Type 1 Diabetes: Nipping Things in the Bud

Evan David Rosen, M.D., Ph.D. Assistant Professor of Medicine, Harvard Medical School

Type 1 diabetes (T1DM) is essentially a disease of the immune system. For mysterious reasons, a person’s immune system can unleash an attack on their own pancreatic beta cells, which produce insulin. Once that assault has progressed far enough (usually to the point where 80-90% of the beta cells have been killed) insulin production drops substantially, and sugar levels rise accordingly. Given the autoimmune nature of T1DM, it is no surprise that several attempts have been made to squelch the process with immunosuppressive drugs, such as those used by transplant recipients. Unfortunately, some immunosuppressive drugs tend to worsen diabetes, including steroids. The other drugs can suppress the diabetes for a while, but as soon as you stop taking them the high blood glucose levels return. Given that these are not benign drugs, there has been little enthusiasm for staying on them for life unless absolutely required, such as after an organ transplant.

There are newer immunosuppressives, though, that have piqued people’s interest as possible anti-diabetes agents. One example is a group of antibodies that attack immune cells called CD3+ lymphocytes, which are known to participate in beta cell destruction. A small study published a few years ago suggested that one such antibody, called hOKT3g1(Ala-Ala), seemed to benefit patients with T1DM. This was an open-label study (i.e. not blinded) on a relatively small number of patients, however, so enthusiasm was somewhat tempered. Now, a new study from Belgium has been published looking at another anti-CD3 antibody, this one called ChAglyCD3. (Yes, these antibody names are no more fun to pronounce than they are to type; fortunately you can bet they will get a nifty name like GlycoMab if ever approved for clinical use.)

This new study looked at 80 people with a recent diagnosis of T1DM. These patients were between 12-39 years old, and had been on insulin for less than a month when enrolled in the study. Half of the patients received ChAglyCD3, and half received placebo, and neither the patients nor their physicians knew who was getting what. The ChAglyCD3 antibody (or placebo) was given in the hospital intravenously once a day for six consecutive days, and then people were followed for as long as 18 months.

So how did they do? Well, first of all, all of the patients receiving ChAglyCD3 developed a fairly significant “flu-like” reaction that included the reappearance of Epstein-Barr virus (EBV) in their blood. EBV is the cause of infectious mononucleosis, and immunosuppressives can “re-activate” the virus in patients who were infected years earlier. In people taking life-long immunosuppressive therapy, this can be a big problem, with EBV leading to major complications. Fortunately, in the patients getting ChAglyCD3, EBV went back to undetectable levels after the treatment ended.

But did it work? Well, yes and no. Overall, those who got the antibody required less insulin over time than did placebo-treated people. But on closer inspection, people either did very well, or not so well at all with the ChAglyCD3. The difference between these “haves” and “have-nots” was explained by how much beta cell destruction had already occurred when the drug was started. If you were one of the people who got the drug after your disease had already advanced significantly, the antibody did little good. But among those with a lot of residual beta cells, the response was excellent—overall they were using roughly one-third the dose of insulin of the placebo-treated folks, and many of them were on almost no insulin at all. After 18 months, hemoglobin A1c levels were lower in the people who received ChAglyCD3 and who also had some residual beta cell function.

In retrospect, this result is not so surprising. We know that beta cells continue to be destroyed after the initial presentation of diabetes, and it makes sense that stopping the autoimmune attack won’t help much if there’s nothing left to save. What this study does, however, is re-focuses our attention onto those who haven’t developed T1DM yet but are at high risk for doing so. This includes first-degree relatives of people with T1DM and those with elevated blood levels of antibodies to beta cell proteins. Presumably, new trials of anti-CD3 antibodies will focus on these groups, who stand to benefit the most from prevention or delay of the autoimmune response. There are a few large ongoing attempts to identify such people, including the TrialNet network (www.diabetestrialnet.org/hindex.html) and The Environmental Determinants of Diabetes in the Young (TEDDY) study

(www.teddystudy.org).
It will be interesting and important to see how long the benefits of ChAglyCD3 continue to last in these patients, and to ensure that the transient re-activation of EBV causes no lasting harm. If so, there may be hope on the horizon for families of patients with T1DM and others at risk for the disease.

Reference: Keymeulen B, Vandemeulebroucke E, Ziegler AG, Mathieu C, Kaufman L, Hale G, Gorus F, Goldman M, Walter M, Candon S, Schandene L, Crenier L, De Block C, Seigneurin JM, De Pauw P, Pierard D, Weets I, Rebello P, Bird P, Berrie E, Frewin M, Waldmann H, Bach JF, Pipeleers D, Chatenoud L. Insulin needs after CD3-antibody therapy in new-onset type 1 diabetes. New England Journal of Medicine. 2005 Jun 23;352(25):2598-608.

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