Neuroretinal xenotransplantation to immunocompetent hosts in a discordant species combination

Abstract

In spite of its immune privileged state, xenotransplantation within the CNS is associated with rapid graft destruction in immunocompetent hosts. Efforts to enhance graft survival have mostly focused on host immune response, whereas relatively little attention has been paid to donor tissue characteristics. In the present paper, we explore long-term survival of xenogeneic full-thickness neuroretinal transplants in immunocompetent hosts and investigate the significance of tissue integrity in relation to graft survival.Adult rabbits receiving no immunosuppression were used as hosts and fetal Sprague-Dowley rat neuroretina as donors. Using vitreoretinal surgical techniques, rabbits received either a full thickness or a fragmented neuroretinal graft to the subretinal space of one eye. Eyes receiving full-thickness grafts were examined morphologically after 91 days and fragmented grafts after 7-14 days.Surviving full thickness grafts were found in 6 out of 8 eyes, 4 of which displayed the normal laminated appearance. Major Histocompatibility Complex (MHC) up-regulation in surviving grafts was minimal and they contained a well organized photoreceptor layer, Protein Kinase C (PKC) labeled rod bipolar cells, parvalbumin labeled AII amacrine cells and glial fibrillary acidic protein (GFAP) labeled Müller cells. Fragmented grafts (n=6) were all destroyed or showed severe signs of rejection. A mass of inflammatory cells derived from the choroid was evident in these specimens, and no labeling of retina-specific cells were seen.We conclude that full-thickness rat neuroretina can survive for several months after subretinal transplantation to the subretinal space of immunocompetent rabbits, while fragmented counterparts are rapidly rejected. Surviving full-thickness grafts can develop many of the normal retinal morphological characteristics, indicating a thriving relationship between the initially immature donor tissue and its foreign host. Our results strongly indicates that donor tissue integrity is a crucial factor for graft survival in CNS xenotransplantation.

Immune privilege of allogeneic neuroretinal transplants in the subconjunctival space

“…If we add to this the possibility of enhanced exposure of conventional transplantation and retina-restricted antigens in fragmented donor tissue, acute rejection of such grafts is hardly surprising [6]. In accordance with our earlier reports on transplantation to the SRS [11,16], donor tissue integrity appears to be an important factor for survival of neuroretinal grafts also in non-immune privileged sites.…”

“…We have here shown that the fullthickness neuroretina enjoys only partial immune privilege, and that this privilege is related to donor age. These results together with previous findings that neuroretinal immune privilege also depends on donor tissue integrity [11,16], and that the immune privilege of the SRS is most likely not complete [3,28], indicate that any strategy to transplant neuroretina should include efforts to keep the donor tissue intact and to minimize disturbance of the SRS. The fact that survival of neuroretinal grafts is related to donor age, tissue integrity, and the immune-privileged state of the recipient site, these important points may help us avoid unnecessary pitfalls when devising strategies and therapies for curing retinal degenerative disease.…”

“…Recently we also found that 50% of subretinal full-thickness grafts survive xenogeneic transplantation (rat-to-rabbit) without immunosuppression [11]. These results are encouraging, but the fact that not all full-thickness grafts survive in the SRS, indicates that the immune privileged state of the intact donor tissue may be incomplete.…”

Exogenous Glutamate Modulates Porcine Retinal Development in vitro

“…The removal of inner retinal layers to isolate photoreceptors has been attempted for more than 2 decades by enzymatic and mechanical disruption [2,32,35]. However, grafts achieved with these techniques have not yet been shown to achieve robust organization, survival or integration after transplantation, possibly because of pretransplantation cell death, Müller cell trauma and an increased immunogenicity [2,36,37,38,39,40]. To overcome these complications, the isolation of specific cell types and the removal of others by modulating retinal development in vitro may offer a more attractive alternative, since disruption of vital cell-to-cell contacts is avoided [4,41,42,43].…”

Delivery strategies for treatment of age-related ocular diseases: From a biological understanding to biomaterial solutions

“…One reason for this is the problem of anoikis, an apoptotic cascade initiated by lack of cell anchorage [197,198]. This is supported by the observation that RPE cells transplanted as a whole sheet survive better than as a suspension [199,200]. An additional contributing factor to cell death is the hostility of the micro-environment, which includes the presence of apoptotic signals, inflammatory cells, and damage to the surrounding architecture [146,201,202].…”