Tuesday, April 20, 2010

What is Tissue Sourcing

Organs and cells of animal origin are being considered as a source of tissue for xenotransplantation. If islet transplantation is to become a widespread treatment for type 1 diabetics, solutions must be found for increasing the availability of insulin-producing tissue and for overcoming the need for continuous immunosuppression. Insulin-producing cells being considered for clinical transplantation include porcine and bovine islets, fish-Brockman bodies, genetically engineered insulin-secreting cell lines and in vitro produced “human” beta-cells.

Both primary tissue and cultured cell lines have been employed in small animal xenotransplantation, including cells that have been genetically modified. Substantial efforts have also been made in the isolation of primary tissue, especially for pancreatic islets, though further improvements are necessary for practical, large-scale processing. The most urgent problem in transplantation is the shortage of donor organs and tissue.

Xenotransplantation could offer some advantages over the use of human organs. Xenotransplantation could be planned in advance, the organ would be transplanted while it was still fresh and undamaged. In addition, a planned transplantation allows the administration of therapeutic regimens that call for the pretreatment of the recipient. Another advantage is the possibility that animal sources could be genetically engineered in order to lower the risk of rejection by expressing specific genes for the benefit of the patient. However, the concern over retroviruses has led to political moratoriums on the clinical use of xenotransplantation. It has yet to be established in nonrodent models as a viable alternative.

Alternative Tissue Sources

The optimal source of xenogeneic islets remains controversial. Islets have been isolated from primates and xenografted into immunosuppressed, diabetic rodents, with short-term reversal of diabetes. However, there are ethical issues surrounding the use of primates for these studies. Other promising islet sources are porcine, bovine and rabbit islets, all of which function remarkably well in diabetic rodents. Long-term human, bovine and porcine islet xenograft survival has been documented in nude mice and rats, suggesting that, in the absence of an immune response, sufficient islet-specific growth factors are present in xenogeneic recipients.

Porcine islets are at present receiving the greatest attention since pigs produce an insulin which is structurally very similar to human insulin and pigs are, on the other hand, the only large animals slaughtered in sufficient quantities to supply the estimated demand from type 1 diabetics. In addition, porcine islets within microcapsules have been reported to correct diabetes in cynomologus monkeys. Elaborate studies are in progress to engineer a “perfect pig”, having adequate levels of complement-inhibiting factors. Thus, porcine sources are

perhaps most likely to provide islets for an inaugural human xeno-islet trial. However, porcine islets are fragile and have poor long-term stability. The in vitro glucose-stimulated insulin secretion rate per unit islet volume appears to be substantially smaller for porcine islets than for other species including human. Lastly, there is significant current concern regarding the potential for transmission of infectious agents from porcine organ sources to human xenograft recipients, and to the population at large. None of these characteristics bode well for their practical large-scale use, and serious consideration and investigation is being given to alternate animal sources. There is also speculation that neonatal porcine islets, which culture better and present minimal infrastructure problems, would be an ultimate substitute. Isolation of bovine islets is technically easier and calf islets are glucose-responsive. However, adult bovine islets are relatively insensitive to glucose. The rabbit pancreas is also an attractive source of islets since rabbit insulin differs from human insulin at only one amino acid and rabbit islets are glucose responsive.

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