Local and systemic immune responses associated with rejection of iPS-derived RPE allografts transplanted into rhesus macaques.

Abstract

Purpose : To determine the viability of allogeneic iPS-derived RPE cells transplanted into the subretinal space of rhesus macaques, and to examine the resulting local and systemic immune response.

Methods : GFP-labelled allogeneic iPS-derived RPE cells were transplanted into the subretinal space of one eye of 4 monkeys, followed by transplantation into the contralateral eye 4-5 weeks later. No immunosuppression was used. Retinas were examined pre- and post-surgery by color fundus photography, fundus autofluorescence, and OCT imaging. Peripheral blood mononuclear cells were monitored weekly for changes in frequency of circulating naïve and memory T- and B-cell subsets. Animals were sacrificed 3 weeks following the second transplantation and retinas were examined morphologically and immunohistochemically.

Results : Ophthalmic imaging revealed successful delivery of the cells in all eyes. In general, GFP fluorescence faded to nonvisible levels by ~3 weeks post-transplantation in the first eye, and by ~2 weeks post-transplantation in the second eye. In all eyes, infiltration of mononuclear cells into the choroid and subretinal space resulted in ablation of grafted cells and disruption of host RPE and choroid in the immediate vicinity of the graft. In one animal, a few residual transplanted cells were observed in the center of a bolus of mononuclear cells. The mononuclear cells stained positively primarily for B-cell and T-cell antibodies. Microglial cell activation was evident in all cell-transplanted eyes. All animals showed systemic immune activation; T and B cell proliferation increased 2- to 3-fold starting ~14 days after the initial surgery, often accompanied by increased frequency of memory T and B cells.

Conclusions : Our data demonstrate that transplantation of allogeneic iPS-derived RPE cells into the subretinal space without immune suppression induces an immune response that could compromise survival of the cells, and this response is accelerated after injection in the second eye. Similar results were observed after allogeneic embryonic-derived RPE transplantation into the same species (Neuringer et al ARVO, 2014). These findings have important implications for clinical application of cell-based therapy, underscoring the need for evaluation of autologous cell sources and/or adequate T- and B-cell immune-suppression to ensure graft survival.

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.