Five diabetic dogs with bellies full of transplanted canine isletsof Langerhans are free of symptoms and no longer need thedaily insulin shots they used to live on.

What's more, they are managing without the lifelongimmunosuppressive drugs that most organ transplantrecipients require to prevent rejection of their grafts.

The canine animal models are being used to test a new type ofalginate microcarrier in which their donor islets areencapsulated. The poly(amino acid) membrane envelope haspores that keep the islets from leaking out and cells of theimmune system from coming in. They do allow nutrients,including glucose, to enter. The glucose sends a signal to theislets' beta cells, which duly turn on insulin production, just asbeta cells in healthy islets do.

Human islets wrapped in alginate carriers for transplantationare nothing new, but neither are they very successful, pointedout Patrick Soon-Shiong of the islet transplant facility atWadsworth Medical Center in Los Angeles. Over time, the graftsdevelop dense fibroblast overgrowth, caused, he said, byresidues of beta-D-mannuronic acid inherent in the molecularmakeup of alginate polysaccharides. This forfends their use inhumans.

Soon-Shiong attributes this fibrosis to the mannuronic acidcomponent, which releases cytokines such as interleukins 1 and2, plus tumor necrosis factor.

His solution: Create an alginate capsule with little or nomannuronic acid and more alpha-L-guluronic acid. The resultwas that the five diabetic dogs -- into whose peritoneal cavitieshe and his associates transplanted 15,000 to 20,000 canineislets per kilogram (inside their newly formulatedimmunoprotective capsules) -- remained euglycemic,symptom-free and off insulin for up to about six months. Theirgrafts remained functional for up to about two years.

The islets were isolated from mongrel donors. Three otherdiabetic control canines received similar grafts -- injected free-floating into the peritoneum -- without benefit ofencapsulation. The trio rejected these transplants on daysthree, seven and 10.

The Wadsworth report appears in the mid-June issue of theProceedings of the National Academy of Sciences (PNAS), titled"Long-term reversal of diabetes by the injection ofimmunoprotected islets." Its authors state that to theirknowledge, "This is the first report of long-term islet function(more than one year) following an intraperitoneal injection ofencapsulated islets in the large animal model."

Because the immunoprotected islets responded to fluctuatingglucose levels on demand rather than episodically, as withdaily insulin shots, Soon-Shiong suggested that such goodmetabolic control "relates to the potential of encapsulated isletsto prevent secondary complications of diabetes," notablykidney failure, blindness and amputation.

Research diabetologist William Chick is familiar with Soon-Shiong's project. Chick, who is president and scientific directorof BioHybrid Technologies Inc. of Shrewsbury, Mass., voicedsome caveats about the Wadsworth islet microcarrier'spotential large-scale use in human diabetics. "The problem,"Chick told BioWorld, "is that the amount of human isletmaterial is extremely limited; there just aren't enough pancreasglands available."

He sees two conceptual ways around this dilemma:

-- "Figure out how to get islet cells to multiply in culture -- andwe're a ways from that.

-- "Turn to xenografts -G islets from animals -G which meansimmunosuppression."

-- David N. Leff Science Editor

(c) 1997 American Health Consultants. All rights reserved.