A view of the future of regulatory immune cell therapy in organ transplantation

On the basis of extensive preclinical research [1–3], there is currently great interest in the potential of specific regulatory immune cell populations for the therapy of organ allograft rejection and the promotion of clinical transplant tolerance. Indeed, clinical trials to assess feasibility, safety and preliminary efficacy of diverse regulatory immune cell populations, that include regulatory T cells (Treg), regulatory myeloid cells (regulatory dendritic cells and macrophages), mesenchymal stromal cells and facilitating cells (that enhance donor hematopoietic cell chimerism) have been instigated in Europe, North America and Asia [4–7]. However, many questions need to be addressed and numerous hurdles need to be overcome if the promise of regulatory immune cell therapy is to be realized [5,8–10]. In this section of Current Opinion in Organ Transplantation, seven articles written by opinion leaders critically review the most recent advances in the field and provide a view of what the future of regulatory immune cell therapy may look like in clinical organ transplantation. Looking towards the future for regulatory T cell (Treg) therapy, Sicard et al. (University of British Columbia, Vancouver, Canada) (pp. 509–515) examine the wave of exciting recent innovations that could be used to overcome current limitations and enhance the antigen (Ag) specificity, stability, function and potential of therapeutic Treg. As they discuss, these approaches include the generation of Ag-specific Treg by genetic modification of polyclonal Treg to express designated T-cell receptors or single-chain chimeric Ag receptors (CAR). Importantly, human Treg expressing allospecific CAR have been shown recently to potently suppress effector T cells in humanized mice. In addition, CRISPR/Cas 9 technology is currently enabling the modification of Treg to make them safer, more stable and long-lived. The authors also discuss the use of third party Treg as a novel approach to develop better-standardized and more accessible therapeutic Treg. In a complementary article written by Vaikunthanathan et al. (King's College London, UK) (pp. 516–523) the authors discuss approaches to optimizing and personalizing the isolation of Treg and their ex-vivo expansion, including the use of mechanistic target of rapamycin (mTOR) inhibitors, all-trans retinoic acid (ATRA), histone deacetylase inhibitors and tumor necrosis factor receptor (TNFR) agonists that increase and stabilize forkhead box p3 (Foxp3) expression. They also address the functional specialization of Treg subsets and the untoward consequences of loss of Foxp3 expression in these subsets, as may occur in a pro-inflammatory environment such as exists in the early posttransplant period. Epigenome editing to promote stable Foxp3 transcription may provide a means to circumvent this limitation. The insertion of suicide genes that act as ‘safety switches’ is also discussed in the context of preventing potential adverse events that may result from the proliferation of genetically modified Treg. Regulatory B cells (Breg) are potent regulators of innate and adaptive immune responses and promote allograft tolerance in rodents. Moreover, patients that develop transplant tolerance have higher frequencies of Breg. However, the absence of a specific phenotype, together with poor understanding of their development and how they exert their regulatory function in vivo has hampered progress in the field. Mohib et al. (University of Pittsburgh, Pittsburgh, USA) (pp. 524–532) discuss the phenotypic markers used to identify murine and human Breg, their induction, maintenance and mechanisms of immune suppression. The authors also highlight recent advances in the in-vitro expansion of Breg, understanding of the influence of immunosuppressive agents on their induction and frequency and the use of Breg defined by their cytokine expression as biomarkers to predict organ allograft rejection. Ex-vivo-generated regulatory innate immune cells (regulatory myeloid cells) are also under evaluation as cellular therapeutic agents for the control of rejection and the promotion of organ transplant tolerance in the clinic. Riquelme and Hutchinson (University of Regensburg, Germany) (pp. 533–537) discuss newly identified mechanisms by which human monocyte-derived regulatory macrophages (Mreg) convert naïve human CD4+ T cells into distinct, IL-10-producing, Foxp3+ Treg that control T-cell-mediated alloimmunity. Their most recent work has focussed on TIGIT+ (T-cell immunoreceptor with Ig and ITIM domains+) induced (i)Treg elicited by human Mreg via mediators that include transforming growth factor β (TGFβ), retinoic acid, indoleamine deoxygenase (IDO), notch and progestogen-associated endometrial protein. Moreover, intravenous infusion of allogeneic Mreg in kidney transplant patients leads to the enrichment of circulating TIGIT+ iTreg. Regulatory dendritic cells (DCreg) have been shown to be highly effective in prolonging organ allograft survival and in promoting transplant tolerance in rodents, whereas their safety and efficacy has been demonstrated in clinically relevant nonhuman primate organ transplantation. Thomson and Ezzelarab (University of Pittsburgh, Pittsburgh, USA) (pp. 538–545) discuss innovative approaches to enhancing dendritic cell tolerogenicity in situ, optimizing the ex-vivo generation of DCreg and the initial testing of DCreg of donor or recipient origin in clinical organ transplantation. Recent ‘omics’ studies are better defining the molecules that enhance the tolerogenic phenotype, stability and longevity of DCreg and their resistance to pro-inflammatory stimuli. It appears that the distinct properties of DCreg result from a specific transcriptional program characterized by the activation of tolerance-enhancing genes. In ‘spontaneous’ liver transplant tolerance in mice, the acquisition of donor MHC gene products via microvesicles (exosomes) by host antigen-presenting cells may be important in expression of immune regulatory function by these cells. Facilitating cells promote hematopoietic stem cell (HSC) engraftment in allogeneic recipients and this function has recently been exploited in the development of chimerism-based approaches to the induction of transplant tolerance in clinical renal transplantation. Chhabra and Ildstad (University of Louisville, Louisville, USA) (pp. 546–551) discuss the heterogeneity of mouse and human facilitating cells, the ability of mouse facilitating cells to enhance clonogenicity, survival and homing of HSC and underlying mechanisms, including the induction of Treg. A gene product that appears to be critical for murine CD8+TCR− graft facilitating cells to home to the hematopoietic niche/enhance HSC engraftment is DOCK2 (dedicator of cytokinesis 2), a protein involved in regulation of lymphocyte migration. Infusion of donor apoptotic cells (dendritic cells or splenocytes) has been shown to exert profound immunomodulatory effects, including the induction of tolerogenic dendritic cells and Treg and to promote donor-specific tolerance in various cell (pancreatic islet and HSC) and organ transplant models. Furthermore, recent clinical trials have demonstrated the safety and potential efficacy of this approach in suppressing acute graft-versus-host disease following HSC transplantation. Dangi et al. (Northwestern University, Chicago, USA) (pp. 552–558) describe how host prior allosensitization and opportunistic infection can antagonize the induction of tolerance by donor apoptotic cells. They also discuss strategies to overcome these potential hurdles and control memory responses and promote tolerance in the context of clinical transplantation. Acknowledgements None. Financial support and sponsorship None. Conflicts of interest There are no conflicts of interest.

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