Immunologic Rejection of Transplanted Retinal Pigmented Epithelium: Mechanisms and Strategies for Prevention

Abstract

Replacement of dysfunctional retinal pigmented epithelium (RPE) with grafts derived from stem cells has the potential to improve vision for patients with retinal disorders. In fact, the potential is such that a great number of groups are attempting to realize this therapy through individual strategies with a variety of stem cell products, hosts, immunomodulatory regimen, and techniques to assess the success of their design. Comparing the findings of different investigators is complicated by a number of factors. The immune response varies greatly between xenogeneic and allogeneic transplantation. A unique immunologic environment is created in the subretinal space, the target of RPE grafts. Both functional assessment and imaging techniques used to evaluate transplants are susceptible to erroneous conclusions. Lastly, the pharmacologic regimens used in RPE transplant trials are as numerous and variable as the trials themselves, making it difficult to determine useful results. This review will discuss the causes of these complicating factors, digest the strategies and results from clinical and preclinical studies, and suggest places for improvement in the design of future transplants and investigations.

Systemic immunosuppression promotes survival and integration of subretinally implanted human ESC-derived photoreceptor precursors in dogs

“…Currently, there are no established clinical criteria to define transplant rejection in the SRS ( Petrash et al., 2021 ), although some recognized signs of rejection are those associated with inflammation. These include hazy vitreous, vasculitis, retinal swelling, and retinal detachment ( Petrash et al., 2021 ).…”

“…Currently, there are no established clinical criteria to define transplant rejection in the SRS ( Petrash et al., 2021 ), although some recognized signs of rejection are those associated with inflammation. These include hazy vitreous, vasculitis, retinal swelling, and retinal detachment ( Petrash et al., 2021 ). Here we observed signs compatible with transplant rejection in animals that did not receive systemic IS, as well as in a single dog whose IS treatment was halted.…”

Outer Retinal Cell Replacement: Putting the Pieces Together

“…While the eye is historically considered to be immune-privileged, current evidence suggests that this privilege is relative rather than absolute, and is perhaps lost in the course of disease. 33 Preclinical xenografts require immunodeficient hosts 46 , 146 , 150 , 224 or immunosuppressive regimens, 147 , 160 , 225 but allograft studies and clinical trials to date report conflicting evidence regarding the degree of immune suppression necessary for long-term donor cell survival. Recent studies suggest that the immunogenicity of hPSC-derived retinal tissues may actually be relatively low, and hPSC-derived retinal cells might even confer a degree of local immune suppression.…”

“…Reports from hPSC-RPE clinical trials, which use a variety of immune suppressive regimens, will be highly informative for designing future clinical trials aimed at outer retinal cell replacement. 26 , 33 …”

“…Readers interested in PR rescue are directed to several excellent reviews of RPE replacement 27 , 28 and other approaches including stem/progenitor trophic cell therapies. 29 In addition, recent reviews of biomaterial transfer, 30 outer retinal scaffolds, 31 , 32 immune responses in subretinal cell therapies, 33 PR replacement in rodents, 34 and clinical trials of cell transplantation in RDDs 25 , 26 may aid the reader in gaining a comprehensive understanding of the field.…”