98th Annual Meeting DOG 2000

V 772

The effect of oral tolerance on RPE xenograft survival in RCS rats

S. Grisanti, P. Esser, N. Kociok, T. Luther, J. Jordan, K. U. Bartz-Schmidt

Introduction: Successful engraftment of retinal pigment epithelial (RPE) cells in treating RPE-related retinopathies will depend, at least in part, on controlling the immune response. The present study evaluates the potential of oral tolerance in preventing immunological rejection of RPE xenografts in Royal College of Surgeons (RCS) rats.

Methods: Freshly isolated adult porcine RPE cells were used as xenografts and implanted when recipients were between 17 to 21 days old. Xenografts were implanted orthotopically in the subretinal space and heterotopically in the anterior chamber and subcutis of RCS rats. The extent of photoreceptor rescue by subretinal transplants was determined by counting the maximum layers of surviving photoreceptor nuclei in the histological sections. The immune response was evaluated by histochemistry. Oral tolerance was induced by pre- and postoperative oral administration of porcine RPE.

Results: Subretinal xenografts were able to induce a dramatic rescue effect compared to non- or sham-injected eyes. However, the effect was not absolute and complete deficiency of the Outer nuclear layer (ONL) occured 2 months later. Despite the quiescent appearance of subretinal transplants, both xenografts in the anterior chamber and subcutaneous tissue displayed an inflammatory cellular infiltration with the highest intensity 2-4 weeks after transplantation. Oral immunization induced a remarkable tolerance such as inflammatory infiltration in heterotopic transplants was suppressed. ONL in orally immunized animals persisted for 6 months compared to 3 months in unfed hosts.

Conclusion: RPE xenografts in subcutaneous space and in the anterior chamber are rejected by a delayed but vigorous inflammatory cellular infiltration. Subretinal RPE xenografts are protected from a strong cellular rejection, but undergo a slow functional deterioration, reflected by a decline in their ability to rescue adjacent photoreceptors. Induction of oral tolerance suppresses cellular infiltration of heterotopic grafts and prolongs retinal survival induced by orthotopic RPE transplants.

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