If the findings do hold up, however, they would mean that the generic TB vaccine, in use since 1921, can regenerate insulin-secreting cells in the pancreas.
But there is no guarantee the results from this early-stage trial, published on Wednesday in PLoS One, will stand up in larger studies, which are now under way. Other diabetes researchers criticized it for going beyond the evidence in its claims about what caused the observed effects.
Dr. Denise Faustman of Massachusetts General Hospital, who led the trial, stated that, "We think we're seeing early evidence of effectiveness." "This simple, inexpensive vaccine attacks the autoimmunity underlying type 1 diabetes."
"We found that even low doses of the vaccine could transiently reverse type 1 diabetes, and this was in patients who have had the disease for 15 years." The effect lasted for about one week. "Our measurements showed that autoimmune T cells that destroy the islet cells died, and we saw evidence that insulin production was restored."
Dr. Domenico Accili of the Naomi Berrie Diabetes Center at Columbia University Medical Center, who did not participate in the study, has doubts. "There is a bit of magical thinking in the concept." "The idea that BCG wipes out autoimmune cells is totally unproved."
Cellular immunologist Dr. Raphael Clynes of the Berrie Center, who was not involved in the research, stated that, "Folks had presumed that by the time patients had overt diabetes, all their islet cells had been destroyed." "We now know there are preserved islet cells many years out. The presumption is, if you can get rid of the inflammatory, autoimmune response, the islet cells could regenerate."
Faustman's research on lab mice, begun in the 1990s, suggested that one way to get them to regenerate was with tumor necrosis factor. TNF is difficult to obtain commercially, but the BCG vaccine increases the body's production of it.
Dr. Faustman reported a decade ago that, raising levels of TNF through the vaccine cured type 1 diabetes in mice. With the autoimmune T cells out of the picture, islet cells regenerated and began producing healthy amounts of insulin. The journal that published the study insisted Dr. Faustman not use the word "regeneration," so controversial was the idea that islets could come back to life. She substituted "restoration."
Three patients with longstanding diabetes received two injections of BCG, four weeks apart. Three others received saline injections.
In two of the three BCG patients, levels of islet-attacking T cells fell, the scientists reported on Wednesday. Dead autoimmune cells were released into the bloodstream, a hint that TNF was killing them as intended. A measure of insulin production rose. The only placebo patient with similar results had become infected with the Epstein-Barr virus, which also triggers production of TNF.
The scientists also reported marked increases in C-peptide levels, a marker of the body's own insulin production. (They did not measure insulin itself because insulin made by the pancreas cannot be distinguished from the injected form.) "It wasn't to the level where they could throw away their syringe, but it was a significant elevation," said Dr. Faustman. "And this was in patients 15 years out: Their islet cells weren't dead, as most people said."
The restored insulin production lasted only a week. In the trial for which Dr. Faustman is recruiting the first of hundreds of patients she therefore plans to give more frequent BCG shots.
This is not the first time that Dr. Faustman has faced significant challenges to her theory. The Juvenile Diabetes Research Foundation rejected her funding requests and circulated a 2003 letter from two of her colleagues at Harvard Medical School, casting doubt on her work and apologizing to diabetics for "having their expectations cruelly raised" by stories about her research. It's worth noting that this is not the first time BCG (tuberculosis vaccine) has been studied – several previous trials have failed -- and several members of the diabetes research community were extremely skeptical about BCG in general, as well as this particular trial. (Faustman believes previous trials failed because of a lack of knowledge about mechanism and incorrect dosing.)
Columbia's Dr. Clynes stated that, "The paper shows that BCG is associated with a transient improvement in a couple of patients, but it's hard to conclude that TNF is the causative factor."
"It's certainly interesting and worth further investigation," said JDRF Chief Executive Jeffrey Brewer. "But it's really important to be careful about how we interpret early results." Curing type 1 diabetes may finally be within reach, he said, "but it will be a marathon, not a sprint."
Dr. Faustman's team says the study was funded "by philanthropic grants only."
PLoS Clinical Trials, 8-15-2912