High Blood Sugar's Impact on Immune System Holds Clues to Improving Islet Cell Transplants

A biological tit for tat may hold clues to improving the success of islet cell transplants intended to cure type 1 diabetes, according to a Medical College of Georgia scientist.

In type 1, the immune system attacks insulin-producing cells causing high blood glucose levels that may temporarily reduce the attack, said Dr. Rafal Pacholczyk, an immunologist in the MCG Center for Biotechnology and Genomic Medicine.

He has received a three-year, $495,000 grant from Juvenile Diabetes Research Foundation to find out whether this counteraction offers insight for transplants.

High blood glucose, or hyperglycemia, causes all sorts of dysregulation throughout the body. "It throws off metabolism, hormonal interplay and increases the risk of severe infections," Dr. Pacholczyk said. A shot of insulin or an islet cell transplant normalizes blood glucose levels, enabling, among other things, restoration of the usual balance between effector T cells which mount an immune or autoimmune response and regulatory T cells which suppress attacks.

He's obviously not saying hyperglycemia is good; in fact if diabetics were to get a transplant while their blood glucose was high the procedure alone could be lethal. But Dr. Pacholczyk hypothesizes it causes a temporary shift in the immune playing field that gives advantage to regulatory T-cells long enough for the body to accept the transplanted cells. One reason may be that suppressive regulatory cells recover differently or are less influenced by hyperglycemia.

Researchers at Canada's University of Alberta were the ones to find high blood glucose causes a short-lived suppression of the attack mode of the immune system followed by a slow return of homeostasis. The result: Islet cell transplants done in mice immediately after a blood glucose spike were dramatically more successful than those done days later, according to the research published in 2007 in the Scandinavian Journal of Immunology.

In fact, the early recipients did not require immunosuppression, which transplants patients receive to reduce the risk that their new insulin-producing cells also will become targets for their immune system. However, this generalized immune suppression puts patients at increased risk for infections, cancer and other diseases. "Basically, your guard is down," Dr. Pacholczyk said.

Seventy percent of mice that got transplants two days after they became hyperglycemic did not need immunosuppression, the Canadian researchers found; after nine days, the acceptance rate was reduced to about 10 percent. "The question is why?" Dr. Pacholczyk said.

Typically the path isn't easy for transplanted cells. Many die from the stress of transplantation or immune system attack either because they are rejected as invaders or because the same autoreactive mechanism that led to destruction of the patient's own cells is resurrected. "Cells that survive are the ones being counted on. Over time, they should increase in mass to a level that should produce sufficient amounts of insulin," the researcher said.