Article,
LONG-TERM REVERSAL OF DIABETES BY THE INJECTION OF IMMUNOPROTECTED ISLETS
Proc. Natl. Acad. Sci. U. S. A., 90 (12): 5843 -- 5847 (June 1993)
Abstract
The intraperitoneal injection of insulin-producing islets immunoprotected
by an alginate-poly(amino acid) membrane is a potential method of
reversing diabetes without the need for lifelong immunosuppression.
Previous attempts to demonstrate this technology in large animals
have failed, preventing application in humans. We have determined
that key factors responsible for these past failures include cytokine
(interleukins 1 and 6 and tumor necrosis factor) stimulation by mannuronic
acid monomers from alginate capsules with weak mechanical integrity,
which results in fibroblast proliferation. With this insight, we
formulated mechanically stable microcapsules by using alginate high
in guluronic acid content and report prolonged reversal of diabetes
in the spontaneous diabetic dog model by the intraperitoneal injection
of encapsulated canine islet allografts. Euglycemia, independent
of any exogenous insulin requirement, was noted for up to 172 days.
Graft survival, evidenced by positive C-peptide release, was noted
for as long as 726 days in a recipient receiving a single injection
of immunoprotected islets. Histological evidence of viable islets
retrieved from the peritoneal cavity 6 months posttransplant confirmed
the biocompatibility and immunoprotective nature of this capsule
formulation. The finding that intraperitoneal injection of alginate-immunoprotected
islets, a minimally invasive surgical procedure, is effective in
prolonged (>1 year) maintenance of glycemic control, without the
need for lifelong immunosuppression, may have significant implications
for the future therapy of type I diabetes in humans.
