A Strategy for Personalized Treatment of iPS-Retinal Immune Rejections Assessed in Cynomolgus Monkey Models

Abstract

Recently, we successfully transplanted an autograft, or major histocompatibility complex (MHC)-matched allografts, from induced-pluripotent-stem-cell-derived retinal pigment epithelial (iPSC-RPE) cells in patients with age-related macular degeneration. However, there was an issue regarding immune rejection after transplantation. In this study, we established a preoperational in vitro “drug–lymphocytes–grafts immune reaction (Drug-LGIR)” test to determine the medication for immune rejection using host immunocompetent cells (lymphocytes) and transplant cells (target iPSC-RPE cells) together with different medications. The adequacy of the test was assessed by in vivo transplantation in monkey models together with medication based on in vitro data. In the results of Drug-LGIR tests, some drugs exhibited significant suppression of RPE cell-related allogeneic reactions, while other drugs did not, and the efficacy of each drug differed among the recipient monkeys. Based on the results of Drug-LGIR, we applied cyclosporine A or local steroid (triamcinolone) therapy to two monkeys, and successfully suppressed RPE-related immune rejections with RPE grafts, which survived without any signs of rejection under drug administration. We propose that our new preoperational in vitro Drug-LGIR test, which specifies the most efficacious medication for each recipient, is useful for controlling immune attacks with personalized treatment for each patient after retinal transplantation.

Capacity of Retinal Ganglion Cells Derived from Human Induced Pluripotent Stem Cells to Suppress T-Cells

“…Immune rejection occurs after allogeneic transplantation of iPSC-RPEs in vivo, despite the fact that the transplant iPSC-RPEs are capable of inhibiting T-cell activity and the transplantation site, the sub-retinal space, is an environment less prone to inflammation as well as the vitreous [54][55][56]. We also reported that immune rejection occurs in one of five age-related macular degeneration patients after allogeneic transplantation of iPSC-RPEs [10].…”

“…Furthermore, transplantation of iPSC-RGCs may be less invasive than the iPSC-RPE transplantation technique. Specifically, transplantation of iPSC-RPEs requires a needle to be injected into the sub-retina [56,57], whereas transplantation of iPSC-RGCs requires only an injection into the vitreous cavity [17][18][19][20][21]. We believe that a minimally invasive procedure would reduce the risk of postoperative inflammation and easily prevent the enhancement of immunogenicity.…”

A ROCK Inhibitor Promotes Graft Survival during Transplantation of iPS-Cell-Derived Retinal Cells

“…We also had similar results with our MLR in the presence of Y-27632 (Supplementary Figure S2). Moreover, in our lab, we established the lymphocytes-grafts immune reaction (LGIR) test to measure immune rejection in vitro by using host immunocompetent cells (mainly lymphocytes) and transplant cells (target iPS-RPE cells) [24][25][26][27][28]. With this system, we have demonstrated that T cells proliferate when MHCs are mismatched between the donor and recipient.…”

Dynamics of Cyclooxygenase-1 Positive Microglia/Macrophage in the Retina of Pathological Model Mice as a Biomarker of the Retinal Inflammatory Diseases

“…As leakage from peripheral retinal blood vessels provides an indication for the evaluation and management of anterior uveitis [ 45 ] and tuberculous posterior uveitis [ 46 ], the importance of evaluating the peripheral retina in uveitis has been recognized. Recently, we showed Iba1-positive cells (microglia/macrophages) invading into the retina and the choroid after retinal pigment epithelial cell–transplantation in mice [ 47 , 48 , 49 ]. Moreover, after transplantation of retinal pigment epithelial cell allografts in patients with age-related macular degeneration, an increase in CD11b-positive cells (monocytes/macrophages) in the blood was shown; one patient suffered from immune rejection [ 50 ].…”