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Natural Born Killers to the Rescue

The immune system is amazingly complex and only partially understood. The primary job of the immune system, of course, is to rid the body of foreign invaders, be they bacteria, viruses, parasites, or even cancer cells. One of the most enduring mysteries in immunology is how the body learns to tell the good guys from the bad guys, or “self” from “non-self”. Our desire to understand this phenomenon is made more urgent by the existence of conditions where the immune system gets it wrong—by failing to discriminate between things that belong and those that don’t, an immune attack can be launched against an otherwise healthy organ. The term for this is “autoimmunity”, and the result is tissue death by friendly fire. If the target organ is the pancreas, specifically the insulin-producing beta cells within the pancreas, the condition shows up as type 1 (juvenile) diabetes.

Scientists have spent years trying to figure out how this process occurs, with an eye on halting the autoimmune attack and potentially reversing the damage to the beta cells. One of the best tools they have in this struggle is a rodent called the NOD mouse, which stands for non-obese diabetic. These mice develop diabetes at a young age, and many if not most aspects of their illness look remarkably like what occurs in type 1-diabetes in humans. Recently, several studies have appeared demonstrating remarkable success in preventing or reversing diabetes in NOD mice, raising hope that some of these advances will work in people as well.

Two new papers in the journal Nature Medicine illustrate what I’m talking about, but in order to understand what they tell us we need to back up and talk a little about some of the complicated ways the immune system works.

In type 1 diabetes, the attack on the beta cells of the pancreas is spearheaded by certain immune cells called T cells; specifically a subclass of T cells called Th1 cells. Normally, Th1 cells play a role in protecting us from disease, but in autoimmune conditions like type 1 diabetes, too many Th1 cells can be bad news. Fortunately, there is another type of T cell called the Th2 cell, and Th2 cells can protect against the mischief caused by Th1 cells run amok. So far, so good, you’re thinking. All we need to do is make fewer Th1 cells and more Th2 cells. Well, there is still another type of T cell that controls how many of these cells are created and how active they’ll be—the natural killer T cell, or NKT cell. NKT cells release special hormones that regulate the Th1 and Th2 cells, and studies have shown that NOD mice and people with type 1-diabetes have fewer NKT cells. Furthermore, the NKT cells they do have don’t secrete the right hormones, and generally do a very poor job of running the show.

Well, as it turns out, there’s a chemical called alpha-galactosylceramide (alpha-GalCer) that both induces the formation of more NKT cells as well as instructs them to make the right hormones. These two new papers show that giving alpha-GalCer to NOD mice can greatly reduce the likelihood that they will develop diabetes. Furthermore, experiments were done with NOD mice that had already become diabetic and that had been given grafts of pancreatic beta cells. If you follow the latest developments on diabetes (and if you’re reading this, you probably do), you know that there are very encouraging data on islet cell transplantation in humans with type 1-diabetes. The problem is that the autoimmune attack that knocked out the patient’s original beta cells will try to destroy the new islets as well. This necessitates a lifetime of immunosuppression; powerful drugs that keep the immune system in check allowing the graft to survive, but predisposing the patient to infections and other nasty side effects. In the diabetic NOD mice, the alpha-GalCer acted to let the grafts in the NOD mice survive. However, because this drug has very specific effects on the immune system, the animals did not seem to suffer from the sort of general immunosuppression caused by the types of drugs in current use. This exciting result opens the possibility of selective immunosuppression in pancreatic graft recipients, which could dramatically reduce the morbidity of that procedure.

There are potential drawbacks– alpha-GalCer is toxic to the liver in mice, although by a stroke of luck it appears humans don’t have the same problem. There is also the problem that bedevils all drugs designed to prevent type 1-diabetes. Because we can’t say for sure who will get type 1-diabetes and who will not, one would have to give alpha-GalCer to a lot of people who would never develop the disease in order to stop the process in those who will. But I have to say that I’m encouraged by the effects on the islet cell grafts given to NOD mice. I hope that this will be a productive line of inquiry for many academic labs and drug companies, and in the event that things pan out it will probably be some chemically modified cousin of alpha-GalCer that makes it to the bedside. I am rooting for this therapy also because I enjoy the irony of conquering a deadly disease by unleashing the killers within.

References:

1. S Hong, M T Wilson, I Serizawa, L Wu, N Singh, O V Naidenko, T Miura, T Haba, D C Scherer, J Wei, M Kronenberg, Y Koezuka & L Van Kaer. The natural killer T-cell ligand alpha-galactosylceramide prevents autoimmune diabetes in non-obese diabetic mice. Nature Medicine. 7:1052, 2001

2. S Sharif, G A Arreaza, P Zucker, Q -S Mi, J Sondhi, O V Naidenko, M Kronenberg, Y Koezuka, T L Delovitch, J -M Gombert, M Leite-de-Moraes, C Gouarin, R Zhu, A Hameg, T Nakayama, M Taniguchi, F Lepault, A Lehuen, J -F Bach & A Herbelin. Activation of natural killer T cells by alpha-galactosylceramide treatment prevents the onset and recurrence of autoimmune Type 1 diabetes. Nature Medicine 7: 1057, 2001.

Written by Evan D. Rosen, M.D., Ph.D.
Content created 09/10/2001

Content last reviewed September 12, 2001