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Long Term Survival of Photoreceptors Transplanted into the Adult Murine Retina Requires Immune Modulation

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From this month’s edition of Stem Cells

By Carla Mellough

One of the limiting factors in the race to replenish ageing, damaged or dysfunctional cells by cell transplantation is the longevity of engrafted replacement cell types within host tissue. Results published in this month’s edition of Stem Cells from the laboratory of Prof. Robin Ali at University College London (UCL)1, indicate a means to overcome this limitation by modulating one of the most common observations following cell transplantation – the innate host immune reaction to grafted cells. The study is focused towards the replacement of the light sensitive photoreceptors that reside within the retina of the eye, a region considered to boast relative immune privilege. The degeneration of this cell type is a feature of numerous hereditary and age-related diseases and a leading cause of untreatable blindness worldwide.

Various animal studies have demonstrated that cells grafted into the subretinal space, adjacent to host photoreceptors, can survive and integrate within the retina. Until recently2 these studies reported the failure of grafted cells to develop the mature photoreceptor morphology necessary for visual transmission, so the lack of definitive evidence for visual improvement was not surprising. A seminal study published in 20062 however, from the same group at UCL, revealed that in a mouse model of retinal degeneration the only donor cells that were capable of integrating to a degree that rendered them indistinguishable from native photoreceptors and which were able to cause an improvement in visual function, were post-mitotic cells already committed to a photoreceptor fate.

Following from their previous work, West et al.1 now examine the long term viability (up to 12 months) of these fully integrated donor cells in the wildtype retina. They show that transplanting donor cells into the eye can yield good engraftment at early stages (up to 2 months), but that over time a significant loss of grafted cells occurs. They go on to determine the immune contribution at short (1 month) and long-term (4 months) post-transplant periods and report the differential distribution of macrophages and T cells. Macrophages were found surrounding the transplanted tissue at early stages, but these persisted in the subretinal space even in the absence of the transplanted cell mass at 4 months. T cells were present in the retina, subretina and choroid near the transplant at 1 month and remained near integrated donor cells at the later stage, suggesting an adaptive immune response against donor cells. The authors demonstrate that the substantial loss of cells with time occurs not as a result of an immune response against the GFP reporter gene used to mark grafted cells, but instead due to a systemic antigen-specific immune response against donor cells. Treatment with the immune-suppressant Cyclosporine A (CsA) did not affect the survival integrated cells at the early stage (at which time acute early cell loss remained significantly negatively associated with the extent of macrophage infiltration, an acute inflammatory response unaffected by CsA treatment), but had a significant effect on the number of integrated donor cells at 4 months. At this time, immune-suppressed recipients retained approximately four-fold the number of integrated cells compared with untreated hosts, in which 90% of engrafted cells had been lost. In half of immune-suppressed graft recipients a similar number of integrated cells were found over the early and late stages, indicating that appropriately integrated, non-autologous cells can survive long-term if the T cell-mediated immune response is controlled.

This paper has particular relevance for the long term reconstitution of tissues using non-autologous cell sources, such as human embryonic stem cells, and provides some insight into the mechanisms affecting the long term survival of grafted cells. As the authors point out, a partial mismatch of H-2 haplotypes existed between grafted tissue and recipients in this study, and is likely to have contributed to the observations of this paper. Clearly, the investigation of long term graft survival in haplotype-matched tissues is of great interest as this has implications for the behaviour of MHC class matched tissue in humans, for example, the transplantation of replacement cell types derived from patient-specific induced pluripotent stem cells. Further, in this study photoreceptor precursors were transplanted into healthy eyes containing a full complement of photoreceptors. It will be interesting to compare this work with similar studies performed using models of retinal degeneration where the photoreceptor population has been depleted.

Read this article in the November edition of Stem Cells.

 

References

1. West EL, Pearson RA, Barker SE, Luhmann UF, Maclaren RE, Barber AC, Duran Y, Smith AJ, Sowden JC, Ali RR. Long Term Survival of Photoreceptors Transplanted into the Adult Murine Neural Retina Requires Immune Modulation. Stem Cells. 2010;28(11):1997-2007.

2. MacLaren RE, Pearson RA, MacNeil A, Douglas RH, Salt TE, Akimoto M, Swaroop A, Sowden JC, Ali RR. Retinal repair by transplantation of photoreceptor precursors. Nature. 2006;444(7116):203-7.