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Immune therapy stems diabetes' progress.

Diabetic mice treated with a particular monoclonal antibody have regained the ability to regulate their blood sugar, leading researchers to hope that a similar treatment may one day stop insulin-dependent diabetes in humans.

Monoclonal antibodies are proteins produced to seek out and attach to specific molecules. The anti-CD3 monoclonal antibody homes in on the CD3 molecule, which sits in the membrane of immune-system cells called T-cells and serves as a docking site that helps these cells recognize their targets. Physicians use this monoclonal antibody to prevent and treat the rejection of organ transplants, with mixed success.

Up to now, researchers had demonstrated that they could use substances that interact with the immune system -- including this anti-CD3 molecule - to stop the development of diabetes, but only if given before the autoimmune attack destroyed most of the pancreas' insulin-producing beta cells (SN: 11/6/93, p.292). Treatment early in the disease process with different monoclonal antibodies, as well as the immune-system-suppressing drug cyclosporin, can keep these mice diabetes-free.

"This is really the first treatment that has shown any ability to cause remission:' says Joan T. Harmon of the National Institute of Diabetes and Digestive and Kidney Diseases in Bethesda, Md. Lucienne Chatenoud and her colleagues at Necker Hospital in Paris tried the approach in adult, nonobese diabetic (NOD) mice. Many such mice lose the ability to regulate their blood sugar as they mature because their T-cells attack their insulin-producing cells.

Within a week of developing high blood sugar or signs of T-cell attack, the NOD mice were given either low doses of the anti-CD3 antibody for five days or hamster immunoglobulin as a control injection. In some experiments, the researchers also gave the mice the drug cyclophosphamide, which speeds the development of diabetic symptoms.

Researchers then monitored the distribution of different T-cells in these mice. They also implanted bits of NOD mouse pancreas into the kidneys of treated

mice or attached pieces of tail skin from a different mouse strain to see what transplants survived. Within a month, 64 to 80 percent of the anti|CD3treated mice regained the ability to regulate their blood sugar, the team reports in the Jan. 4 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES.

T-cells still seemed to infiltrate the pancreas, but they stopped attacking beta cells. Also, these mice rejected the skin grafts but not the pancreas implants, indicating that the treatment quelled the T-cell attack but did not totally destroy immune-system function, says Chatenoud. The anti-CD3 treated mice remained diabetes-free for at least four months.

A study by Chatenoud's colleague Jean-Francois Bach had shown that this same anti-CD3 monoclonal antibody causes side effects too severe to make it a useful treatment in people, she notes. But she hopes that an anti-CD3 antibody fragment, which also halted diabetes in mice, will prove beneficial to people without causing side effects.

However, "it's a long way before we know whether a similar method will work in humans:' Harmon cautions.

Important differences exist between human and mouse diabetes and between the immune systems of these two organisms.

"It's easier to manipulate the disease in the NOD mouse than in humans," says George S. Eisenbarth, an endocrinologist at the University of Colorado Health Sciences Center in Denver. "In man, it might be too late to intervene when [we] see the high blood sugar."

Nevertheless, the French work "suggests there is an injury mechanism that is reparable:' says C. Garrison Fathman of Stanford University School of Medicine. Autoimmune diseases often progress in fits and starts: Many diabetics go through a "honeymoon" period after their first signs of high blood sugar and seem to recover temporarily.

This study indicates that a one-time intervention with some immune-system regulator during this period may prevent the development of full-blown diabetes, he adds.
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Title Annotation:anti-CD3 monoclonal antibody experiments on mice
Author:Pennisi, Elizabeth
Publication:Science News
Date:Jan 15, 1994
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