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.

Highlights

  • Retinal diseases with degeneration or dystrophy of photoreceptors are visually devastating and there are no current therapies to regenerate retinal tissue

  • This review will primarily focus on studies involving transplantation of retinal pigmented epithelium (RPE) derived from embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) as they have the greatest potential as graft tissue

  • As evidence for this approach, when MHC-matched macaque-iPSC-RPE was transplanted in the subretinal space (SRS) of allogeneic hosts, grafts survived without immune suppressants for 6 months and were associated with no development of donor specific antibody (DSA), reactive PBMCs, or infiltration of inflammatory cells compared to MHC-mismatched controls [33]

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Summary

INTRODUCTION

Retinal diseases with degeneration or dystrophy of photoreceptors are visually devastating and there are no current therapies to regenerate retinal tissue. This review will primarily focus on studies involving transplantation of RPE derived from ESCs and iPSCs as they have the greatest potential as graft tissue. The “immune privilege” of the eye is not what it was once hoped; features of the subretinal space (SRS) create a relatively safe target for transplantation of iPSCs [12]. Both stem cells and RPE are attributed with antiinflammatory properties that enhance compatibility [13, 14]. Stem cell derived RPE is susceptible to immune rejection from days to months following transplantation [15,16,17]. New directions will be discussed, and specific strategies proposed to prevent rejection of RPE transplants in future trials

SECTION I: TRANSPLANT IMMUNOLOGY
SECTION II: SUB-RETINAL IMMUNE RESPONSE AND PRIVILEGE
SECTION III: EVALUATING REJECTION AND LACK OF REJECTION
SECTION IV: PREVENTING REJECTION OF RPE GRAFTS
Findings
DISCUSSION
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