gradient to recruit Tregs. 10) MDSCs promoting the suppressive function of Tregs via interaction between PD-L1 and PD-1. 11) IL-10 secreted by B10 cells promoting expansion of Tregs and exerting a broad array of anti-inflammatory effects. 12) Tregs inducing apoptosis of autoreactive B cells via interaction of PD-1 expressed on Tregs with PD-L1 on B cells.