The Holy Grail of Islet Research?

There’s a buzz in the diabetes community from a recent islet transplantation success with a drug called anti-CD154. Given to monkeys once per month after islet transplants, anti-CD154 kept the islets working, and kept the monkeys free of insulin injections, and other harmful immunosuppressive drugs, for one year.

Six monkeys have remained free of insulin injections one year after receiving islet transplants with anti-CD154. The Diabetes Research Institute (DRI) at the University of Miami is performing this research, which the institute calls a significant breakthrough in islet transplantation.

The results point to success in solving two major problems hindering successful transplants: rejection of the transplant, because the body always rejects foreign bodies, and the body’s autoimmune response, the unsolved attack in which type 1 diabetes is caused, through the body’s killing its own islets.

“Anti-CD154 is an immune system modulator that prevents rejection without harming islet cells, and seemingly, without stunting growth or causing infection, like traditional immunosuppressive agents,” says Norma S. Kenyon, PhD, the study’s lead author. “As a transplant immunologist who has worked in this field for almost 20 years, this is the most exciting development I’ve seen in a long time.”

Kenyon adds a cautionary statement, “However, as the mother of a daughter with diabetes, I don’t want to raise false hopes.”

Some Off Drugs Completely

One year after the transplant, all six monkeys are still insulin independent. Three no longer require monthly injections of anti-CD154, suggesting that the drug, with transplanted islet, may lead to long-term functioning of the islets.

“There is evidence that with anti-CD154, we can re-educate the immune system, so that you can discontinue treatment and still have tolerance of the transplant,” reports Camillo Ricordi, MD, another of this study’s authors.

Ricordi looks at how this leads to future developments. “It seems that it’s possible to discontinue treatment [with anti-CD154] and continue to have the grafts functioning. Now, the big question will be, how long can they function?”

Details of the Study

The monkeys, prior to transplant, had their pancreases removed. The donated islets came from other monkeys. DRI calls the transplant “mismatched.” Normally, humans are hooked up for transplants based on a good match of certain biological factors. To challenge the power of anti-CD154, the DRI doctors purposely set up monkeys who did not match well together.

Besides anti-CD154, they received no other antirejection drug. After the transplant and initial doses of anti-CD154, they were given maintenance doses every 28 days. Anti-CD154 is administered into the veins. During the first four weeks, four of the monkeys needed small doses of insulin to achieve normal blood sugars. After the first month, all six had normal fasting and post-meal blood glucose levels, without insulin injections.

After one year, three of the monkeys were taken off anti-CD154. At the time the study was published, 54 days later, all three still had normal glucose levels without insulin shots.

Kenyon reports that the monkeys received 6,000 islets for every kilogram (or 2.2 pounds) of body weight, which is more than humans require.

Side Effects

Anti-CD154 has no side effects so far. According to Ricordi, “In all the monkeys that were treated, we haven’t seen any problems so far. It’s just the tip of the iceberg. We need to be very cautious, but so far, there were no increased problems of infections or growth that we could clinically see.”

There is debate, but many in the diabetes world say that immunosuppressive drugs currently used have side effects that are more dangerous than diabetes itself.

Autoimmunity-Future Uses

Could anti-CD154 really turn off the autoimmune response that causes the body to attack its own, original islets, causing diabetes?

“The honest answer is that there is no primate model of type 1 diabetes,” Kenyon replies. “Removing the pancreas is not autoimmunity.”

The monkeys who received transplants in this trial do not have type 1 diabetes. They had their pancreases removed, but they do not have the autoimmune response that humans with type 1 diabetes have. Still, DRI researchers say anti-CD154 could have some effect on a type 1 human’s autoimmune response that kills transplanted islets.

Ricordi answers, “We are confident that there will be an effect on autoimmunity [with anti-CD154], because it has been shown, for other autoimmune diseases, that anti-CD154 has a definite effect on preventing or delaying the progression of autoimmunity.”

This evidence comes from trials in rodents, says Ricordi, so much more work needs to be done.

DRI has tested anti-CD154 in mice with autoimmune diabetes, known as N.O.D. (non-obese diabetic) mice.

“In N.O.D. mice, it [anti-CD154] hasn’t completely, by itself, prevented autoimmunity forever, but, depending on the dose and timing, it will delay it,” says Kenyon.

Whether or not it can do the same in humans remains to be seen.

“Anti-CD154 has been known to delay the onset of diabetes in mice,” says Ricordi, “but [diabetes in mice] is such a different disease, with such a fast onset, we are not sure it will represent the human disease.”

Kenyon and Ricordi believe that anti-CD154, in combination with another treatment, may be the key to cutting off the autoimmune response.

Improvement in Islet Function Over Time

A good sign is that after the transplants, the islets’ functioning did not weaken, but improved. With past islet transplants using other antirejection drugs, islets sometimes secrete less and less insulin as time goes on. Anti-CD154 seems to work better with time.

The first phase of insulin release is the key to islet functioning, according to Kenyon.

“When there’s a peak of insulin that is released right in the beginning, it is called first phase insulin release,” Kenyon explains. This first phase insulin release indicates how well islets are functioning in the body, and in this trial, the monkeys’ first phase insulin release improved over time.

The doctors tested one monkey’s first phase insulin release 42 days after the transplant, and found the release had decreased. But, 100 days later, the release had improved significantly, revealing that anti-CD154 could possibly protect islets.

Just the Beginning

“This is just the beginning of a series of combination strategies,” cautions Ricordi. “We are planning to test additional approaches in the next few years. Maybe we can shorten the treatment. Instead of one year of anti-CD154, we can do just one month, or three months.”

Other therapies in combination with anti-CD154 are also possibilities to be explored. Ricordi says they will look at adding bone marrow cells, or other cells that will help combat autoimmunity, from the same donor that gives the islets.

Both Ricordi and Kenyon say that these trials are just the beginning, but they also celebrate this huge stride.

How Anti-CD154 Works

Transplants are rejected by the recipient’s body because they are foreign, and the body doesn’t want anything that doesn’t belong to it. When foreign substances are spotted, the body sends signals to start the rejection response.

A critical part of this rejection response is the CD40-CD154 costimulation pathway, say the DRI researchers. This pathway “has proven to be a critical interaction in the generation of a T dependent immune response,” states their study. Anti-CD154 blocks this pathway, plus more.

“Blockade of this pathway, therefore, has the potential to prevent allograft rejection, recurrent autoimmunity…without the adverse effects of conventional, generalized immunosuppressive drugs on islet function,” the study says.

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