Three separate groups of researchers have reported that they've failed to replicate a controversial 2003 report of a way to cure Type 1 diabetes in mice.

Yet, "we're actually pretty elated," said Denise Faustman, M.D., Ph.D., of Harvard Medical School, who was the senior scientist involved in the 2003 report.

Dr. Faustman said in an interview that the three new papers -- published together in the March 24 issue of Science -- didn't get identical results to her earlier work, and they appear to refute part of it, but they all agree on one thing, that it is possible to cure diabetic mice and one day perhaps people.

"The big picture is confirmed," Dr. Faustman said.

In 2003, Dr. Faustman and colleagues reported that they had treated non-obese diabetic (NOD) mice dying of diabetes with injections of Freunds complete adjuvant (FCA), which is known to stop auto-immune attacks on beta cells. Also, the mice were given injections of spleen cells from healthy animals, which the researchers concluded had differentiated into new insulin-producing cells. The treatment, Dr. Faustman and colleagues reported, resulted in "cure" rates of 67%.

"We showed this amazing treatment that could cure end-stage mice," she said. "And there was pretty much disbelief that you could cure end-stage mice."

All three of the new papers -- by independent groups at Harvard, Washington University in St. Louis, and at the University of Chicago -- also showed that the procedure cured some of the mice, from a low of 19% to a high of 56%. The difference is that all three groups concluded that the spleen cells played no role in the cure.

"All three papers have this in common -- that we did see, to varying degrees, a certain percentage of mice that maintained normal blood glucose after being diabetic," said Anish Suri, Ph.D., of Washington University.

But, he added, "we found no evidence of in vivo differentiation" of spleen cells. Instead, the conclusion of all three groups is that, in a few mice, simply stopping the auto-immune assault on the beta cells allows the animals to regain their ability to produce insulin.

In other words, Dr. Suri said, the treatment allows rescue, rather than regeneration.

Dr. Faustman said that while all three groups had followed almost the same procedures she and her colleagues had done in 2003, there were some differences that might have led to different results.

The 2003 study used spleen cells from male mice, injected into females; the researchers said they later found evidence of a Y chromosome among insulin-producing cells in the target mice, indicating that the spleen cells had in fact differentiated as hoped.
That procedure can produce "technical artifacts," said Louis Philipson, M.D., Ph.D., senior author of the University of Chicago paper. So he and colleagues used a different marker: spleen cells with an added gene that causes them to glow green. If any insulin-producing cells in the mice later glowed green, it would be clear they had derived from the transplanted spleen cells.
Of the 22 mice they treated, seven (32%) became normoglycemic, Dr. Philipson and colleagues reported, and all had insulin-producing beta cells. But none of those cells glowed green, they found.

"The question we are now addressing is the source of these beta cells," Dr. Philipson said. "They could be beta cells that survived the initial immune onslaught, recovered and replicated. Or they could be pancreatic stem cells, which had matured into beta cells once autoimmunity was controlled."