Correspondence

Reversal of Type 1 Diabetes in Mice

N Engl J Med 2007; 356:311-312January 18, 2007

Article

To the Editor:

Dr. Melton (July 6 issue)1 misrepresents my study on the reversal of type 1 diabetes in mice and its implications for new treatment strategies in humans.2 As in a previous study,3 my colleagues and I discovered that an immune therapy triggered a permanent reversal of end-stage type 1 diabetes in mice. The treatment involved two components: injecting the mice with an immune adjuvant (to induce the production of tumor necrosis factor, which destroys autoreactive T cells) and injecting splenocytes from a donor mouse.

Dr. Melton writes that we ascribed the reversal of type 1 diabetes in a mouse model solely to the transplantation of spleen cells and that we claimed to have identified a stem cell among the donor splenocytes that contributed to regrowth of the islets in the recipient. It is true that we observed adult stem cells and that these cells can contribute, in part, to the regrowth of the islets. However, Dr. Melton does not acknowledge that we also observed regeneration of pancreatic islets and complete reversal of type 1 diabetes without the introduction of any live donor splenocytes.2 Infusion of live splenic cells hastened the development of permanent normoglycemia in the mice but did not enhance the rate of cure. We did not claim that the regenerative process required a stem cell, and we did not rule out other mechanisms, such as regrowth or rescue of host islets. Our research simply found regeneration of the pancreas once the autoimmune process was removed.

Instead of cheering the fact that our laboratory's immunomodulatory approach was replicated successfully by three recent studies,4-6 Dr. Melton places emphasis on the failure of these cited studies to identify a splenocyte contribution to the observed regeneration of the pancreas. It is possible that methodologic differences between our protocol and theirs precluded finding a contribution of splenic stem cells to pancreatic regeneration in these studies. But since then, the optional splenic contribution has been replicated.7

From a clinical perspective, the existence of an adult stem cell in the spleen seems to be beside the point. Many studies have since shown that the regenerative process in the pancreas is likely to be intact and that targeted immune intervention may unleash the spontaneous regeneration of the pancreas. It seems reasonable to test the hypothesis that for end-stage diabetes, an immune intervention that destroys autoreactive T cells in the mouse can also work in the clinic.

Denise L. Faustman, M.D., Ph.D.
Harvard Medical School, Boston, MA 02115

Dr. Faustman reports owning stock in General Electric, Pfizer, Microsoft, IBM, Keel, and Johnson & Johnson, all of which have research programs or products involving stem cells. Dr. Faustman's employer, Massachusetts General Hospital, owns patent applications on the nuclear factor-κB–tumor necrosis factor pathway for the treatment of autoimmunity. Should the hospital receive income from those applications, Dr. Faustman or her laboratory could receive income.

7 References

1. 1

   Melton DA. Reversal of type 1 diabetes in mice. N Engl J Med 2006;355:89-90
   Full Text | Web of Science | Medline

2. 2

   Kodama S, Kuhtreiber W, Fujimura S, Dale EA, Faustman DL. Islet regeneration during the reversal of autoimmune diabetes in NOD mice. Science 2003;302:1223-1227
   CrossRef | Web of Science | Medline

3. 3

   Ryu S, Kodama S, Ryu K, Schoenfeld DA, Faustman DL. Reversal of established autoimmune diabetes by restoration of endogenous beta cell function. J Clin Invest 2001;108:63-72
   CrossRef | Web of Science | Medline

4. 4

   Nishio J, Gaglia JL, Turvey SE, Campbell C, Benoist C, Mathis D. Islet recovery and reversal of murine type 1 diabetes in the absence of any infused spleen cell contribution. Science 2006;311:1775-1778
   CrossRef | Web of Science | Medline

5. 5

   Suri A, Calderon B, Esparza TJ, Frederick K, Bittner P, Unanue ER. Immunological reversal of autoimmune diabetes without hematopoietic replacement of beta cells. Science 2006;311:1778-1780
   CrossRef | Web of Science | Medline

6. 6

   Chong AS, Shen J, Tao J, et al. Reversal of diabetes in non-obese diabetic mice without spleen cell-derived beta cell regeneration. Science 2006;311:1774-1775
   CrossRef | Web of Science | Medline

7. 7

   Faustman DL, Tran SD, Kodama S, et al. Comment on papers by Chong et al., Nishio et al., and Suri et al. on diabetes reversal in NOD mice. Science 2006;314:1243-1243
   CrossRef | Web of Science | Medline