Reversal of Type 1 Diabetes in Mice
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《新英格兰医药杂志》
In 2003, the field of diabetes was shaken up by an article published in Science,1 stating that established autoimmune diabetes in mice could be permanently reversed with the injection of spleen cells. Kodama et al. reported that a known immune modulator, complete Freund's adjuvant, and the temporary transplantation of islets to the kidney capsule could be coupled with the injection of splenocytes to cure diabetes in mice. The idea was that the adjuvant modulates the immune attack and the transplanted islets maintain normal blood glucose levels long enough for the spleen cells to regenerate the insulin-producing beta cells. The authors described the approach as follows: "Stem cells of the spleen have been demonstrated to home to the pancreas where they mature into fully functional islet cells responsible for restoring normoglycemia."2 This article was important because of its claim that readily available cells, spleen cells, could be used to produce pancreatic beta cells.
The report attracted considerable attention because it pointed to new clinical strategies for treating type 1 diabetes. In addition, the use of spleen cells avoided the ethical questions surrounding the use of embryonic stem cells as a possible route to the production of beta cells. At the same time, some scientists were skeptical of the claim that spleen cells could form pancreatic beta cells. To their credit, Kodama et al. provided detailed protocols so that others could repeat and independently verify their conclusions.
Recently, the results of three independent efforts to replicate the experiment were reported, again in Science.3,4,5 The results were remarkably consistent: no splenocyte contribution to the islets was observed, and no evidence was found to support the principal conclusion of Kodama et al. All three studies showed, as others had previously,6,7 that diabetes can be reversed in this mouse model. However, the recovered host beta cells, rather than spleen cells, were responsible for this reversal. Each of the three studies supports the conclusion that the adjuvant-dependent dampening of the autoimmune attack, coupled with the recovery of residual host islets, underlies the cure in mice.
What does all this mean for possible clinical treatment? It is noteworthy that in these studies, the progression of autoimmune diabetes was reversed in control mice receiving the adjuvant. (Unfortunately, controlled studies have shown that neither the complete Freund's adjuvant nor the bacille Calmette–Guérin adjuvant appears to have this effect in humans.8) Although a mechanistic understanding of the autoimmune reversal in mice due to the adjuvant is still lacking, the finding emphasizes the importance of identifying the initiating antigen or antigens and the subsequent cascade of immune T and B cells responsible for the autoimmune attack. This approach is the best way to find interventions that can be effectively designed and applied. The value of this approach is supported by the promising results of early-stage clinical trials wherein other modulators of the immune system — for example, the anti-CD3 antibody9 — are administered during the "honeymoon" period of type 1 diabetes, when there is still considerable beta-cell mass.
The three recent studies also illustrate the dramatic response of beta cells to environmental signals. In each study, the beta cells recovered from an immune attack and proliferated to restore beta-cell mass. Beta-cell mass has been shown to increase in several other circumstances, including pregnancy, obesity, and in some patients, after gastric bypass surgery. Mice in which the insulin receptor in the liver cells has been knocked out respond by increasing beta-cell mass by a factor of 10.10 If we can harness this endogenous capacity of beta cells to proliferate and can combine this ability with a more effective blunting of the autoimmune attack in humans, it may well be possible to devise important new treatments for type 1 diabetes.
No potential conflict of interest relevant to this article was reported.
Source Information
From the Harvard Stem Cell Institute, Department of Molecular and Cellular Biology, Harvard University, Boston.
References
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.
Kodama S, Faustman DL. Routes to regenerating islet cells: stem cells and other biological therapies for type 1 diabetes. Pediatr Diabetes 2004;5:Suppl 2:38-44.
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.
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.
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.
Sadelain MW, Qin HY, Lauzon J, Singh B. Prevention of type I diabetes in NOD mice by adjuvant immunotherapy. Diabetes 1990;39:583-589.
Wang T, Singh B, Warnock GL, Rajotte RV. Prevention of recurrence of IDDM in islet-transplanted diabetic NOD mice by adjuvant immunotherapy. Diabetes 1992;41:114-117.
Huppmann M, Baumgarten A, Ziegler A, Bonifacio E. Neonatal bacille Calmette-Guerin vaccination and type 1 diabetes. Diabetes Care 2005;28:1204-1206.
Herold KC, Hagopian W, Auger JA, et al. Anti-CD3 monoclonal antibody in new-onset type 1 diabetes mellitus. N Engl J Med 2002;346:1692-1698.
Kulkarni RN, Jhala US, Winnay JN, Krajewski S, Montminy M, Kahn CR. PDX-1 haploinsufficiency limits the compensatory islet hyperplasia that occurs in response to insulin resistance. J Clin Invest 2004;114:828-836.(Douglas A. Melton, Ph.D.)
The report attracted considerable attention because it pointed to new clinical strategies for treating type 1 diabetes. In addition, the use of spleen cells avoided the ethical questions surrounding the use of embryonic stem cells as a possible route to the production of beta cells. At the same time, some scientists were skeptical of the claim that spleen cells could form pancreatic beta cells. To their credit, Kodama et al. provided detailed protocols so that others could repeat and independently verify their conclusions.
Recently, the results of three independent efforts to replicate the experiment were reported, again in Science.3,4,5 The results were remarkably consistent: no splenocyte contribution to the islets was observed, and no evidence was found to support the principal conclusion of Kodama et al. All three studies showed, as others had previously,6,7 that diabetes can be reversed in this mouse model. However, the recovered host beta cells, rather than spleen cells, were responsible for this reversal. Each of the three studies supports the conclusion that the adjuvant-dependent dampening of the autoimmune attack, coupled with the recovery of residual host islets, underlies the cure in mice.
What does all this mean for possible clinical treatment? It is noteworthy that in these studies, the progression of autoimmune diabetes was reversed in control mice receiving the adjuvant. (Unfortunately, controlled studies have shown that neither the complete Freund's adjuvant nor the bacille Calmette–Guérin adjuvant appears to have this effect in humans.8) Although a mechanistic understanding of the autoimmune reversal in mice due to the adjuvant is still lacking, the finding emphasizes the importance of identifying the initiating antigen or antigens and the subsequent cascade of immune T and B cells responsible for the autoimmune attack. This approach is the best way to find interventions that can be effectively designed and applied. The value of this approach is supported by the promising results of early-stage clinical trials wherein other modulators of the immune system — for example, the anti-CD3 antibody9 — are administered during the "honeymoon" period of type 1 diabetes, when there is still considerable beta-cell mass.
The three recent studies also illustrate the dramatic response of beta cells to environmental signals. In each study, the beta cells recovered from an immune attack and proliferated to restore beta-cell mass. Beta-cell mass has been shown to increase in several other circumstances, including pregnancy, obesity, and in some patients, after gastric bypass surgery. Mice in which the insulin receptor in the liver cells has been knocked out respond by increasing beta-cell mass by a factor of 10.10 If we can harness this endogenous capacity of beta cells to proliferate and can combine this ability with a more effective blunting of the autoimmune attack in humans, it may well be possible to devise important new treatments for type 1 diabetes.
No potential conflict of interest relevant to this article was reported.
Source Information
From the Harvard Stem Cell Institute, Department of Molecular and Cellular Biology, Harvard University, Boston.
References
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.
Kodama S, Faustman DL. Routes to regenerating islet cells: stem cells and other biological therapies for type 1 diabetes. Pediatr Diabetes 2004;5:Suppl 2:38-44.
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.
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.
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.
Sadelain MW, Qin HY, Lauzon J, Singh B. Prevention of type I diabetes in NOD mice by adjuvant immunotherapy. Diabetes 1990;39:583-589.
Wang T, Singh B, Warnock GL, Rajotte RV. Prevention of recurrence of IDDM in islet-transplanted diabetic NOD mice by adjuvant immunotherapy. Diabetes 1992;41:114-117.
Huppmann M, Baumgarten A, Ziegler A, Bonifacio E. Neonatal bacille Calmette-Guerin vaccination and type 1 diabetes. Diabetes Care 2005;28:1204-1206.
Herold KC, Hagopian W, Auger JA, et al. Anti-CD3 monoclonal antibody in new-onset type 1 diabetes mellitus. N Engl J Med 2002;346:1692-1698.
Kulkarni RN, Jhala US, Winnay JN, Krajewski S, Montminy M, Kahn CR. PDX-1 haploinsufficiency limits the compensatory islet hyperplasia that occurs in response to insulin resistance. J Clin Invest 2004;114:828-836.(Douglas A. Melton, Ph.D.)