The immune response of stem cells in subretinal transplantation

Abstract

Stem cell transplantation is a potential curative treatment for degenerative diseases of the retina. Among cell injection sites, the subretinal space (SRS) is particularly advantageous as it is maintained as an immune privileged site by the retinal pigment epithelium (RPE) layer. Thus, the success of subretinal transplantation depends on maintenance of RPE integrity. Moreover, both embryonic stem cells (ESCs) and mesenchymal stem cells (MSCs) have negligible immunogenicity and in fact are immunosuppressive. Indeed, many studies have demonstrated that immunosuppressive drugs are not necessary for subretinal transplantation of stem cells if the blood-retinal barrier is not breached during surgery. The immunogenicity of induced pluripotent stem cells (iPSCs) appears more complex, and requires careful study before clinical application. Despite low rates of graft rejection in animal models, survival rates for ESCs, MSCs, and iPSCs in retina are generally poor, possibly due to resident microglia activated by cell transplantation. To improve graft survival in SRS transplantation, damage to the blood-retinal barrier must be minimized using appropriate surgical techniques. In addition, agents that inhibit microglial activation may be required. Finally, immunosuppressants may be required, at least temporarily, until the blood-retinal barrier heals. We review surgical methods and drug regimens to enhance the likelihood of graft survival after SRS transplantation.

Cell-based therapeutic strategies for replacement and preservation in retinal degenerative diseases

“…Once cells are transplanted, one of the main issues from both a biological and therapeutic aspect is the possibility of adverse immune responses to injected cells. While transplanted cell survival rates are generally low, certain measures can guard against loss of cells, such as the use of immunosuppressive agents and maintaining the blood retinal barrier during surgery (Del Priore et al, 2003; Lu et al, 2010; Xian and Huang, 2015). Resident immune cells of the retina, including microglia, can become activated during degeneration and in this heightened immune state may affect the viability of the grafted cells (Barker and Widner, 2004; Karlstetter and Langmann, 2014).…”

Subretinal adipose tissue-derived mesenchymal stem cell implantation in advanced stage retinitis pigmentosa: a phase I clinical safety study

“…Thus, the success of subretinal transplantation depends on maintenance of RPE integrity. Moreover, both ESCs and MSCs have negligible immunogenicity, reducing the chance of rejection [40, 41]. On the other hand, some authors believe that there may be a disruption of the blood-retinal barrier by subretinal injection; the balance of the subretinal microenvironment may be broken and immunosuppression will be necessary until recovery of the barrier.…”

“…On the other hand, some authors believe that there may be a disruption of the blood-retinal barrier by subretinal injection; the balance of the subretinal microenvironment may be broken and immunosuppression will be necessary until recovery of the barrier. There is also some evidence that suppression of the recipient’s immune response will increase the survival rate of transplanted cells [41]. Cyclosporin A is one of the most frequently used immunosuppressive drugs in ophthalmology.…”

Subretinal Cell-Based Therapy

“…It is likely this material will elicit some form of tissue reaction. Activation of microglial cells and/or greater disruption of the blood retinal barrier are undesirable events and so the introduction of material that will need to be cleared from the subretinal space should be avoided if possible 4 .…”