Toward a cure for type 1 diabetes mellitus: Diabetes-suppressive dendritic cells and beyond

Pediatric Diabetes

Volumn 9, Issue 3 PART 2, 2008, Pages 4-13

  Giannoukakis, Nick ^a   Phillips, Brett ^a   Trucco, Massimo ^a,b  

^a UNIVERSITY OF PITTSBURGH SCHOOL OF MEDICINE   (United States)

^b CHILDREN S HOSPITAL OF PITTSBURGH   (United States)

Author keywords

Dendritic cells; Diabetes mellitus; Immunotherapy

Indexed keywords

ANTIDIABETIC AGENT; ANTISENSE OLIGONUCLEOTIDE; ASPARTIC PROTEINASE; B7 ANTIGEN; CD3 ANTIBODY; CD40 ANTIGEN; CD86 ANTIGEN; DIAPEP 277; DNA VACCINE; GLUTAMATE DECARBOXYLASE 65; HLA ANTIGEN; HLA DQ8 ANTIGEN; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; INSULIN; NBI 6024; OKT 3; TRANSCRIPTION FACTOR FOXP3;

ANTIGEN PRESENTING CELL; ARTICLE; AUTOIMMUNE DISEASE; AUTOLOGOUS HEMATOPOIETIC STEM CELL TRANSPLANTATION; CD4+ CD25+ T LYMPHOCYTE; CD8+ T LYMPHOCYTE; CELL BASED GENE THERAPY; CELL DESTRUCTION; CLINICAL TRIAL; DENDRITIC CELL; DIABETES MELLITUS; DRUG EFFICACY; DRUG SAFETY; GENETIC IMMUNIZATION; GENETIC PREDISPOSITION; GENETIC RISK; HUMAN; HYPERGLYCEMIA; IMMUNOMODULATION; IMMUNOSUPPRESSIVE TREATMENT; INSULIN DEPENDENT DIABETES MELLITUS; MAJOR HISTOCOMPATIBILITY COMPLEX; NONHUMAN; PANCREAS ISLET TRANSPLANTATION; PRIORITY JOURNAL; REGULATORY T LYMPHOCYTE; RISK ASSESSMENT; SIDE EFFECT; T LYMPHOCYTE;

AUTOIMMUNITY; DENDRITIC CELLS; DIABETES MELLITUS, TYPE 1; HUMANS; IMMUNOLOGIC FACTORS; IMMUNOSUPPRESSION; MODELS, IMMUNOLOGICAL; OLIGONUCLEOTIDES, ANTISENSE; TRANSPLANTATION, AUTOLOGOUS;

EID: 44649181615     PISSN: 1399543X     EISSN: 13995448     Source Type: Journal    
DOI: 10.1111/j.1399-5448.2008.00401.x     Document Type: Article

References (122)

1. Pugliese A. Genetics of type 1 diabetes. Endocrinol Metab Clin North Am 2004: 33: 1-16. vii.
2. Lang J, Bellgrau D. Animal models of type 1 diabetes: Genetics and immunological function. Adv Exp Med Biol 2004: 552: 91-116.
3. Pociot F, McDermott MF. Genetics of type 1 diabetes mellitus. Genes Immun 2002: 3: 235-249.
4. Todd JA. Genetics of type 1 diabetes. Pathol Biol (Paris) 1997: 45: 219-227.
5. Trucco M, Giannoukakis N. MHC tailored for diabetes cell therapy. Gene Ther 2005: 12: 553-554.
6. Ge X, Piganelli JD, Tse HM et al. The modulatory role of DR4 to DQ8-restricted CD4 T cell responses and type 1 diabetes susceptibility. Diabetes 2006: 55: 3455-3462.
7. Rudert WA, Trucco M. To be DR8 or not to be DQ8: That is the question. Pediatr Diabetes 2007: 8: 1-7.
8. Lehmann PV, Forsthuber T, Miller A, Sercarz EE. Spreading of T-cell autoimmunity to cryptic determinants of an autoantigen. Nature 1992: 358: 155-157.
9. Todd JA, Bell JI, McDevitt HO. HLA-DQ beta gene contributes to susceptibility and resistance to insulin-dependent diabetes mellitus. Nature 1987: 329: 599-604.
10. Morel PA, Dorman JS, Todd JA, McDevitt HO, Trucco M. Aspartic acid at position 57 of the HLA-DQ beta chain protects against type 1 diabetes: A family study. Proc Natl Acad Sci U S A 1988: 85: 8111-8115.
11. Trucco M. To be or not to be Asp 57, that is the question. Diabetes Care 1992: 15: 705-715.
12. McDevitt HO. Closing in on type 1 diabetes. N Engl J Med 2001: 345: 1060-1061.
13. Zorina TD, Subbotin VM, Bertera S, Alexander A, Styche AJ, Trucco M. Distinct characteristics and features of allogeneic chimerism in the NOD mouse model of autoimmune diabetes. Cell Transplant 2002: 11: 113-123.
14. Zorina TD, Subbotin VM, Bertera S et al. Recovery of the endogenous beta cell function in autoimmune diabetes. Stem Cells 2003: 21: 377-388.
15. Tian C, Bagley J, Cretin N, Seth N, Wucherpfennig KW, Iacomini J. Prevention of type 1 diabetes by gene therapy. J Clin Invest 2004: 114: 969-978.
16. Rood PPM, Bottino R, Balamurugan AN, Fan Y, Cooper DKC, Trucco M. Facilitating physiologic self-regeneration: A step beyond islet cell replacement. Pharm Res 2006: 23: 227-242.
17. Pasquali L, Giannoukakis N, Trucco M. Induction of immune tolerance to facilitate beta cell regeneration in type 1 diabetes. Adv Drug Deliv Rev 2008: 60: 106-111.
18. Voltarelli J, Couri C, Stracieri A et al. Autologous nonmyeloablative hematopoietic stem cell transplantation in newly diagnosed type 1 diabetes mellitus. JAMA 2007: 297: 1568-1576.
19. Czechowicz A, Kraft D, Weissman IL, Bhattacharya D. Efficient transplantation via antibody-based clearance of hematopoietic stem cell niches. Science 2007: 318: 1296-1299.
20. Beard BC, Dickerson D, Beebe K et al. Comparison of HIV-derived lentiviral and MLV-based gammaretroviral vector integration sites in primate repopulating cells. Mol Ther 2007: 15: 1356-1365.
21. Chen ZY, He CY, Kay MA. Improved production and purification of minicircle DNA vector free of plasmid bacterial sequences and capable of persistent transgene expression in vivo. Hum Gene Ther 2005: 16: 126-131.
22. Sclimenti CR, Neviaser AS, Baba EJ, Meuse L, Kay MA, Calos MP. Epstein-Barr virus vectors provide prolonged robust factor IX expression in mice. Biotechnol Prog 2003: 19: 144-151.
23. 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.
24. 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.
25. 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.
26. Xu X, D'Hoker J, Stange G et al. Beta cells can be generated from endogenous progenitors in injured adult mouse pancreas. Cell 2008: 132: 197-207.
27. Atkinson MA, Leiter EH. The NOD mouse model of type 1 diabetes: As good as it gets? Nat Med 1999: 5: 601-604.
28. Brown WM. TRX-4 (TolerRx Inc). IDrugs 2006: 9: 283-291.
29. Brown WM. Anti-CD3 antibody MacroGenics Inc. Curr Opin Investig Drugs 2006: 7: 381-388.
30. Bisikirska BC, Herold KC. Use of anti-CD3 monoclonal antibody to induce immune regulation in type 1 diabetes. Ann N Y Acad Sci 2004: 1037: 1-9.
31. 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.
32. 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: 2598-2608.
33. Bach JF, Chatenoud L. Tolerance to islet autoantigens in type 1 diabetes. Annu Rev Immunol 2001: 19: 131-161.
34. Weiner HL, Zhang SJ, Khoury SJ et al. Antigen-driven peripheral immune tolerance. Suppression of organ-specific autoimmune diseases by oral administration of autoantigens. Ann N Y Acad Sci 1991: 636: 227-232.
35. Weiner HL, Miller A, Khoury SJ et al. Treatment of autoimmune diseases by oral tolerance to autoantigens. Adv Exp Med Biol 1995: 371B: 1217-1223.
36. Whitacre CC, Gienapp IE, Meyer A, Cox KL, Javed N. Treatment of autoimmune disease by oral tolerance to autoantigens. Clin Immunol Immunopathol 1996: 80: S31-39.
37. Eisenbarth GS, Moriyama H, Robles DT et al. Insulin autoimmunity: prediction/precipitation/prevention type 1A diabetes. Autoimmun Rev 2002: 1: 139-145.
38. Nakayama M, Abiru N, Moriyama H et al. Prime role for an insulin epitope in the development of type 1 diabetes in NOD mice. Nature 2005: 435: 220-223.
39. Devendra D, Paronen J, Liu E et al. Comparative study of oral versus subcutaneous B: 9-23 insulin peptide in Balb/c mice as an experimental model for autoimmune diabetes. Ann N Y Acad Sci 2004: 1029: 331-333.
40. Devendra D, Paronen J, Liu E et al. Differential immune induction with subcutaneous versus oral administration of a diabetogenic insulin peptide in the NOD mouse. Ann N Y Acad Sci 2004: 1029: 328-330.
41. Liu E, Yu L, Moriyama H, Eisenbarth GS. Animal models of insulin-dependent diabetes. Methods Mol Med 2004: 102: 195-212.
42. Gottlieb PA, Eisenbarth GS. Insulin-specific tolerance in diabetes. Clin Immunol 2002: 102: 2-11.
43. Wegmann DR, Eisenbarth GS. It's insulin. J Autoimmun 2000: 15: 286-291.
44. Alleva DG, Maki RA, Putnam AL et al. Immunomodulation in type 1 diabetes by NBI-6024, an altered peptide ligand of the insulin B epitope. Scand J Immunol 2006: 2006: 59-69.
45. Giannoukakis N. NBI-6024 (Neurocrine Biosciences). IDrugs 2002: 5: 1162-1167.
46. Abiru N, Eisenbarth GS. Multiple genes/multiple autoantigens role in type 1 diabetes. Clin Rev Allergy Immunol 2000: 18: 27-40.
47. Atkinson MA, Maclaren NK. Islet cell autoantigens in insulin-dependent diabetes. J Clin Invest 1993: 92: 1608-1616.
48. Christie MR. Islet cell autoantigens in type 1 diabetes. Eur J Clin Invest 1996: 26: 827-838.
49. Dotta F, Anastasi E, Tiberti C, DiMario U. Autoantigens in type 1 diabetes mellitus. J Endocrinol Invest 1994: 17: 497-508.
50. Kallan AA, de Vries RR, Roep BO. T-cell recognition of beta-cell autoantigens in insulin-dependent diabetes mellitus. APMIS 1996: 104: 3-11.
51. Yoon JW, Jun HS. Cellular and molecular roles of beta cell autoantigens, macrophages and T cells in the pathogenesis of autoimmune diabetes. Arch Pharm Res 1999: 22: 437-447.
52. Brugman S, Klatter FA, Visser J, Bos NA, Elias D, Rozing J. Neonatal oral administration of DiaPep277, combined with hydrolysed casein diet, protects against Type 1 diabetes in BB-DP rats. An experimental study. Diabetologia 2004: 47: 1331-1333.
53. Elias D, Avron A, Tamir M, Raz I. DiaPep277 preserves endogenous insulin production by immunomodulation in type 1 diabetes. Ann N Y Acad Sci 2006: 1079: 340-344.
54. Giannoukakis N. DiaPep277 (DeveloGen). Curr Opin Investig Drugs 2005: 6: 1043-1050.
55. Huurman VA, Decochez K, Mathieu C, Cohen IR, Roep BO. Therapy with the hsp60 peptide DiaPep277 in C-peptide positive type 1 diabetes patients. Diabetes Metab Res Rev 2007: 23: 269-275.
56. Lazar L, Ofan R, Weintrob N et al. Heat-shock protein peptide DiaPep277 treatment in children with newly diagnosed type 1 diabetes: A randomised, double-blind phase II study. Diabetes Metab Res Rev 2007: 23: 286-291.
57. Raz I, Avron A, Tamir M et al. Treatment of new-onset type 1 diabetes with peptide DiaPep277 is safe and associated with preserved beta-cell function: Extension of a randomized, double-blind, phase II trial. Diabetes Metab Res Rev 2007: 23: 292-298.
58. Raz I, Elias D, Avron A, Tamir M, Metzger M, Cohen IR. Beta-cell function in new-onset type 1 diabetes and immunomodulation with a heat-shock protein peptide (DiaPep277): A randomised, double-blind, phase II trial. Lancet 2001: 358: 1749-1753.
59. Schloot NC, Meierhoff G, Lengyel C et al. Effect of heat shock protein peptide DiaPep277 on beta-cell function in paediatric and adult patients with recent-onset diabetes mellitus type 1: Two prospective, randomized, double-blind phase II trials. Diabetes Metab Res Rev 2007: 23: 276-285.
60. Agardh CD, Cilio CM, Lethagen A et al. Clinical evidence for the safety of GAD65 immunomodulation in adult-onset autoimmune diabetes. J Diabetes Complications 2005: 19: 238-246.
61. Chatenoud L. Monoclonal antibody-based strategies in autoimmunity and transplantation. Methods Mol Med 2005: 109: 297-328.
62. Herold KC, Gitelman SE, Masharani U et al. 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 2005: 54: 1763-1769.
63. Bacchetta R, Gambineri E, Roncarolo MG. Role of regulatory T cells and FOXQ3 in human diseases. J Allergy Clin Immunol 2007: 120: 227-235: quiz 236-1227.
64. Kim CH. Molecular targets of FoxP3+ regulatory T cells. Mini Rev Med Chem 2007: 7: 1136-1143.
65. Ochs HD, Gambineri E, Torgerson TR. IPEX, FOXP3 and regulatory T-cells: a model for autoimmunity. Immunol Res 2007: 38: 112-121.
66. Stephens GL, Shevach EM. Foxp3+ regulatory T cells: Selfishness under scrutiny. Immunity 2007: 27: 417-419.
67. Valencia X, Lipsky PE. CD4+CD25+FoxP3+ regulatory T cells in autoimmune diseases. Nat Clin Pract Rheumatol 2007: 3: 619-626.
68. Luo X, Tarbell KV, Yang H et al. Dendritic cells with TGF-beta1 differentiate naive CD4+CD25- T cells into islet-protective Foxp3+ regulatory T cells. Proc Natl Acad Sci U S A 2007: 104: 2821-2826.
69. Yamazaki S, Bonito AJ, Spisek R, Dhodapkar M, Inaba K, Steinman RM. Dendritic cells are specialized accessory cells along with TGF- for the differentiation of Foxp3+ CD4+ regulatory T cells from peripheral Foxp3 precursors. Blood 2007: 110: 4293-4302.
70. Banchereau J, Steinman RM. Dendritic cells and the control of immunity. Nature 1998: 392: 245-252.
71. Lutz MB, Schuler G. Immature, semi-mature and fully mature dendritic cells: Which signals induce tolerance or immunity? Trends Immunol 2002: 23: 445-449.
72. Steinman RM, Hawiger D, Nussenzweig MC. Tolerogenic dendritic cells. Annu Rev Immunol 2003: 21: 685-711.
73. Steinman RM, Turley S, Mellman I, Inaba K. The induction of tolerance by dendritic cells that have captured apoptotic cells. J Exp Med 2000: 191: 411-416.
74. Vlad G, Cortesini R, Suciu-Foca N. License to heal: Bidirectional interaction of antigen-specific regulatory T cells and tolerogenic APC. J Immunol 2005: 174: 5907-5914.
75. Smits HH, de Jong EC, Wierenga EA, Kapsenberg ML. Different faces of regulatory DCs in homeostasis and immunity. Trends Immunol 2005: 26: 123-129.
76. Smits HH, Engering A, van der Kleij D et al. Selective probiotic bacteria induce IL-10-producing regulatory T cells in vitro by modulating dendritic cell function through dendritic cell-specific intercellular adhesion molecule 3-grabbing nonintegrin. J Allergy Clin Immunol 2005: 115: 1260-1267.
77. Yamazaki S, Iyoda T, Tarbell K et al. Direct expansion of functional CD25+ CD4+ regulatory T cells by antigen-processing dendritic cells. J Exp Med 2003: 198: 235-247.
78. Inaba K, Metlay JP, Crowley MT, Steinman RM. Dendritic cells pulsed with protein antigens in vitro can prime antigen-specific, MHC-restricted T cells in situ. J Exp Med 1990: 172: 631-640.
79. Kubach J, Becker C, Schmitt E et al. Dendritic cells: Sentinels of immunity and tolerance. Int J Hematol 2005: 81: 197-203.
80. Steinman RM. Some interfaces of dendritic cell biology. APMIS 2003: 111: 675-697.
81. Steinman RM, Bonifaz L, Fujii S et al. The innate functions of dendritic cells in peripheral lymphoid tissues. Adv Exp Med Biol 2005: 560: 83-97.
82. Steinman RM, Nussenzweig MC. Avoiding horror autotoxicus: The importance of dendritic cells in peripheral T cell tolerance. Proc Natl Acad Sci U S A 2002: 99: 351-358.
83. Liu YJ. Dendritic cell subsets and lineages, and their functions in innate and adaptive immunity. Cell 2001: 106: 259-262.
84. Liu YJ, Kanzler H, Soumelis V, Gilliet M. Dendritic cell lineage, plasticity and cross-regulation. Nat Immunol 2001: 2: 585-589.
85. Bluestone JA. Co stimulation and its role in organ transplantation. Clin Transplant 1996: 10: 104-109.
86. Clarkson MR, Sayegh MH. T-cell costimulatory pathways in allograft rejection and tolerance. Transplantation 2005: 80: 555-563.
87. Kishimoto K, Dong VM, Sayegh MH. The role of costimulatory molecules as targets for new immunosuppressives in transplantation. Curr Opin Urol 2000: 10: 57-62.
88. Lenschow DJ, Walunas TL, Bluestone JA. CD28/B7 system of T cell costimulation. Annu Rev Immunol 1996: 14: 233-258.
89. Rothstein DM, Sayegh MH. T-cell costimulatory pathways in allograft rejection and tolerance. Immunol Rev 2003: 196: 85-108.
90. Sayegh MH, Turka LA. T cell costimulatory pathways: Promising novel targets for immunosuppression and tolerance induction. J Am Soc Nephrol 1995: 6: 1143-1150.
91. Coates PT, Thomson AW. Dendritic cells, tolerance induction and transplant outcome. Am J Transplant 2002: 2: 299-307.
92. Hackstein H, Morelli AE, Thomson AW. Designer dendritic cells for tolerance induction: Guided not misguided missiles. Trends Immunol 2001: 22: 437-442.
93. Morelli AE, Thomson AW. Dendritic cells: Regulators of alloimmunity and opportunities for tolerance induction. Immunol Rev 2003: 196: 125-146.
94. Nouri-S hirazi M, Thomson AW. Dendritic cells as promoters of transplant tolerance. Expert Opin Biol Ther 2006: 6: 325-339.
95. Steinman RM, Inaba K, Turley S, Pierre P, Mellman I. Antigen capture, processing, and presentation by dendritic cells: Recent cell biological studies. Hum Immunol 1999: 60: 562-567.
96. Bottino R, Lemarchand P, Trucco M, Giannoukakis N. Gene- and cell-based therapeutics for type I diabetes mellitus. Gene Ther 2003: 10: 875-889.
97. Chen D, Sung R, Bromberg JS. Gene therapy in transplantation. Transpl Immunol 2002: 9: 301-314.
98. Giannoukakis N, Rudert WA, Robbins PD, Trucco M. Targeting autoimmune diabetes with gene therapy. Diabetes 1999: 48: 2107-2121.
99. Giannoukakis N, Thomson A, Robbins PD. Gene therapy in transplantation. Gene Ther 1999: 6: 1499-1511.
100. Giannoukakis N, Trucco M. Gene therapy for type 1 diabetes. Am J Ther 2005: 12: 512-528.
101. Tarner IH, Fathman CG. The potential for gene therapy in the treatment of autoimmune disease. Clin Immunol 2002: 104: 204-216.
102. Tarner IH, Slavin AJ, McBride J et al. Treatment of autoimmune disease by adoptive cellular gene therapy. Ann N Y Acad Sci 2003: 998: 512-519.
103. Trucco M, Robbins PD, Thomson AW, Giannoukakis N. Gene therapy strategies to prevent autoimmune disorders. Curr Gene Ther 2002: 2: 341-354.
104. Chen W. Dendritic cells and (CD4+)CD25+ T regulatory cells: Crosstalk between two professionals in immunity versus tolerance. Front Biosci 2006: 11: 1360-1370.
105. Hugues S, Boissonnas A, Amigorena S, Fetler L. The dynamics of dendritic cell-T cell interactions in priming and tolerance. Curr Opin Immunol 2006: 18: 491-495.
106. Beissert S, Schwarz A, Schwarz T. Regulatory T cells. J Invest Dermatol 2006: 126: 15-24.
107. Enk AH. DCs and cytokines cooperate for the induction of tregs. Ernst Schering Res Found Workshop 2006: 56: 97-106.
108. Huber S, Schramm C. TGF-beta and CD4+CD25+ regulatory T cells. Front Biosci 2006: 11: 1014-1023.
109. Lohr J, Knoechel B, Abbas AK. Regulatory T cells in the periphery. Immunol Rev 2006: 212: 149-162.
110. Roncarolo MG, Gregori S, Battaglia M, Bacchetta R, Fleischhauer K, Levings MK. Interleukin-10-secreting type 1 regulatory T cells in rodents and humans. Immunol Rev 2006: 212: 28-50.
111. Shevach EM, DiPaolo RA, Andersson J, Zhao DM, Stephens GL, Thornton AM. The lifestyle of naturally occurring CD4+ CD25+ Foxp3+ regulatory T cells. Immunol Rev 2006: 212: 60-73.
112. Tang Q, Bluestone JA. Regulatory T-cell physiology and application to treat autoimmunity. Immunol Rev 2006: 212: 217-237.
113. Verhagen J, Blaser K, Akdis CA, Akdis M. Mechanisms of allergen-specific immunotherapy: T-regulatory cells and more. Immunol Allergy Clin North Am 2006: 26: 207-231. vi.
114. Zhang L, Yi H, Xia XP, Zhao Y. Transforming growth factor-beta: An important role in CD4+CD25+ regulatory T cells and immune tolerance. Autoimmunity 2006: 39: 269-276.
115. Harnaha J, Machen J, Wright M et al. Interleukin-7 is a survival factor for CD4+ CD25+ T-cells and is expressed by diabetes-suppressive dendritic cells. Diabetes 2006: 55: 158-170.
116. Ma L, Qian S, Liang X et al. Prevention of diabetes in NOD mice by administration of dendritic cells deficient in nuclear transcription factor-kappaB activity. Diabetes 2003: 52: 1976-1985.
117. Machen J, Harnaha J, Lakomy R, Styche A, Trucco M, Giannoukakis N. Antisense oligonucleotides down-regulating costimulation confer diabetes-preventive properties to nonobese diabetic mouse dendritic cells. J Immunol 2004: 173: 4331-4341.
118. Giannoukakis N, Rudert WA, Trucco M. Dendritic cells for immunotherapy of type 1 diabetes. Cell Science Rev 2007: 3: 250-278.
119. Waeckerle-Men Y, Allmen EU, Gander B et al. Encapsulation of proteins and peptides into biodegradable poly(D,L-lactide-co-glycolide) microspheres prolongs and enhances antigen presentation by human dendritic cells. Vaccine 2006: 24: 1847-1857.
120. Yoshida M, Babensee JE. Molecular aspects of microparticle phagocytosis by dendritic cells. J Biomater Sci Polym Ed 2006: 17: 893-907.
121. Mandal TK. Inhaled insulin for diabetes mellitus. Am J Health Syst Pharm 2005: 62: 1359-1364.
122. Phillips B, Nylander K, Harnaha J et al. A microsphere-based vaccine prevents and reverses new-onset autoimmune diabetes. Diabetes 2008 (in press).