The BB Rat

  • Ulla Nøhr Dalberg
  • Claus Haase
  • Lars Hornum
  • Helle Markholst
Chapter
Part of the Contemporary Endocrinology book series (COE)

Abstract

Diabetes-prone BioBreeding (BBDP) rats develop a spontaneous diabetic syndrome resembling human type 1 diabetes (T1D). Foremost, BBDP rats lose the majority of their beta cells during a rapid and aggressive inflammation of the islets during the last 2 weeks prior to overt hyperglycemia (1  ). Once hyperglycemia occurs, the rats become highly polyuric – they may lose well over 20 g (10–15% of body weight) overnight despite an excessive drinking behavior – and they proceed within 24–48 h to become ketotic. They die in ketoacidosis unless rescued by exogenous insulin therapy within the first 2 days of hyperglycemia (2, 3) – i.e. this clearly separates their diabetic phenotype from that of NOD mice that can easily survive for longer time after the onset of clinical diabetes. Indeed, within the first week, all insulin release and immunoreactivity in the pancreas is entirely lost – i.e. the phenotype of hypoinsulinemia is complete in BBDP rats (4–7).

Key Words

Diabetes Animal model diabetes Genetics diabetes Lymphopenia T cells Regulatory T cells Biobreeding diabetes-resistant rat 

References

  1. 1.
    Logothetopoulos J, Valiquette N, Madura E, Cvet D. The onset and progression of pancreatic insulitis in the overt, spontaneously diabetic, young adult BB rat studied by pancreatic biopsy. Diabetes. 1984; 33(1):33–36.PubMedCrossRefGoogle Scholar
  2. 2.
    Mordes JP, Desemone J, Rossini AA. The BB rat. Diabetes Metab Rev. 1987; 3(3):725–750.PubMedCrossRefGoogle Scholar
  3. 3.
    Markholst H, Eastman S, Wilson D, Fisher L, Lernmark A. Decreased weight gain in BB rats before the clinical onset of insulin-dependent diabetes. Diabetes Res Clin Pract. 1993; 21(1):31–38.PubMedCrossRefGoogle Scholar
  4. 4.
    Tannenbaum GS, Colle E, Wanamaker L, Gurd W, Goldman H, Seemayer TA. Dynamic time-course studies of the spontaneously diabetic BB Wistar rat. II. Insulin-, glucagon-, and somatostatin-reactive cells in the pancreas. Endocrinology. 1981; 109(6):1880–1887.PubMedCrossRefGoogle Scholar
  5. 5.
    Seemayer TA, Tannenbaum GS, Goldman H, Colle E. Dynamic time course studies of the spontaneously diabetic BB Wistar rat. III. Light-microscopic and ultrastructural observations of pancreatic islets of Langerhans. Am J Pathol. 1982; 106(2):237–249.PubMedGoogle Scholar
  6. 6.
    Svenningsen A, Dyrberg T, Markholst H, Binder C, Lernmark A. Insulin release and pancreatic insulin is reduced in young prediabetic BB rats. Acta Endocrinol (Copenh). 1986; 112(3):367–371.Google Scholar
  7. 7.
    Löhr M, Markholst H, Dyrberg T, Klöppel G, Oberholzer M, Lernmark A. Insulitis and diabetes are preceded by a decrease in beta cell volume in diabetes-prone BB rats. Pancreas. 1989; 4(1):95–100.PubMedCrossRefGoogle Scholar
  8. 8.
    Colle E, Guttmann RD, Seemayer TA. Association of spontaneous thyroiditis with the major histocompatibility complex of the rat. Endocrinology. 1985; 116(4):1243–1247.PubMedCrossRefGoogle Scholar
  9. 9.
    Awata T, Guberski DL, Like AA. Genetics of the BB rat: association of autoimmune disorders (diabetes, insulitis, and thyroiditis) with lymphopenia and major histocompatibility complex class II. Endocrinology. 1995; 136(12):5731–5735.PubMedCrossRefGoogle Scholar
  10. 10.
    Zipris D. Evidence that Th1 lymphocytes predominate in islet inflammation and thyroiditis in the BioBreeding (BB) rat. J Autoimmun. 1996; 9(3):315–319.PubMedCrossRefGoogle Scholar
  11. 11.
    Markholst H, Eastman S, Wilson D, Andreasen BE, Lernmark A. Diabetes segregates as a single locus in crosses between inbred BB rats prone or resistant to diabetes. J Exp Med. 1991; 174(1):297–300.PubMedCrossRefGoogle Scholar
  12. 12.
    Colle E, Guttmann RD, Seemayer TA, Michel F. Spontaneous diabetes mellitus syndrome in the rat. IV. Immunogenetic interactions of MHC and non-MHC components of the syndrome. Metabolism. 1983; 32(7 Suppl 1):54–61.PubMedCrossRefGoogle Scholar
  13. 13.
    Colle E, Ono SJ, Fuks A, Guttmann RD, Seemayer TA. Association of susceptibility to spontaneous diabetes in rat with genes of major histocompatibility complex. Diabetes. 1988; 37(10):1438–1443.PubMedCrossRefGoogle Scholar
  14. 14.
    Boitard C, Michie S, Serrurier P, Butcher GW, Larkins AP, McDevitt HO. 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. 1985; 82(19):6627–6631.PubMedCrossRefGoogle Scholar
  15. 15.
    Lee KU, Kim MK, Amano K, et al. Preferential infiltration of macrophages during early stages of insulitis in diabetes-prone BB rats. Diabetes. 1988; 37(8):1053–1058.PubMedCrossRefGoogle Scholar
  16. 16.
    Voorbij HA, Jeucken PH, Kabel PJ, De HM, Drexhage HA. Dendritic cells and scavenger macrophages in pancreatic islets of prediabetic BB rats. Diabetes. 1989; 38(12):1623–1629.PubMedCrossRefGoogle Scholar
  17. 17.
    Walker R, Bone AJ, Cooke A, Baird JD. Distinct macrophage subpopulations in pancreas of prediabetic BB-E rats. Possible role for macrophages in pathogenesis of IDDM. Diabetes. 1988; 37(9):1301–1304.PubMedCrossRefGoogle Scholar
  18. 18.
    Hanenberg H, Kolb-Bachofen V, Kantwerk-Funke G, Kolb H. Macrophage infiltration precedes and is a prerequisite for lymphocytic insulitis in pancreatic islets of pre-diabetic BB rats. Diabetologia. 1989; 32(2):126–134.PubMedCrossRefGoogle Scholar
  19. 19.
    Hosszufalusi N, Chan E, Teruya M, Takei S, Granger G, Charles MA. Quantitative phenotypic and functional analyses of islet immune cells before and after diabetes onset in the BB rat. Diabetologia. 1993; 36(11):1146–1154.PubMedCrossRefGoogle Scholar
  20. 20.
    Jarpe AJ, Hickman MR, Anderson JT, Winter WE, Peck AB. Flow cytometric enumeration of mononuclear cell populations infiltrating the islets of Langerhans in prediabetic NOD mice: development of a model of autoimmune insulitis for type I diabetes. Reg Immunol. 1990; 3(6):305–317.PubMedGoogle Scholar
  21. 21.
    Jansen A, Homo-Delarche F, Hooijkaas H, Leenen PJ, Dardenne M, Drexhage HA. Immunohistochemical characterization of monocytes-macrophages and dendritic cells involved in the initiation of the insulitis and beta-cell destruction in NOD mice. Diabetes. 1994; 43(5):667–675.PubMedCrossRefGoogle Scholar
  22. 22.
    Debussche X, Lormeau B, Boitard C, Toublanc M, Assan R. Course of pancreatic beta cell destruction in prediabetic NOD mice: a histomorphometric evaluation. Diabetes Metab. 1994; 20(3):282–290.Google Scholar
  23. 23.
    Dahlen E, Dawe K, Ohlsson L, Hedlund G. Dendritic cells and macrophages are the first and major producers of TNF-alpha in pancreatic islets in the nonobese diabetic mouse. J Immunol. 1998; 160(7):3585–3593.PubMedGoogle Scholar
  24. 24.
    Foulis AK, Liddle CN, Farquharson MA, Richmond JA, Weir RS. The histopathology of the pancreas in type 1 (insulin-dependent) diabetes mellitus: a 25-year review of deaths in patients under 20 years of age in the United Kingdom. Diabetologia. 1986; 29(5):267–274.PubMedCrossRefGoogle Scholar
  25. 25.
    Foulis AK, McGill M, Farquharson MA. Insulitis in type 1 (insulin-dependent) diabetes mellitus in man–macrophages, lymphocytes, and interferon-gamma containing cells. J Pathol. 1991; 165(2):97–103.PubMedCrossRefGoogle Scholar
  26. 26.
    Santamaria P, Nakhleh RE, Sutherland DE, Barbosa JJ. Characterization of T lymphocytes infiltrating human pancreas allograft affected by isletitis and recurrent diabetes. Diabetes. 1992; 41(1):53–61.PubMedCrossRefGoogle Scholar
  27. 27.
    Itoh N, Hanafusa T, Miyazaki A, et al. Mononuclear cell infiltration and its relation to the expression of major histocompatibility complex antigens and adhesion molecules in pancreas biopsy specimens from newly diagnosed insulin-dependent diabetes mellitus patients. J Clin Invest. 1993; 92(5):2313–2322.PubMedCrossRefGoogle Scholar
  28. 28.
    Reddy S, Bibby NJ, Fisher SL, Elliott RB. Longitudinal study of first phase insulin release in the BB rat. Diabetologia. 1986; 29(11):802–807.PubMedCrossRefGoogle Scholar
  29. 29.
    Markholst H, Lernmark A. Reduced pancreatic insulin is associated with retarded growth of the pancreas in young prediabetic BB rats. Pancreas. 1988; 3(2):140–144.PubMedCrossRefGoogle Scholar
  30. 30.
    Kanazawa M, Ikeda J, Sato J, et al. Alteration of insulin and glucagon secretion from the perfused BB rat pancreas before and after the onset of diabetes. Diabetes Res Clin Pract. 1988; 5(3):201–204.PubMedCrossRefGoogle Scholar
  31. 31.
    Markholst H, Laursen HV. Decreased levels of serum alpha-isoamylase prior to diabetes onset in BB rats. Pancreas. 1990; 5(2):144–150.PubMedCrossRefGoogle Scholar
  32. 32.
    Komiya I, Unger RH. Absence of glucopenic inhibition of the insulin response to arginine at the onset of diabetes in BB/W rats. Diabetologia. 1988; 31(4):225–227.PubMedCrossRefGoogle Scholar
  33. 33.
    Faustman DL, Steinman RM, Gebel HM, Hauptfeld V, Davie JM, Lacy PE. Prevention of rejection of murine islet allografts by pretreatment with anti-dendritic cell antibody. Proc Natl Acad Sci USA. 1984; 81(12):3864–3868.PubMedCrossRefGoogle Scholar
  34. 34.
    Nocera A, Leprini A, Fontana I. HLA-DR-bearing cells in the human pancreas. Transplant Proc. 1985; 17(Suppl 2):144–145.Google Scholar
  35. 35.
    Pipeleers DG, In’t Veld PA, Pipeleers-Marichal MA, Gepts W, van de Winkel M. Presence of pancreatic hormones in islet cells with MHC-class II antigen expression. Diabetes. 1987; 36(7):872–876.CrossRefGoogle Scholar
  36. 36.
    In’t Veld PA, Pipeleers DG. In situ analysis of pancreatic islets in rats developing diabetes. Appearance of nonendocrine cells with surface MHC class II antigens and cytoplasmic insulin immunoreactivity. J Clin Invest. 1988; 82(3):1123–1128.PubMedCrossRefGoogle Scholar
  37. 37.
    Charre S, Rosmalen JG, Pelegri C, et al. Abnormalities in dendritic cell and macrophage accumulation in the pancreas of nonobese diabetic (NOD) mice during the early neonatal period. Histol Histopathol. 2002; 17(2):393–401.PubMedGoogle Scholar
  38. 38.
    Lee KU, Pak CY, Amano K, Yoon JW. Prevention of lymphocytic thyroiditis and insulitis in diabetes-prone BB rats by the depletion of macrophages. Diabetologia. 1988; 31(6):400–402.PubMedCrossRefGoogle Scholar
  39. 39.
    Ziegler AG, Erhard J, Lampeter EF, Nagelkerken LM, Standl E. Involvement of dendritic cells in early insulitis of BB rats. J Autoimmun. 1992; 5(5):571–579.PubMedCrossRefGoogle Scholar
  40. 40.
    Oschilewski U, Kiesel U, Kolb H. Administration of silica prevents diabetes in BB-rats. Diabetes. 1985; 34(2):197–199.PubMedCrossRefGoogle Scholar
  41. 41.
    Ihm SH, Lee KU, Yoon JW. Studies on autoimmunity for initiation of beta-cell destruction. VII. Evidence for antigenic changes on beta-cells leading to autoimmune destruction of beta-cells in BB rats. Diabetes. 1991; 40(2):269–274.PubMedCrossRefGoogle Scholar
  42. 42.
    Nerup J, Mandrup-Poulsen T, Helqvist S, et al. On the pathogenesis of IDDM. Diabetologia. 1994; 37(Suppl 2):S82–89.PubMedCrossRefGoogle Scholar
  43. 43.
    Kay TWH, Thomas HE, Harrison LC, Allison J. The beta cell in autoimmune diabetes: Many mechanisms and pathways of loss. Trends Endocrinol Metab. 2000; 11(1):11–15.PubMedCrossRefGoogle Scholar
  44. 44.
    Wu G, Flynn NE. The activation of the arginine-citrulline cycle in macrophages from the spontaneously diabetic BB rat. Biochem J. 1993; 294(1):113–118.PubMedGoogle Scholar
  45. 45.
    Lee KU. Nitric oxide produced by macrophages mediates suppression of ConA-induced proliferative responses of splenic leukocytes in the diabetes-prone BB rat. Diabetes. 1994; 43(10):1218–1220.PubMedCrossRefGoogle Scholar
  46. 46.
    Lau A, Ramanathan S, Poussier P. Excessive production of nitric oxide by macrophages from DP-BB rats is secondary to the T-lymphopenic state of these animals. Diabetes. 1998; 47(2):197–205.PubMedCrossRefGoogle Scholar
  47. 47.
    Tafuri A, Bowers WE, Handler ES, et al. High stimulatory activity of dendritic cells from diabetes-prone biobreeding/Worcester rats exposed to macrophage-derived factors. J Clin Invest. 1993; 91(5):2040–2048.PubMedCrossRefGoogle Scholar
  48. 48.
    Delemarre FG, Simons PJ, de Heer HJ, Drexhage HA. Signs of immaturity of splenic dendritic cells from the autoimmune prone biobreeding rat: consequences for the in vitro expansion of regulator and effector T cells. J Immunol. 1999; 162(3):1795–1801.PubMedGoogle Scholar
  49. 49.
    Delemarre FGA, Hoogeveen PG, de Haan-Meulman M, Simons PJ, Drexhage HA. Homotypic cluster formation of dendritic cells, a close correlate of their state of maturation. Defects in the biobreeding diabetes-prone rat. J Leukoc Biol. 2001; 69(3):373–380.PubMedGoogle Scholar
  50. 50.
    Sommandas V, Rutledge EA, Van YB, Fuller J, Lernmark A, Drexhage HA. Aberrancies in the differentiation and maturation of dendritic cells from bone-marrow precursors are linked to various genes on chromosome 4 and other chromosomes of the BB-DP rat. J Autoimmun. 2005; 25(1):1–12.PubMedCrossRefGoogle Scholar
  51. 51.
    Sommandas V, Rutledge EA, Van YB, Fuller J, Lernmark A, Drexhage HA. Defects in differentiation of bone-marrow derived dendritic cells of the BB rat are partly associated with IDDM2 (the lyp gene) and partly associated with other genes in the BB rat background. J Autoimmun. 2005; 25(1):46–56.PubMedCrossRefGoogle Scholar
  52. 52.
    Like AA, Kislauskis E, Williams RR, Rossini AA. Neonatal thymectomy prevents spontaneous diabetes mellitus in the BB/W rat. Science. 1982; 216(4546):644–646.PubMedCrossRefGoogle Scholar
  53. 53.
    Like AA, Biron CA, Weringer EJ, Byman K, Sroczynski E, Guberski DL. Prevention of diabetes in BioBreeding/Worcester rats with monoclonal antibodies that recognize T lymphocytes or natural killer cells. J Exp Med. 1986; 164(4):1145–1159.PubMedCrossRefGoogle Scholar
  54. 54.
    Rabinovitch A, Sumoski WL. Theophylline protects against diabetes in BB rats and potentiates cyclosporine protection. Diabetologia. 1990; 33(8):506–508.PubMedCrossRefGoogle Scholar
  55. 55.
    Crisá L, Mordes JP, Rossini AA. Autoimmune diabetes mellitus in the BB rat. Diabetes Metab Rev. 1992; 8(1):4–37.PubMedCrossRefGoogle Scholar
  56. 56.
    Zipris D, Greiner DL, Malkani S, Whalen B, Mordes JP, Rossini AA. Cytokine gene expression in islets and thyroids of BB rats. IFN-gamma and IL-12p40 mRNA increase with age in both diabetic and insulin-treated nondiabetic BB rats. J Immunol. 1996; 156(3):1315–1321.PubMedGoogle Scholar
  57. 57.
    Hosszufalusi N, Chan E, Granger G, Charles MA. Quantitative analyses comparing all major spleen cell phenotypes in BB and normal rats: autoimmune imbalance and double negative T cells associated with resistant, prone and diabetic animals. J Autoimmun. 1992; 5(3):305–318.PubMedCrossRefGoogle Scholar
  58. 58.
    Jacob HJ, Pettersson A, Wilson D, Mao Y, Lernmark A, Lander ES. Genetic dissection of autoimmune type I diabetes in the BB rat. Nat Genet. 1992; 2(1):56–60.PubMedCrossRefGoogle Scholar
  59. 59.
    Hornum L, Rømer J, Markholst H. The diabetes-prone BB rat carries a frameshift mutation in Ian4, a positional candidate of Iddm1. Diabetes. 2002; 51(6):1972–1979.PubMedCrossRefGoogle Scholar
  60. 60.
    MacMurray AJ, Moralejo DH, Kwitek AE, et al. Lymphopenia in the BB rat model of type 1 diabetes is due to a mutation in a novel immune-associated nucleotide (Ian)-related gene. Genome Res. 2002; 12(7):1029–1039.PubMedCrossRefGoogle Scholar
  61. 61.
    Zadeh HH, Greiner DL, Wu DY, Tausche F, Goldschneider I. Abnormalities in the export and fate of recent thymic emigrants in diabetes-prone BB/W rats. Autoimmunity. 1996; 24(1):35–46.PubMedCrossRefGoogle Scholar
  62. 62.
    Iwakoshi NN, Goldschneider I, Tausche F, Mordes JP, Rossini AA, Greiner DL. High frequency apoptosis of recent thymic emigrants in the liver of lymphopenic diabetes-prone BioBreeding rats. J Immunol. 1998; 160(12):5838–5850.PubMedGoogle Scholar
  63. 63.
    Ramanathan S, Norwich K, Poussier P. Antigen activation rescues recent thymic emigrants from programmed cell death in the BB rat. J Immunol. 1998; 160(12):5757–5764.PubMedGoogle Scholar
  64. 64.
    Hernández-Hoyos G, Joseph S, Miller NG, Butcher GW. The lymphopenia mutation of the BB rat causes inappropriate apoptosis of mature thymocytes. Eur J Immunol. 1999; 29(6):1832–1841.PubMedCrossRefGoogle Scholar
  65. 65.
    Dalberg U, Markholst H, Hornum L. Both Gimap5 and the diabetogenic BBDP allele of Gimap5 induce apoptosis in T cells. Int Immunol. 2007; 19(4):447–453.PubMedCrossRefGoogle Scholar
  66. 66.
    Bell EB, Sparshott SM, Drayson MT, Ford WL. The stable and permanent expansion of functional T lymphocytes in athymic nude rats after a single injection of mature T cells. J Immunol. 1987; 139(5):1379–1384.PubMedGoogle Scholar
  67. 67.
    Khoruts A, Fraser JM. A causal link between lymphopenia and autoimmunity. Immunol Lett. 2005; 98(1):23–31.PubMedCrossRefGoogle Scholar
  68. 68.
    Gold DP, Bellgrau D. Identification of a limited T-cell receptor beta chain variable region repertoire associated with diabetes in the BB rat. Proc Natl Acad Sci USA. 1991; 88(21):9888–9891.PubMedCrossRefGoogle Scholar
  69. 69.
    Bourgeois C, Stockinger B. CD25+CD4+ regulatory T cells and memory T cells prevent lymphopenia-induced proliferation of naive T cells in transient states of lymphopenia. J Immunol. 2006; 177(7):4558–4566.PubMedGoogle Scholar
  70. 70.
    Lang JA, Kominski D, Bellgrau D, Scheinman RI. Partial activation precedes apoptotic death in T cells harboring an IAN gene mutation. Eur J Immunol. 2004; 34(9):2396–2406.PubMedCrossRefGoogle Scholar
  71. 71.
    Kupfer R, Lang J, Williams-Skipp C, Nelson M, Bellgrau D, Scheinman RI. Loss of a gimap/ian gene leads to activation of NF-kappaB through a MAPK-dependent pathway. Mol Immunol. 2007; 44(4):479–487.PubMedCrossRefGoogle Scholar
  72. 72.
    Moore JK, Bellgrau D. Promiscuous activation and cell cycle entry in T cells from autoimmune animals. Transplant Proc. 1999; 31(3):1606–1610.PubMedCrossRefGoogle Scholar
  73. 73.
    Bottini N, Musumeci L, Alonso A, et al. A functional variant of lymphoid tyrosine phosphatase is associated with type I diabetes. Nat Genet. 2004; 36(4):337–338.PubMedCrossRefGoogle Scholar
  74. 74.
    Kyogoku C, Langefeld CD, Ortmann WA et al. Genetic association of the R620W polymorphism of protein tyrosine phosphatase PTPN22 with human SLE. Am J Hum Genet. 2004; 75(3):504–507.PubMedCrossRefGoogle Scholar
  75. 75.
    Moore JK, Scheinman RI, Bellgrau D. The identification of a novel T cell activation state controlled by a diabetogenic gene. J Immunol. 2001; 166(1):241–248.PubMedGoogle Scholar
  76. 76.
    Appleman LJ, Berezovskaya A, Grass I, Boussiotis VA. CD28 costimulation mediates T cell expansion via IL-2-independent and IL-2-dependent regulation of cell cycle progression. J Immunol. 2000; 164(1):144–151.PubMedGoogle Scholar
  77. 77.
    Kubsch S, Graulich E, Knop J, Steinbrink K. Suppressor activity of anergic T cells induced by IL-10-treated human dendritic cells: association with IL-2- and CTLA-4-dependent G1 arrest of the cell cycle regulated by p27Kip1. Eur J Immunol. 2003; 33(7):1988–1997.PubMedCrossRefGoogle Scholar
  78. 78.
    Li L, Iwamoto Y, Berezovskaya A, Boussiotis VA. A pathway regulated by cell cycle inhibitor p27Kip1 and checkpoint inhibitor Smad3 is involved in the induction of T cell tolerance. Nat Immunol. 2006; 7(11):1157–1165.PubMedCrossRefGoogle Scholar
  79. 79.
    Sellins KS, Gold DP, Bellgrau D. Resistance to tolerance induction in the diabetes-prone biobreeding rat as one manifestation of abnormal responses to superantigens. Diabetologia. 1996; 39(1):28–36.PubMedGoogle Scholar
  80. 80.
    Beaudette-Zlatanova BC, Whalen B, Zipris D, et al. Costimulation and autoimmune diabetes in BB rats. Am J Transplant. 2006; 6(5 Pt 1):894–902.PubMedCrossRefGoogle Scholar
  81. 81.
    Rozing J, Coolen C, Tielen FJ, et al. Defects in the thymic epithelial stroma of diabetes prone BB rats. Thymus. 1989; 14(1–3):125–135.PubMedGoogle Scholar
  82. 82.
    Doukas J, Mordes JP, Swymer C et al. Thymic epithelial defects and predisposition to autoimmune disease in BB rats. Am J Pathol. 1994; 145(6):1517–1525.PubMedGoogle Scholar
  83. 83.
    Whalen BJ, Rossini AA, Mordes JP, Greiner DL. DR-BB rat thymus contains thymocyte populations predisposed to autoreactivity. Diabetes. 1995; 44(8):963–967.PubMedCrossRefGoogle Scholar
  84. 84.
    Sommandas V, Rutledge EA, Van YB, Fuller J, Lernmark A, Drexhage HA. Low-density cells isolated from the rat thymus resemble branched cortical macrophages and have a reduced capability of rescuing double-positive thymocytes from apoptosis in the BB-DP rat. J Leukoc Biol. 2007; 82(4):869–876.PubMedCrossRefGoogle Scholar
  85. 85.
    Georgiou HM, Bellgrau D. Thymus transplantation and disease prevention in the diabetes-prone Bio-Breeding rat. J Immunol. 1989; 142(10):3400–3405.PubMedGoogle Scholar
  86. 86.
    Plamondon C, Kottis V, Brideau C, Metroz-Dayer MD, Poussier P. Abnormal thymocyte maturation in spontaneously diabetic BB rats involves the deletion of CD48+ cells. J Immunol 1990; 144(3):923–928.PubMedGoogle Scholar
  87. 87.
    Groen H, Klatter FA, Brons NH, Mesander G, Nieuwenhuis P, Kampinga J. Abnormal thymocyte subset distribution and differential reduction of CD4+ and CD8+ T cell subsets during peripheral maturation in diabetes-prone BioBreeding rats. J Immunol. 1996; 156(3):1269–1275.PubMedGoogle Scholar
  88. 88.
    Jung CG, Kamiyama T, Agui T. Elevated apoptosis of peripheral T lymphocytes in diabetic BB rats. Immunology. 1999; 98(4):590–594.PubMedCrossRefGoogle Scholar
  89. 89.
    Poussier P, Ning T, Murphy T, Dabrowski D, Ramanathan S. Impaired post-thymic development of regulatory CD4+25+ T cells contributes to diabetes pathogenesis in BB rats. J Immunol. 2005; 174(7):4081–4089.PubMedGoogle Scholar
  90. 90.
    Hillebrands JL, Whalen B, Visser JT et al. A regulatory CD4+ T cell subset in the BB rat model of autoimmune diabetes expresses neither CD25 nor Foxp3. J Immunol. 2006; 177(11):7820–7832.PubMedGoogle Scholar
  91. 91.
    Francfort JW, Barker CF, Kimura H, Silvers WK, Frohman M, Naji A. Increased incidence of Ia antigen-bearing T lymphocytes in the spontaneously diabetic BB rat. J Immunol. 1985; 134(3):1577–1582.PubMedGoogle Scholar
  92. 92.
    Lundsgaard D, Holm TL, Hornum L, Markholst H. In vivo control of diabetogenic T-cells by regulatory CD4+CD25+ T-cells expressing Foxp3. Diabetes. 2005; 54(4):1040–1047.PubMedCrossRefGoogle Scholar
  93. 93.
    Greiner DL, Mordes JP, Handler ES, Angelillo M, Nakamura N, Rossini AA. Depletion of RT6.1+ T lymphocytes induces diabetes in resistant biobreeding/Worcester (BB/W) rats. J Exp Med. 1987; 166(2):461–475.PubMedCrossRefGoogle Scholar
  94. 94.
    Whalen BJ, Greiner DL, Mordes JP, Rossini AA. Adoptive transfer of autoimmune diabetes mellitus to athymic rats: synergy of CD4+ and CD8+ T cells and prevention by RT6+ T cells. J Autoimmun. 1994; 7(6):819–831.PubMedCrossRefGoogle Scholar
  95. 95.
    Groen H, Klatter F, Pater J, Nieuwenhuis P, Rozing J. Temporary, but essential requirement of CD8+ T cells early in the pathogenesis of diabetes in BB rats as revealed by thymectomy and CD8 depletion. Clin Dev Immunol. 2003; 10(2–4):141–151.PubMedCrossRefGoogle Scholar
  96. 96.
    Guberski DL, Thomas VA, Shek WR, et al. Induction of type I diabetes by Kilham’s rat virus in diabetes-resistant BB/Wor rats. Science. 1991; 254(5034):1010–1013.PubMedCrossRefGoogle Scholar
  97. 97.
    Zipris D, Lien E, Nair A, et al. TLR9-signaling pathways are involved in Kilham rat virus-induced autoimmune diabetes in the biobreeding diabetes-resistant rat. J Immunol. 2007; 178(2):693–701.PubMedGoogle Scholar
  98. 98.
    Chung YH, Jun HS, Son M, et al. Cellular and molecular mechanism for Kilham rat virus-induced autoimmune diabetes in DR-BB rats. J Immunol. 2000; 165(5):2866–2876.PubMedGoogle Scholar
  99. 99.
    Zipris D, Hillebrands JL, Welsh RM, et al. Infections that induce autoimmune diabetes in BBDR rats modulate CD4+CD25+ T cell populations. J Immunol. 2003; 170(7):3592–3602.PubMedGoogle Scholar
  100. 100.
    Zipris D, Lien E, Xie JX, Greiner DL, Mordes JP, Rossini AA. TLR activation synergizes with Kilham rat virus infection to induce diabetes in BBDR rats. J Immunol. 2005; 174(1):131–142.PubMedGoogle Scholar
  101. 101.
    Sobel DO, Newsome J, Ewel CH, et al. Poly I:C induces development of diabetes mellitus in BB rat. Diabetes. 1992; 41(4):515–520.PubMedCrossRefGoogle Scholar
  102. 102.
    Hornum L, Lundsgaard D, Markholst H. PolyI:C induction of diabetes is controlled by Iddm4 in rats with a full regulatory T cell pool. Ann N Y Acad Sci. 2007; 1110:65–72.PubMedCrossRefGoogle Scholar
  103. 103.
    Blankenhorn EP, Rodemich L, Martin-Fernandez C, Leif J, Greiner DL, Mordes JP. The rat diabetes susceptibility locus Iddm4 and at least one additional gene are required for autoimmune diabetes induced by viral infection. Diabetes. 2005; 54(4):1233–1237.PubMedCrossRefGoogle Scholar
  104. 104.
    Blankenhorn EP, Descipio C, Rodemich L, et al. Refinement of the Iddm4 diabetes susceptibility locus reveals TCRVbeta4 as a candidate gene. Ann N Y Acad Sci. 2007; 1103:128–131.PubMedCrossRefGoogle Scholar
  105. 105.
    Elder ME, Maclaren NK. Identification of profound peripheral T lymphocyte immunodeficiencies in the spontaneously diabetic BB rat. J Immunol. 1983; 130(4):1723–1731.PubMedGoogle Scholar
  106. 106.
    Dyrberg T, Schwimmbeck P, Oldstone M. The incidence of diabetes in BB rats is decreased following acute LCMV infection. Adv Exp Med Biol. 1988; 246: 397–402.PubMedCrossRefGoogle Scholar
  107. 107.
    Dyrberg T, Schwimmbeck PL, Oldstone MB. Inhibition of diabetes in BB rats by virus infection. J Clin Invest. 1988; 81(3):928–931.PubMedCrossRefGoogle Scholar
  108. 108.
    Oldstone MB, Tishon A, Schwimmbeck PL, Shyp S, Lewicki H, Dyrberg T. Cytotoxic T lymphocytes do not control lymphocytic choriomeningitis virus infection of BB diabetes-prone rats. J Gen Virol. 1990; 71(Pt 4):785–791.PubMedCrossRefGoogle Scholar
  109. 109.
    Schwimmbeck PL, Dyrberg T, Oldstone MB. Abrogation of diabetes in BB rats by acute virus infection. Association of viral-lymphocyte interactions. J Immunol. 1988; 140(10):3394–3400.PubMedGoogle Scholar
  110. 110.
    Tullin S, Farris P, Petersen JS, Hornum L, Jackerott M, Markholst H. A pronounced thymic B cell deficiency in the spontaneously diabetic BB rat. J Immunol. 1997; 158(11):5554–5559.PubMedGoogle Scholar
  111. 111.
    Dyrberg T, Poussier P, Nakhooda F, Marliss EB, Lernmark A. Islet cell surface and lymphocyte antibodies often precede the spontaneous diabetes in the BB rat. Diabetologia. 1984; 26(2):159–165.PubMedCrossRefGoogle Scholar
  112. 112.
    Markholst H, Klaff LJ, Klöppel G, Lernmark A, Mordes JP, Palmer J. Lack of systematically found insulin autoantibodies in spontaneously diabetic BB rats. Diabetes. 1990; 39(6):720–727.PubMedCrossRefGoogle Scholar
  113. 113.
    DeSilva MG, Jun HS, Yoon JW, Notkins AL, Lan MS. Autoantibodies to IA-2 not detected in NOD mice or BB rats. Diabetologia. 1996; 39(10):1237–1238.PubMedCrossRefGoogle Scholar
  114. 114.
    Kitagawa Y, Greiner DL, Reynolds CW et al. Islet cells but not thyrocytes are susceptible to lysis by NK cells. J Autoimmun. 1991; 4(5):703–716.PubMedCrossRefGoogle Scholar
  115. 115.
    MacKay P, Jacobson J, Rabinovitch A. Spontaneous diabetes mellitus in the Bio-Breeding/Worcester rat. Evidence in vitro for natural killer cell lysis of islet cells. J Clin Invest. 1986; 77(3):916–924.PubMedCrossRefGoogle Scholar
  116. 116.
    Woda BA, Biron CA. Natural killer cell number and function in the spontaneously diabetic BB/W rat. J Immunol 1986; 137(6):1860–1866.PubMedGoogle Scholar
  117. 117.
    Jacobson JD, Markmann JF, Brayman KL, Barker CF, Naji A. Prevention of recurrent autoimmune diabetes in BB rats by anti-asialo-GM1 antibody. Diabetes. 1988; 37(6):838–841.PubMedCrossRefGoogle Scholar
  118. 118.
    Sobel DO, Azumi N, Creswell K, et al. The role of NK cell activity in the pathogenesis of poly I: C accelerated and spontaneous diabetes in the diabetes prone BB rat. J Autoimmun. 1995; 8(6):843–857.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Ulla Nøhr Dalberg
    • 1
  • Claus Haase
    • 1
  • Lars Hornum
    • 1
  • Helle Markholst
    • 2
  1. 1.Department of ImmunopharmacologyNovo Nordisk ParkMåløvDenmark
  2. 2.Department of ImmunopharmacologyNovo Nordisk a/sMåløvDenmark

Personalised recommendations