Get 20M+ Full-Text Papers For Less Than $1.50/day. Start a 14-Day Trial for You and Your Team.

Learn More →

Cellular Therapy for Type 1 Diabetes: Has the Time Come?

Cellular Therapy for Type 1 Diabetes: Has the Time Come? Type 1 diabetes mellitus (DM) arises from selective immunologically mediated destruction of the insulin-producing beta cells in the pancreatic islets of Langerhans with consequent insulin deficiency.1,2 This occurs in genetically susceptible individuals and is a cellular-mediated process, presumably a specific reaction to 1 or more beta cell proteins (autoantigens), although probably initiated by some environmental factors. There is consequent progressive impairment of beta cell function and decline in beta cell mass. The immunologic nature of the type 1 DM disease process was firmly established in humans by studies in the late 1980s and early 1990s demonstrating that immune intervention in patients with newly diagnosed type 1 DM resulted in a slower decline in beta cell function than in control groups.3,4 Over the last several years, there have been major efforts to interdict the type 1 DM disease process either in newly diagnosed patients5,6 or in relatives of individuals with type 1 DM in whom evidence of the disease process has been found to be under way.7-9 Although some promising studies have suggested better sustained beta cell function, no definitive intervention has resulted in an increase of beta cell function. To further the conduct of studies to interdict the type 1 DM disease process, the National Institutes of Health has created a clinical trials network entitled Type 1 Diabetes TrialNet10 to conduct randomized controlled trials both in patients with new-onset type 1 DM and in relatives at risk for the disease. In this issue of JAMA, Voltarelli and colleagues11 report provocative findings in a small group of patients who underwent autologous hematopoietic stem cell transplantation (AHSCT) within 6 weeks of receiving a type 1 DM diagnosis. The authors report that patients who underwent AHSCT had increased beta cell function as evidenced by an increment in C-peptide levels and by low levels of hemoglobin A1c despite very low doses or frank discontinuation of insulin therapy. The potential use of bone marrow transplantation (BMT) to alter the course of the type 1 DM disease process was first proposed in animal studies in 1985 using allogenic bone marrow.12 Other animal studies supported the concept.13 Human studies in the 1990s suggested that type 1 DM could be transferred to recipients of allogenic BMT14,15 and that use of allogenic BMT for treatment of malignancy resulted in reversal of several autoimmune diseases including type 1 DM.16 In the 1990s, several groups examined the potential use of BMT for type 1 DM, particularly focusing on animal models to explore the mechanisms involved.17,18 Human experience with BMT, particularly in malignant diseases, was improving, such that by the early part of the 2000s, enthusiasm was increasing for testing BMT in humans with autoimmune diseases,19,20 including calls for BMT to be tested in type 1 DM.21,22 Meanwhile, use of AHSCT in patients with other autoimmune diseases showed promise—including systemic sclerosis,23 rheumatoid arthritis,24 refractory Crohn disease,25 and systemic lupus erythematosus.26 A recent review summarized the current status of AHSCT for autoimmune diseases27 despite the lack of understanding of how AHSCT affects the pathological processes of autoimmune diseases.28 Although the goal of AHSCT for patients with autoimmune diseases is to generate new self-tolerant lymphocytes after elimination of self-reactive or autoreactive lymphocytes, other mechanisms have not been excluded, such as generation of relatively larger numbers of regulatory lymphocytes or stem cell differentiation to new healthier cells within the organs being damaged by the autoimmune disease process. Autologous human stem cell transplantation involves 3 steps: (1) stem cell mobilization of peripheral blood CD34+ cells, (2) conditioning (immune ablation) of the recipient to eliminate self-reactive lymphocytes within the body, and (3) reinfusion of the autologous human stem cells harvested in step 1 and stored in liquid nitrogen until use. Myeloablative conditioning, such as with total lymphoid irradiation, is not used for AHSCT. This 3-step approach was used by Voltarelli et al.11 Voltarelli et al enrolled individuals with new-onset type 1 DM in contrast to the studies of AHSCT in other autoimmune diseases that enrolled individuals with refractory disease. At first blush this might appear to be inappropriate. However, there is demonstrable benefit from immunomodulatory therapies in other autoimmune diseases, whereas in type 1 DM there is not. Moreover, if the target of therapy with AHSCT is the type 1 DM disease process leading to beta cell destruction, this intervention should be applied when sufficient beta cells are available for salvage (ie, relatively early in the course of the disease). Thus, the timing of therapy seems appropriate. In addition, due to the measurement of a single autoantibody (anti-GAD) that may be present in as many as 10% of patients with type 2 DM,29 another question is whether individuals with type 2 DM were inadvertently enrolled; however, the patients are sufficiently well characterized that this is not likely the case. All but 2 patients carried the type 1 DM high-risk HLA alleles DR3,DQB1*0201 or DR4,DQB1*0302, and the other 2 carried the type 1 DM moderate-risk allele DR1,DQB1*0501. All patients were young (aged 15-27 years), and all had a body mass index of less than 25, all presented with weight loss, and all but one presented with significant hyperglycemia; these characteristics are typical of type 1 DM. Although the study demonstrates a significant improvement in beta cell function as measured by C-peptide levels, there are several important limitations. First, the study design did not include a randomized control group that either received no intervention or received only immunosuppression or immunomodulation. Second, the duration of follow-up for all patients who underwent AHSCT was insufficient to determine whether the apparent improvement in C-peptide levels was sustained. Third, it is not known whether the putative beneficial effects of AHSCT are due to immune reconstitution or otherwise altering the immune-mediated beta cell destruction that eventuates in the type 1 DM disease process or to regeneration of beta cells.30 Fourth, there is the well-known honeymoon period of relative remission after the onset of type 1 DM that complicates interpretation of the results.31 Voltarelli et al11 acknowledge these limitations stating “further follow-up is necessary to confirm the duration of insulin independence and the mechanisms of action of the procedure. In addition, randomized controlled trials and further biological studies are necessary to confirm the role of this treatment in changing the natural history of type 1 DM and to evaluate the contribution of hematopoietic stem cells to this change.” These appropriate cautionary notes deserve emphasis to avoid creating false hope based on the preliminary nature of the study results. This study by Voltarelli et al11 is the first of what likely will be many attempts at cellular therapy to interdict the type 1 DM disease process. Other approaches under consideration include infusion of dendritic cells,32,33 T-regulatory lymphocytes,34 umbilical cord cells,35 embryonic or adult stem cells,36-38 and allogenic BMT21,39 in addition to further studies with AHSCT. Research in this field is likely to explode in the next few years and should include randomized controlled trials as well as mechanistic studies. As these further studies confirm and build on the results of Voltarelli et al11—the time may indeed be coming for starting to reverse and prevent type 1 DM. Back to top Article Information Corresponding Author: Jay S. Skyler, MD, Diabetes Research Institute, University of Miami Miller School of Medicine, 1450 NW 10th Ave, Miami, FL 33136 (jskyler@miami.edu). Financial Disclosures: None reported. Funding/Support: This work was supported by grant U01 DK61041 from the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health. Role of the Sponsor: The funding agency had no role in the preparation, review, or approval of the manuscript. Editorials represent the opinions of the authors and JAMA and not those of the American Medical Association. References 1. Atkinson MA, Eisenbarth G. Type 1 diabetes. Lancet. 2001;358:221-22911476858Google ScholarCrossref 2. Atkinson MA. Thirty years of investigating the autoimmune basis for type 1 diabetes. Diabetes. 2005;54:1253-126315855308Google ScholarCrossref 3. Skyler JS, Marks JB. Immune intervention in type 1 diabetes mellitus. Diabetes Reviews. 1993;1:15-42Google Scholar 4. Skyler JS. Immunotherapy for interdicting the type 1 diabetes disease process. In: Pickup J, Williams G, eds. Textbook of Diabetes. 3rd ed. Oxford, England: Blackwell Publishing Ltd; 2003:74.1-74.12 5. Herold KC, Hagopian W, Auger JA. et al. Anti-CD3 monoclonal antibody in new-onset type 1 diabetes mellitus. N Engl J Med. 2002;346:1692-169812037148Google ScholarCrossref 6. Keymeulen B, Vandemeulebroucke E, Ziegler AG. et al. Insulin needs after CD3-antibody therapy in new-onset type 1 diabetes. N Engl J Med. 2005;352:2598-260815972866Google ScholarCrossref 7. Diabetes Prevention Trial–Type 1 Diabetes Study Group. Effects of insulin in relatives of patients with type 1 diabetes mellitus N Engl J Med. 2002;346:1685-169112037147Google ScholarCrossref 8. European Nicotinamide Diabetes Intervention Trial (ENDIT) Group. European Nicotinamide Diabetes Intervention Trial (ENDIT). Lancet. 2004;363:925-93115043959Google ScholarCrossref 9. Diabetes Prevention Trial–Type 1 Study Group. Effects of oral insulin in relatives of patients with type 1 diabetes mellitus. Diabetes Care. 2005;28:1068-107615855569Google ScholarCrossref 10. Type 1 Diabetes TrialNet Web Site. http://www.diabetestrialnet.org. Accessibility verified March 15, 2007 11. Voltarelli JC, Couri CEB, Stracieri ABPL. et al. Autologous nonmyeloablative hematopoietic stem cell transplantation in newly diagnosed type 1 diabetes mellitus. JAMA. 2007;297:1568-1576Google ScholarCrossref 12. Ikehara S, Ohtsuki H, Good RA. et al. Prevention of type I diabetes in nonobese diabetic mice by allogenic bone marrow transplantation. Proc Natl Acad Sci U S A. 1985;82:7743-77473906651Google ScholarCrossref 13. Mathieu C, Casteels K, Bouillon R, Waer M. Protection against autoimmune diabetes in mixed bone marrow chimeras. J Immunol. 1997;158:1453-14579013991Google Scholar 14. Lampeter EF, Homberg M, Quabeck K. et al. Transfer of type 1 diabetes between HLA-identical siblings by bone marrow transplantation. Lancet. 1993;341:1243-12448098394Google ScholarCrossref 15. Lampeter EF, McCann SR, Kolb H. Transfer of diabetes type 1 by bone-marrow transplantation. Lancet. 1998;351:568-5699492780Google ScholarCrossref 16. Nelson JL, Torrez R, Louie FM. et al. Pre-existing autoimmune disease in patients with longterm survival after allogeneic bone marrow transplantation. J Rheumatol Suppl. 1997;48:23-299150114Google Scholar 17. Leiter EH, Serreze DV. Autoimmune diabetes in the nonobese diabetic mouse. Clin Immunol Immunopathol. 1991;59:323-3342029789Google ScholarCrossref 18. Sorli CH, Greiner DL, Mordes JP, Rossini AA. Stem cell transplantation for treatment of autoimmune diseases. Graft. 1998;1:71-81Google Scholar 19. Burt RK, Slavin S, Burns WH, Marmont AM. Induction of tolerance in autoimmune diseases by hematopoietic stem cell transplantation. Blood. 2002;99:768-78411806976Google ScholarCrossref 20. Burt RK, Verda L, Oyama Y. et al. Non-myeloablative stem cell transplantation for autoimmune diseases. Springer Semin Immun. 2004;26:57-69Google ScholarCrossref 21. Domenick MA, Ildstad ST. Impact of bone marrow transplantation on type I diabetes. World J Surg. 2001;25:474-48011344401Google ScholarCrossref 22. Burt RK, Oyama Y, Traynor A, Kenyon NS. Hematopoietic stem cell therapy for type 1 diabetes. Autoimmun Rev. 2002;1:133-13812849006Google ScholarCrossref 23. Burt RK, Oyama Y, Traynor A. et al. Hematopoietic stem cell transplantation for systemic sclerosis with rapid improvement in skin scores. Bone Marrow Transplant. 2003;32:(suppl 1) S65-S6712931246Google ScholarCrossref 24. Snowden JA, Passweg J, Moore JJ. et al. Autologous hemopoietic stem cell transplantation in severe rheumatoid arthritis. J Rheumatol. 2004;31:482-48814994391Google Scholar 25. Oyama Y, Craig RM, Traynor AE. et al. Autologous hematopoietic stem cell transplantation in patients with refractory Crohn's disease. Gastroenterology. 2005;128:552-56315765390Google ScholarCrossref 26. Burt RK, Traynor A, Statkute L. et al. Nonmyeloablative hematopoietic stem cell transplantation for systemic lupus erythematosus. JAMA. 2006;295:527-53516449618Google ScholarCrossref 27. Burt RK, Marmont A, Oyama Y. et al. Randomized controlled trials of autologous hematopoietic stem cell transplantation for autoimmune diseases. Arthritis Rheum. 2006;54:3750-376017133541Google ScholarCrossref 28. Illei GG. Hematopoietic stem cell transplantation in autoimmune diseases. Arthritis Rheum. 2006;54:3730-373417133534Google ScholarCrossref 29. Gale EA. Latent autoimmune diabetes in adults. Diabetologia. 2005;48:2195-219916193287Google ScholarCrossref 30. Pasquali L, Fan Y, Trucco M, Ringquist S. Rehabilitation of adaptive immunity and regeneration of beta cells. Trends Biotechnol. 2006;24:516-52216963140Google ScholarCrossref 31. Martin S, Pawlowski B, Greulich B. et al. Natural course of remission in IDDM during 1st year after diagnosis. Diabetes Care. 1992;15:66-741737543Google ScholarCrossref 32. Lo J, Clare-Salzler MJ. Dendritic cell subsets and type I diabetes. Autoimmun Rev. 2006;5:419-42316890897Google ScholarCrossref 33. Perone MJ, Bertera S, Tawadrous ZS. et al. Dendritic cells expressing transgenic galectin-1 delay onset of autoimmune diabetes in mice. J Immunol. 2006;177:5278-528917015713Google Scholar 34. Tang Q, Bluestone JA. Regulatory T-cell physiology and application to treat autoimmunity. Immunol Rev. 2006;212:217-23716903917Google ScholarCrossref 35. Ende N, Chen R, Reddi AS. Effect of human umbilical cord blood cells on glycemia and insulitis in type 1 diabetic mice. Biochem Biophys Res Commun. 2004;325:665-66915541340Google ScholarCrossref 36. Santana A, Ensenat-Waser R, Arribas MI. et al. Insulin-producing cells derived from stem cells. J Cell Mol Med. 2006;10:866-88317125591Google ScholarCrossref 37. Tuch BE. Stem cells–a clinical update. Aust Fam Physician. 2006;35:719-72116969445Google Scholar 38. Hampton T. Stem cells probed as diabetes treatment. JAMA. 2006;296:2785-278617179447Google ScholarCrossref 39. Elkin G, Prigozhina TB, Slavin S. Prevention of diabetes in nonobese diabetic mice by nonmyeloablative allogeneic bone marrow transplantation. Exp Hematol. 2004;32:579-58415183899Google ScholarCrossref http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png JAMA American Medical Association

Cellular Therapy for Type 1 Diabetes: Has the Time Come?

JAMA , Volume 297 (14) – Apr 11, 2007

Loading next page...
 
/lp/american-medical-association/cellular-therapy-for-type-1-diabetes-has-the-time-come-dOuImJpZnC
Publisher
American Medical Association
Copyright
Copyright © 2007 American Medical Association. All Rights Reserved.
ISSN
0098-7484
eISSN
1538-3598
DOI
10.1001/jama.297.14.1599
Publisher site
See Article on Publisher Site

Abstract

Type 1 diabetes mellitus (DM) arises from selective immunologically mediated destruction of the insulin-producing beta cells in the pancreatic islets of Langerhans with consequent insulin deficiency.1,2 This occurs in genetically susceptible individuals and is a cellular-mediated process, presumably a specific reaction to 1 or more beta cell proteins (autoantigens), although probably initiated by some environmental factors. There is consequent progressive impairment of beta cell function and decline in beta cell mass. The immunologic nature of the type 1 DM disease process was firmly established in humans by studies in the late 1980s and early 1990s demonstrating that immune intervention in patients with newly diagnosed type 1 DM resulted in a slower decline in beta cell function than in control groups.3,4 Over the last several years, there have been major efforts to interdict the type 1 DM disease process either in newly diagnosed patients5,6 or in relatives of individuals with type 1 DM in whom evidence of the disease process has been found to be under way.7-9 Although some promising studies have suggested better sustained beta cell function, no definitive intervention has resulted in an increase of beta cell function. To further the conduct of studies to interdict the type 1 DM disease process, the National Institutes of Health has created a clinical trials network entitled Type 1 Diabetes TrialNet10 to conduct randomized controlled trials both in patients with new-onset type 1 DM and in relatives at risk for the disease. In this issue of JAMA, Voltarelli and colleagues11 report provocative findings in a small group of patients who underwent autologous hematopoietic stem cell transplantation (AHSCT) within 6 weeks of receiving a type 1 DM diagnosis. The authors report that patients who underwent AHSCT had increased beta cell function as evidenced by an increment in C-peptide levels and by low levels of hemoglobin A1c despite very low doses or frank discontinuation of insulin therapy. The potential use of bone marrow transplantation (BMT) to alter the course of the type 1 DM disease process was first proposed in animal studies in 1985 using allogenic bone marrow.12 Other animal studies supported the concept.13 Human studies in the 1990s suggested that type 1 DM could be transferred to recipients of allogenic BMT14,15 and that use of allogenic BMT for treatment of malignancy resulted in reversal of several autoimmune diseases including type 1 DM.16 In the 1990s, several groups examined the potential use of BMT for type 1 DM, particularly focusing on animal models to explore the mechanisms involved.17,18 Human experience with BMT, particularly in malignant diseases, was improving, such that by the early part of the 2000s, enthusiasm was increasing for testing BMT in humans with autoimmune diseases,19,20 including calls for BMT to be tested in type 1 DM.21,22 Meanwhile, use of AHSCT in patients with other autoimmune diseases showed promise—including systemic sclerosis,23 rheumatoid arthritis,24 refractory Crohn disease,25 and systemic lupus erythematosus.26 A recent review summarized the current status of AHSCT for autoimmune diseases27 despite the lack of understanding of how AHSCT affects the pathological processes of autoimmune diseases.28 Although the goal of AHSCT for patients with autoimmune diseases is to generate new self-tolerant lymphocytes after elimination of self-reactive or autoreactive lymphocytes, other mechanisms have not been excluded, such as generation of relatively larger numbers of regulatory lymphocytes or stem cell differentiation to new healthier cells within the organs being damaged by the autoimmune disease process. Autologous human stem cell transplantation involves 3 steps: (1) stem cell mobilization of peripheral blood CD34+ cells, (2) conditioning (immune ablation) of the recipient to eliminate self-reactive lymphocytes within the body, and (3) reinfusion of the autologous human stem cells harvested in step 1 and stored in liquid nitrogen until use. Myeloablative conditioning, such as with total lymphoid irradiation, is not used for AHSCT. This 3-step approach was used by Voltarelli et al.11 Voltarelli et al enrolled individuals with new-onset type 1 DM in contrast to the studies of AHSCT in other autoimmune diseases that enrolled individuals with refractory disease. At first blush this might appear to be inappropriate. However, there is demonstrable benefit from immunomodulatory therapies in other autoimmune diseases, whereas in type 1 DM there is not. Moreover, if the target of therapy with AHSCT is the type 1 DM disease process leading to beta cell destruction, this intervention should be applied when sufficient beta cells are available for salvage (ie, relatively early in the course of the disease). Thus, the timing of therapy seems appropriate. In addition, due to the measurement of a single autoantibody (anti-GAD) that may be present in as many as 10% of patients with type 2 DM,29 another question is whether individuals with type 2 DM were inadvertently enrolled; however, the patients are sufficiently well characterized that this is not likely the case. All but 2 patients carried the type 1 DM high-risk HLA alleles DR3,DQB1*0201 or DR4,DQB1*0302, and the other 2 carried the type 1 DM moderate-risk allele DR1,DQB1*0501. All patients were young (aged 15-27 years), and all had a body mass index of less than 25, all presented with weight loss, and all but one presented with significant hyperglycemia; these characteristics are typical of type 1 DM. Although the study demonstrates a significant improvement in beta cell function as measured by C-peptide levels, there are several important limitations. First, the study design did not include a randomized control group that either received no intervention or received only immunosuppression or immunomodulation. Second, the duration of follow-up for all patients who underwent AHSCT was insufficient to determine whether the apparent improvement in C-peptide levels was sustained. Third, it is not known whether the putative beneficial effects of AHSCT are due to immune reconstitution or otherwise altering the immune-mediated beta cell destruction that eventuates in the type 1 DM disease process or to regeneration of beta cells.30 Fourth, there is the well-known honeymoon period of relative remission after the onset of type 1 DM that complicates interpretation of the results.31 Voltarelli et al11 acknowledge these limitations stating “further follow-up is necessary to confirm the duration of insulin independence and the mechanisms of action of the procedure. In addition, randomized controlled trials and further biological studies are necessary to confirm the role of this treatment in changing the natural history of type 1 DM and to evaluate the contribution of hematopoietic stem cells to this change.” These appropriate cautionary notes deserve emphasis to avoid creating false hope based on the preliminary nature of the study results. This study by Voltarelli et al11 is the first of what likely will be many attempts at cellular therapy to interdict the type 1 DM disease process. Other approaches under consideration include infusion of dendritic cells,32,33 T-regulatory lymphocytes,34 umbilical cord cells,35 embryonic or adult stem cells,36-38 and allogenic BMT21,39 in addition to further studies with AHSCT. Research in this field is likely to explode in the next few years and should include randomized controlled trials as well as mechanistic studies. As these further studies confirm and build on the results of Voltarelli et al11—the time may indeed be coming for starting to reverse and prevent type 1 DM. Back to top Article Information Corresponding Author: Jay S. Skyler, MD, Diabetes Research Institute, University of Miami Miller School of Medicine, 1450 NW 10th Ave, Miami, FL 33136 (jskyler@miami.edu). Financial Disclosures: None reported. Funding/Support: This work was supported by grant U01 DK61041 from the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health. Role of the Sponsor: The funding agency had no role in the preparation, review, or approval of the manuscript. Editorials represent the opinions of the authors and JAMA and not those of the American Medical Association. References 1. Atkinson MA, Eisenbarth G. Type 1 diabetes. Lancet. 2001;358:221-22911476858Google ScholarCrossref 2. Atkinson MA. Thirty years of investigating the autoimmune basis for type 1 diabetes. Diabetes. 2005;54:1253-126315855308Google ScholarCrossref 3. Skyler JS, Marks JB. Immune intervention in type 1 diabetes mellitus. Diabetes Reviews. 1993;1:15-42Google Scholar 4. Skyler JS. Immunotherapy for interdicting the type 1 diabetes disease process. In: Pickup J, Williams G, eds. Textbook of Diabetes. 3rd ed. Oxford, England: Blackwell Publishing Ltd; 2003:74.1-74.12 5. Herold KC, Hagopian W, Auger JA. et al. Anti-CD3 monoclonal antibody in new-onset type 1 diabetes mellitus. N Engl J Med. 2002;346:1692-169812037148Google ScholarCrossref 6. Keymeulen B, Vandemeulebroucke E, Ziegler AG. et al. Insulin needs after CD3-antibody therapy in new-onset type 1 diabetes. N Engl J Med. 2005;352:2598-260815972866Google ScholarCrossref 7. Diabetes Prevention Trial–Type 1 Diabetes Study Group. Effects of insulin in relatives of patients with type 1 diabetes mellitus N Engl J Med. 2002;346:1685-169112037147Google ScholarCrossref 8. European Nicotinamide Diabetes Intervention Trial (ENDIT) Group. European Nicotinamide Diabetes Intervention Trial (ENDIT). Lancet. 2004;363:925-93115043959Google ScholarCrossref 9. Diabetes Prevention Trial–Type 1 Study Group. Effects of oral insulin in relatives of patients with type 1 diabetes mellitus. Diabetes Care. 2005;28:1068-107615855569Google ScholarCrossref 10. Type 1 Diabetes TrialNet Web Site. http://www.diabetestrialnet.org. Accessibility verified March 15, 2007 11. Voltarelli JC, Couri CEB, Stracieri ABPL. et al. Autologous nonmyeloablative hematopoietic stem cell transplantation in newly diagnosed type 1 diabetes mellitus. JAMA. 2007;297:1568-1576Google ScholarCrossref 12. Ikehara S, Ohtsuki H, Good RA. et al. Prevention of type I diabetes in nonobese diabetic mice by allogenic bone marrow transplantation. Proc Natl Acad Sci U S A. 1985;82:7743-77473906651Google ScholarCrossref 13. Mathieu C, Casteels K, Bouillon R, Waer M. Protection against autoimmune diabetes in mixed bone marrow chimeras. J Immunol. 1997;158:1453-14579013991Google Scholar 14. Lampeter EF, Homberg M, Quabeck K. et al. Transfer of type 1 diabetes between HLA-identical siblings by bone marrow transplantation. Lancet. 1993;341:1243-12448098394Google ScholarCrossref 15. Lampeter EF, McCann SR, Kolb H. Transfer of diabetes type 1 by bone-marrow transplantation. Lancet. 1998;351:568-5699492780Google ScholarCrossref 16. Nelson JL, Torrez R, Louie FM. et al. Pre-existing autoimmune disease in patients with longterm survival after allogeneic bone marrow transplantation. J Rheumatol Suppl. 1997;48:23-299150114Google Scholar 17. Leiter EH, Serreze DV. Autoimmune diabetes in the nonobese diabetic mouse. Clin Immunol Immunopathol. 1991;59:323-3342029789Google ScholarCrossref 18. Sorli CH, Greiner DL, Mordes JP, Rossini AA. Stem cell transplantation for treatment of autoimmune diseases. Graft. 1998;1:71-81Google Scholar 19. Burt RK, Slavin S, Burns WH, Marmont AM. Induction of tolerance in autoimmune diseases by hematopoietic stem cell transplantation. Blood. 2002;99:768-78411806976Google ScholarCrossref 20. Burt RK, Verda L, Oyama Y. et al. Non-myeloablative stem cell transplantation for autoimmune diseases. Springer Semin Immun. 2004;26:57-69Google ScholarCrossref 21. Domenick MA, Ildstad ST. Impact of bone marrow transplantation on type I diabetes. World J Surg. 2001;25:474-48011344401Google ScholarCrossref 22. Burt RK, Oyama Y, Traynor A, Kenyon NS. Hematopoietic stem cell therapy for type 1 diabetes. Autoimmun Rev. 2002;1:133-13812849006Google ScholarCrossref 23. Burt RK, Oyama Y, Traynor A. et al. Hematopoietic stem cell transplantation for systemic sclerosis with rapid improvement in skin scores. Bone Marrow Transplant. 2003;32:(suppl 1) S65-S6712931246Google ScholarCrossref 24. Snowden JA, Passweg J, Moore JJ. et al. Autologous hemopoietic stem cell transplantation in severe rheumatoid arthritis. J Rheumatol. 2004;31:482-48814994391Google Scholar 25. Oyama Y, Craig RM, Traynor AE. et al. Autologous hematopoietic stem cell transplantation in patients with refractory Crohn's disease. Gastroenterology. 2005;128:552-56315765390Google ScholarCrossref 26. Burt RK, Traynor A, Statkute L. et al. Nonmyeloablative hematopoietic stem cell transplantation for systemic lupus erythematosus. JAMA. 2006;295:527-53516449618Google ScholarCrossref 27. Burt RK, Marmont A, Oyama Y. et al. Randomized controlled trials of autologous hematopoietic stem cell transplantation for autoimmune diseases. Arthritis Rheum. 2006;54:3750-376017133541Google ScholarCrossref 28. Illei GG. Hematopoietic stem cell transplantation in autoimmune diseases. Arthritis Rheum. 2006;54:3730-373417133534Google ScholarCrossref 29. Gale EA. Latent autoimmune diabetes in adults. Diabetologia. 2005;48:2195-219916193287Google ScholarCrossref 30. Pasquali L, Fan Y, Trucco M, Ringquist S. Rehabilitation of adaptive immunity and regeneration of beta cells. Trends Biotechnol. 2006;24:516-52216963140Google ScholarCrossref 31. Martin S, Pawlowski B, Greulich B. et al. Natural course of remission in IDDM during 1st year after diagnosis. Diabetes Care. 1992;15:66-741737543Google ScholarCrossref 32. Lo J, Clare-Salzler MJ. Dendritic cell subsets and type I diabetes. Autoimmun Rev. 2006;5:419-42316890897Google ScholarCrossref 33. Perone MJ, Bertera S, Tawadrous ZS. et al. Dendritic cells expressing transgenic galectin-1 delay onset of autoimmune diabetes in mice. J Immunol. 2006;177:5278-528917015713Google Scholar 34. Tang Q, Bluestone JA. Regulatory T-cell physiology and application to treat autoimmunity. Immunol Rev. 2006;212:217-23716903917Google ScholarCrossref 35. Ende N, Chen R, Reddi AS. Effect of human umbilical cord blood cells on glycemia and insulitis in type 1 diabetic mice. Biochem Biophys Res Commun. 2004;325:665-66915541340Google ScholarCrossref 36. Santana A, Ensenat-Waser R, Arribas MI. et al. Insulin-producing cells derived from stem cells. J Cell Mol Med. 2006;10:866-88317125591Google ScholarCrossref 37. Tuch BE. Stem cells–a clinical update. Aust Fam Physician. 2006;35:719-72116969445Google Scholar 38. Hampton T. Stem cells probed as diabetes treatment. JAMA. 2006;296:2785-278617179447Google ScholarCrossref 39. Elkin G, Prigozhina TB, Slavin S. Prevention of diabetes in nonobese diabetic mice by nonmyeloablative allogeneic bone marrow transplantation. Exp Hematol. 2004;32:579-58415183899Google ScholarCrossref

Journal

JAMAAmerican Medical Association

Published: Apr 11, 2007

Keywords: diabetes mellitus, type 1

References