Prospective Clinical Testing of Regulatory Dendritic Cells in Organ Transplantation

Abstract

Dendritic cells (DC) are rare, professional antigen-presenting cells with ability to induce or regulate alloimmune responses. Regulatory DC (DCreg) with potential to down-modulate acute and chronic inflammatory conditions that occur in organ transplantation can be generated in vitro under a variety of conditions. Here, we provide a rationale for evaluation of DCreg therapy in clinical organ transplantation with the goal of promoting sustained, donor-specific hyporesponsiveness, while lowering the incidence and severity of rejection and reducing patients' dependence on anti-rejection drugs. Generation of donor- or recipient-derived DCreg that suppress T cell responses and prolong transplant survival in rodents or non-human primates has been well-described. Recently, good manufacturing practice (GMP)-grade DCreg have been produced at our Institution for prospective use in human organ transplantation. We briefly review experience of regulatory immune therapy in organ transplantation and describe our experience generating and characterizing human monocyte-derived DCreg. We propose a phase I/II safety study in which the influence of donor-derived DCreg combined with conventional immunosuppression on subclinical and clinical rejection and host alloimmune responses will be examined in detail.

Keywords: dendritic cells; immune regulation; renal transplantation.

Figure 1

DCreg infusion enhances programed death (PD)-1 and cytotoxic T lymphocyte antigen-4 (CTLA4) expression by donor-reactive CD4⁺Tmem in renal allograft recipient monkeys. Incidences of PD1⁺ CTLA4⁺ populations in ex vivo-stimulated CD95⁺CD4⁺Tmem from representative control and DCreg-treated monkeys (n = 4 monkeys analyzed/group). Recipient PBMC obtained 28 days after transplantation, were co-cultured with either donor or third party stimulators (T cell-depleted PBMC) for 5 days before flow cytometric analysis. The enhanced incidence of PD1⁺CTLA4⁺Tmem in response to donor, but not third party stimulation suggests selective attenuation (exhaustion) of donor-reactive Tmem. According to Ezzelarab et al. (25), Figure 5.

Figure 2

Generation of DCreg from elutriated blood monocytes of the prospective renal allograft donor in GM-CSF, VitD3, and IL-10, and infusion of the validated cell product into the graft recipient 7 days before transplant.