Abstract
Type 1 diabetes mellitus is a complex autoimmune disease process encompassing a number of stages, the most significant of which is the loss of immunological tolerance and the initiation of immune dysfunction resulting in the selective destruction of pancreatic β cells. Although exogenous insulin therapy has proven efficacious, it does not address the underlying cause of the disease. A treatment strategy encompassing immunosuppressive and β cell replacement therapy that will promote immunological tolerance, without toxicity or the induction of lymphopenia is required for treatment of patients with hypoglycaemic unawareness. Importantly, this combination strategy must harness a therapy that provides a replacement source of insulin producing β cells without toxic side-effects associated with long term immunosuppression and induces tolerance to the replacement β cells in order to prevent destruction by allo- and autoreactive T cells. Here we discuss the current immunosuppressive therapies and potential sources of replacement β cells and review the pitfalls in current combined immunosuppression and islet transplant therapy. Finally we examine possible combination strategies including stem cells that are likely to succeed in fulfilling the above criteria for the treatment of diabetes in the future.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Moore DJ, Gregory JM, Kumah-Crystal YA et al (2009) Mitigating micro-and macro-vascular complications of diabetes beginning in adolescence. Vasc Health Risk Manag 5:1015–1031
Patterson CC, Dahlquist GG, Gyurus E et al (2009) Incidence trends for childhood type 1 diabetes in Europe during 1989–2003 and predicted new cases 2005–20: a multicentre prospective registration study. Lancet 373:2027–2033
Powers AC (2008) Insulin therapy versus cell-based therapy for type 1 diabetes mellitus: what lies ahead? Nat Clin Pract Endocrinol Metab 4:664–665
Nejentsev S, Howson JM, Walker NM et al (2007) Localization of type 1 diabetes susceptibility to the MHC class I genes HLAHLA-B and HLA-A. Nature 450:887–892
Gianani R, Eisenbarth GS (2005) The stages of type 1A diabetes: 2005. Immunol Rev 204:232–249
Bruno G, Cerutti F, Merletti F et al (2005) Residual beta-cell function and male/female ratio are higher in incident young adults than in children: the registry of type 1 diabetes of the province of Turin, Italy, 1984–2000. Diabetes Care 28:312–317
Sabbah E, Savola K, Ebeling T et al (2000) Genetic, autoimmune, and clinical characteristics of childhood- and adult-onset type 1 diabetes. Diabetes Care 23:1326–1332
Valdes AM, Thomson G, Erlich HA et al (1999) Association between type 1 diabetes age of onset and HLAHLA among sibling pairs. Diabetes 48:1658–1661
Vendrame F, Pileggi A, Laughlin E et al (2010) Recurrence of type 1 diabetes after simultaneous pancreas-kidney transplantation, despite immunosuppression, is associated with autoantibodies and pathogenic autoreactive CD4 T-cells. Diabetes 59:947–957
Bougneres PF, Carel JC, Castano L et al (1988) Factors associated with early remission of type I diabetes in children treated with cyclosporine. N Engl J Med 318:663–670
Stiller CR, Dupre J, Gent M et al (1984) Effects of cyclosporine immunosuppression in insulin-dependent diabetes mellitus of recent onset. Science 223:1362–1367
Harrison LC, Colman PG, Dean B et al (1985) Increase in remission rate in newly diagnosed type I diabetic subjects treated with azathioprine. Diabetes 34:1306–1308
Silverstein J, Maclaren N, Riley W et al (1988) Immunosuppression with azathioprine and prednisone in recent-onset insulin-dependent diabetes mellitus. N Engl J Med 319:599–604
Eisenbarth GS, Srikanta S, Jackson R et al (1985) Anti-thymocyte globulin and prednisone immunotherapy of recent onset type 1 diabetes mellitus. Diabetes Res 2:271–276
Pescovitz MD, Greenbaum CJ, Krause-Steinrauf H et al (2009) Rituximab, B-lymphocyte depletion, and preservation of beta-cell function. N Engl J Med 361:2143–2152
Parving HH, Tarnow L, Nielsen FS et al (1999) Cyclosporine nephrotoxicity in type 1 diabetic patients. A 7-year follow-up study. Diabetes Care 22:478–483
Cicero A, Lappin JA (2010) Pancreas transplantation: experience at University of Texas, Houston. Transplant Proc 42:314–316
Shapiro AM, Lakey JR, Ryan EA et al (2000) Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen. N Engl J Med 343:230–238
Bergerot I, Ploix C, Petersen J et al (1997) A cholera toxoid-insulin conjugate as an oral vaccine against spontaneous autoimmune diabetes. Proc Natl Acad Sci USA 94:4610–4614
Daniel D, Wegmann DR (1996) Protection of nonobese diabetic mice from diabetes by intranasal or subcutaneous administration of insulin peptide B-(9–23). Proc Natl Acad Sci USA 93:956–960
Harrison LC, Dempsey-Collier M, Kramer DR et al (1996) Aerosol insulin induces regulatory CD8 gamma delta T cells that prevent murine insulin-dependent diabetes. J Exp Med 184:2167–2174
Karounos DG, Bryson JS, Cohen DA (1997) Metabolically inactive insulin analog prevents type I diabetes in prediabetic NOD mice. J Clin Invest 100:1344–1348
Zhang ZJ, Davidson L, Eisenbarth G et al (1991) Suppression of diabetes in nonobese diabetic mice by oral administration of porcine insulin. Proc Natl Acad Sci USA 88:10252–10256
Goudy KS, Wang B, Tisch R (2008) Gene gun-mediated DNA vaccination enhances antigen-specific immunotherapy at a late preclinical stage of type 1 diabetes in nonobese diabetic mice. Clin Immunol 129:49–57
Kaufman DL, Clare-Salzler M, Tian J et al (1993) Spontaneous loss of T-cell tolerance to glutamic acid decarboxylase in murine insulin-dependent diabetes. Nature 366:69–72
Li AF, Escher A (2003) Intradermal or oral delivery of GAD-encoding genetic vaccines suppresses type 1 diabetes. DNA Cell Biol 22:227–232
Olcott AP, Tian J, Walker V et al (2005) Antigen-based therapies using ignored determinants of beta cell antigens can more effectively inhibit late-stage autoimmune disease in diabetes-prone mice. J Immunol 175:1991–1999
Elias D, Cohen IR (1994) Peptide therapy for diabetes in NOD mice. Lancet 343:704–706
Elias D, Reshef T, Birk OS et al (1991) Vaccination against autoimmune mouse diabetes with a T-cell epitope of the human 65-kDa heat shock protein. Proc Natl Acad Sci USA 88:3088–3091
Pozzilli P, Pitocco D, Visalli N et al (2000) No effect of oral insulin on residual beta-cell function in recent-onset type I diabetes (the IMDIAB VII). IMDIAB group. Diabetologia 43:1000–1004
Walter M, Philotheou A, Bonnici F et al (2009) No effect of the altered peptide ligand NBI-6024 on beta-cell residual function and insulin needs in new-onset type 1 diabetes. Diabetes Care 32:2036–2040
Boitard C, Michie S, Serrurier P et al (1985) In vivo prevention of thyroid and pancreatic autoimmunity in the BB rat by antibody to class II major histocompatibility complex gene products. Proc Natl Acad Sci USA 82:6627–6631
Chatenoud L, Thervet E, Primo J et al (1994) Anti-CD3 antibody induces long-term remission of overt autoimmunity in nonobese diabetic mice. Proc Natl Acad Sci USA 91:123–127
Hutchings P, O’Reilly L, Parish NM et al (1992) The use of a non-depleting anti-CD4 monoclonal antibody to re-establish tolerance to beta cells in NOD mice. Eur J Immunol 22:1913–1918
Lenschow DJ, Ho SC, Sattar H et al (1995) Differential effects of anti-B7-1 and anti-B7-2 monoclonal antibody treatment on the development of diabetes in the nonobese diabetic mouse. J Exp Med 181:1145–1155
Molano RD, Berney T, Li H et al (2001) Prolonged islet graft survival in NOD mice by blockade of the CD40-CD154 pathway of T-cell costimulation. Diabetes 50:270–276
Sempe P, Bedossa P, Richard MF et al (1991) Anti-alpha/beta T cell receptor monoclonal antibody provides an efficient therapy for autoimmune diabetes in nonobese diabetic (NOD) mice. Eur J Immunol 21:1163–1169
Wang B, Gonzalez A, Benoist C et al (1996) The role of CD8+ T cells in the initiation of insulin-dependent diabetes mellitus. Eur J Immunol 26:1762–1769
Chatenoud L, Primo J, Bach JF (1997) CD3 antibody-induced dominant self tolerance in overtly diabetic NOD mice. J Immunol 158:2947–2954
Herold KC, Gitelman SE, Masharani U et al (2005) A single course of anti-CD3 monoclonal antibody hOKT3gamma1(Ala-Ala) results in improvement in C-peptide responses and clinical parameters for at least 2 years after onset of type 1 diabetes. Diabetes 54:1763–1769
Herold KC, Hagopian W, Auger JA et al (2002) Anti-CD3 monoclonal antibody in new-onset type 1 diabetes mellitus. N Engl J Med 346:1692–1698
Keymeulen B, Vandemeulebroucke E, Ziegler AG et al (2005) Insulin needs after CD3-antibody therapy in new-onset type 1 diabetes. N Engl J Med 352:2598–2608
Keymeulen B, Walter M, Mathieu C et al (2010) Four-year metabolic outcome of a randomised controlled CD3-antibody trial in recent-onset type 1 diabetic patients depends on their age and baseline residual beta cell mass. Diabetologia 53:614–623
Herold KC, Gitelman S, Greenbaum C et al (2009) Treatment of patients with new onset Type 1 diabetes with a single course of anti-CD3 mAb Teplizumab preserves insulin production for up to 5 years. Clin Immunol 132:166–173
Ablamunits V, Sherry NA, Kushner JA et al (2007) Autoimmunity and beta cell regeneration in mouse and human type 1 diabetes: the peace is not enough. Ann N Y Acad Sci 1103:19–32
Aoki CA, Borchers AT, Ridgway WM et al (2005) NOD mice and autoimmunity. Autoimmun Rev 4:373–379
Baecher-Allan C, Hafler DA (2006) Human regulatory T cells and their role in autoimmune disease. Immunol Rev 212:203–216
Homann D, von Herrath M (2004) Regulatory T cells and type 1 diabetes. Clin Immunol 112:202–209
Szypowska A, Stelmaszczyk-Emmel A, Demkow U, Luczynski W (2012) Low frequency of regulatory T cells in the peripheral blood of children with type 1 diabetes diagnosed under the age of five. Arch Immunol Ther Exp (Warsz) 60:307–313
Dendrou CA, Wicker LS (2008) The IL-2/CD25 pathway determines susceptibility to T1D in humans and NOD mice. J Clin Immunol 28:685–696
You S, Leforban B, Garcia C et al (2007) Adaptive TGF-beta-dependent regulatory T cells control autoimmune diabetes and are a privileged target of anti-CD3 antibody treatment. Proc Natl Acad Sci USA 104:6335–6340
Gregori S, Giarratana N, Smiroldo S et al (2003) Dynamics of pathogenic and suppressor T cells in autoimmune diabetes development. J Immunol 171:4040–4047
You S, Belghith M, Cobbold S et al (2005) Autoimmune diabetes onset results from qualitative rather than quantitative age-dependent changes in pathogenic T-cells. Diabetes 54:1415–1422
Lindley S, Dayan CM, Bishop A et al (2005) Defective suppressor function in CD4(+)CD25(+) T-cells from patients with type 1 diabetes. Diabetes 54:92–99
Belghith M, Bluestone JA, Barriot S et al (2003) TGF-beta-dependent mechanisms mediate restoration of self-tolerance induced by antibodies to CD3 in overt autoimmune diabetes. Nat Med 9:1202–1208
Pop SM, Wong CP, He Q et al (2007) The type and frequency of immunoregulatory CD4+ T-cells govern the efficacy of antigen-specific immunotherapy in nonobese diabetic mice. Diabetes 56:1395–1402
Marek-Trzonkowska N, Mysliwiec M, Dobyszuk A, Grabowska M, Techmanska I, Juscinska J, Wujtewicz MA, Witkowski P, Mlynarski W, Balcerska A, Mysliwska J, Trzonkowski P (2012) Administration of CD4+CD25highCD127- regulatory T cells preserves beta-cell function in type 1 diabetes in children. Diabetes Care
Tang Q, Henriksen KJ, Bi M et al (2004) In vitro-expanded antigen-specific regulatory T cells suppress autoimmune diabetes. J Exp Med 199:1455–1465
Zhang Q, Shi S, Liu Y et al (2009) Mesenchymal stem cells derived from human gingiva are capable of immunomodulatory functions and ameliorate inflammation-related tissue destruction in experimental colitis. J Immunol 183:7787–7798
Zappia E, Casazza S, Pedemonte E et al (2005) Mesenchymal stem cells ameliorate experimental autoimmune encephalomyelitis inducing T-cell anergy. Blood 106:1755–1761
Augello A, Tasso R, Negrini SM et al (2007) Cell therapy using allogeneic bone marrow mesenchymal stem cells prevents tissue damage in collagen-induced arthritis. Arthritis Rheum 56:1175–1186
Fiorina P, Jurewicz M, Augello A et al (2009) Immunomodulatory function of bone marrow-derived mesenchymal stem cells in experimental autoimmune type 1 diabetes. J Immunol 183:993–1004
Bassi EJ, Moraes-Vieira PM, Moreira Sa CS, Almeida DC, Vieira LM, Cunha CS, Hiyane MI, Basso AS, Pacheco-Silva A, Camara NO (2012) Immune regulatory properties of allogeneic adipose-derived mesenchymal stem cells in the treatment of experimental autoimmune diabetes. Diabetes
English K, French A, Wood KJ (2010) Mesenchymal stromal cells: facilitators of successful transplantation? Cell Stem Cell 7:431–442
Bartholomew A, Sturgeon C, Siatskas M et al (2002) Mesenchymal stem cells suppress lymphocyte proliferation in vitro and prolong skin graft survival in vivo. Exp Hematol 30:42–48
Casiraghi F, Azzollini N, Cassis P et al (2008) Pretransplant infusion of mesenchymal stem cells prolongs the survival of a semiallogeneic heart transplant through the generation of regulatory T cells. J Immunol 181:3933–3946
Le Blanc K, Frassoni F, Ball L et al (2008) Mesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versus-host disease: a phase II study. Lancet 371:1579–1586
Ding Y, Xu D, Feng G et al (2009) Mesenchymal stem cells prevent the rejection of fully allogenic islet grafts by the immunosuppressive activity of matrix metalloproteinase-2 and -9. Diabetes 58:1797–1806
Ryan EA, Paty BW, Senior PA et al (2005) Five-year follow-up after clinical islet transplantation. Diabetes 54:2060–2069
Schroeder IS, Rolletschek A, Blyszczuk P et al (2006) Differentiation of mouse embryonic stem cells to insulin-producing cells. Nat Protoc 1:495–507
Soria B, Roche E, Berna G et al (2000) Insulin-secreting cells derived from embryonic stem cells normalize glycemia in streptozotocin-induced diabetic mice. Diabetes 49:157–162
D’Amour KA, Bang AG, Eliazer S et al (2006) Production of pancreatic hormone-expressing endocrine cells from human embryonic stem cells. Nat Biotechnol 24:1392–1401
Kroon E, Martinson LA, Kadoya K et al (2008) Pancreatic endoderm derived from human embryonic stem cells generates glucose-responsive insulin-secreting cells in vivo. Nat Biotechnol 26:443–452
Wu DC, Boyd AS, Wood KJ (2008) Embryonic stem cells and their differentiated derivatives have a fragile immune privilege but still represent novel targets of immune attack. Stem Cells 26:1939–1950
Boyd AS, Wu DC, Higashi Y et al (2008) A comparison of protocols used to generate insulin-producing cell clusters from mouse embryonic stem cells. Stem Cells 26:1128–1137
Boyd AS, Wood KJ (2010) Characteristics of the immune response and relative immune privilege at the incipient stages following transplantation of ES cell derived insulin-producing cell clusters. PLoS ONE 5:e10965
Boyd AS, Wood KJ (2009) Variation in MHC expression between undifferentiated mouse ES cells and ES cell-derived insulin-producing cell clusters. Transplantation 87:1300–1304
Takahashi K, Yamanaka S (2006) Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126:663–676
Tateishi K, He J, Taranova O et al (2008) Generation of insulin-secreting islet-like clusters from human skin fibroblasts. J Biol Chem 283:31601–31607
Maehr R, Chen S, Snitow M et al (2009) Generation of pluripotent stem cells from patients with type 1 diabetes. Proc Natl Acad Sci USA 106:15768–15773
Hess D, Li L, Martin M et al (2003) Bone marrow-derived stem cells initiate pancreatic regeneration. Nat Biotechnol 21:763–770
Gabr MM, Sobh MM, Zakaria MM et al (2008) Transplantation of insulin-producing clusters derived from adult bone marrow stem cells to treat diabetes in rats. Exp Clin Transplant 6:236–243
Oh SH, Muzzonigro TM, Bae SH et al (2004) Adult bone marrow-derived cells trans-differentiating into insulin-producing cells for the treatment of type I diabetes. Lab Invest 84:607–617
Chao KC, Chao KF, Fu YS et al (2008) Islet-like clusters derived from mesenchymal stem cells in Wharton’s Jelly of the human umbilical cord for transplantation to control type 1 diabetes. PLoS ONE 3:e1451
Jacob F (1979) Cell surface and early stages of mouse embryogenesis. Curr Top Dev Biol 13:117–137
Zhao T, Zhang ZN, Rong Z, Xu Y (2011) Immunogenicity of induced pluripotent stem cells. Nature 474:212–215
Sibley RK, Sutherland DE, Goetz F et al (1985) Recurrent diabetes mellitus in the pancreas iso- and allograft. A light and electron microscopic and immunohistochemical analysis of four cases. Lab Invest 53:132–144
Sutherland DE, Sibley R, Xu XZ et al (1984) Twin-to-twin pancreas transplantation: reversal and reenactment of the pathogenesis of type I diabetes. Trans Assoc Am Physicians 97:80–87
Sibley RK, Sutherland DE (1987) Pancreas transplantation. An immunohistologic and histopathologic examination of 100 grafts. Am J Pathol 128:151–170
Barthlott T, Kassiotis G, Stockinger B (2003) T cell regulation as a side effect of homeostasis and competition. J Exp Med 197:451–460
Marleau AM, Sarvetnick N (2005) T cell homeostasis in tolerance and immunity. J Leukoc Biol 78:575–584
Surh CD, Boyman O, Purton JF et al (2006) Homeostasis of memory T cells. Immunol Rev 211:154–163
Calzascia T, Pellegrini M, Lin A et al (2008) CD4 T cells, lymphopenia, and IL-7 in a multistep pathway to autoimmunity. Proc Natl Acad Sci USA 105:2999–3004
Wood K (2008) Outlook for longer-lasting islets. Nat Med 14:1156–1157
Monti P, Scirpoli M, Maffi P et al (2008) Islet transplantation in patients with autoimmune diabetes induces homeostatic cytokines that expand autoreactive memory T cells. J Clin Invest 118:1806–1814
Long SA, Rieck M, Sanda S, Bollyky JB, Samuels PL, Goland R, Ahmann A, Rabinovitch A, Aggarwal S, Phippard D, Turka LA, Ehlers MR, Bianchine PJ, Boyle KD, Adah SA, Bluestone JA, Buckner JH, Greenbaum CJ (2012) Rapamycin/IL-2 combination therapy in patients with type 1 diabetes qaugments tregs yet transiently ibeta-cell function. Diabetes
Huurman VA, Hilbrands R, Pinkse GG et al (2008) Cellular islet autoimmunity associates with clinical outcome of islet cell transplantation. PLoS ONE 3:e2435
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2013 Springer Science+Business Media New York
About this chapter
Cite this chapter
English, K., Wood, K.J. (2013). Addressing the Challenge of Autoimmunity in the Treatment of Diabetes with Stem Cells. In: Fairchild, P. (eds) The Immunological Barriers to Regenerative Medicine. Stem Cell Biology and Regenerative Medicine. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4614-5480-9_16
Download citation
DOI: https://doi.org/10.1007/978-1-4614-5480-9_16
Published:
Publisher Name: Humana Press, New York, NY
Print ISBN: 978-1-4614-5479-3
Online ISBN: 978-1-4614-5480-9
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)