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Bridging Mice to Men: Using HLA Transgenic Mice to Enhance the Future Prediction and Prevention of Autoimmune Type 1 Diabetes in Humans

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Mouse Models for Drug Discovery

Part of the book series: Methods in Molecular Biology ((MIMB,volume 1438))

Abstract

Similar to the vast majority of cases in humans, the development of type 1 diabetes (T1D) in the NOD mouse model is due to T-cell mediated autoimmune destruction of insulin producing pancreatic β cells. Particular major histocompatibility complex (MHC) haplotypes (designated HLA in humans; and H2 in mice) provide the primary genetic risk factor for T1D development. It has long been appreciated that within the MHC, particular unusual class II genes contribute to the development of T1D in both humans and NOD mice by allowing for the development and functional activation of β cell autoreactive CD4 T cells. However, studies in NOD mice have revealed that through interactions with other background susceptibility genes, the quite common class I variants (Kd, Db) characterizing this strain’s H2 g7 MHC haplotype aberrantly acquire an ability to support the development of β cell autoreactive CD8 T cell responses also essential to T1D development. Similarly, recent studies indicate that in the proper genetic context some quite common HLA class I variants also aberrantly contribute to T1D development in humans. This review focuses on how “humanized” HLA transgenic NOD mice can be created and used to identify class I dependent β cell autoreactive CD8 T cell populations of clinical relevance to T1D development. There is also discussion on how HLA transgenic NOD mice can be used to develop protocols that may ultimately be useful for the prevention of T1D in humans by attenuating autoreactive CD8 T cell responses against pancreatic β cells.

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References

  1. Anderson MS, Bluestone JA (2005) The NOD mouse: a model of immune dysregulation. Annu Rev Immunol 23:447–485

    Article  CAS  PubMed  Google Scholar 

  2. Serreze DV, Leiter EH (2001) Genes and pathways underlying autoimmune diabetes in NOD mice. In: von Herrath MG (ed) Molecular pathology of insulin dependent diabetes mellitus. Karger Press, New York, pp 31–67

    Chapter  Google Scholar 

  3. Onengut-Gumuscu S, Concannon P (2006) Recent advances in the immunogenetics of human type 1 diabetes. Curr Opin Immunol 18:634–638

    Article  CAS  PubMed  Google Scholar 

  4. Mellman I (2007) Private lives: reflections and challenges in understanding the cell biology of the immune system. Science 317:625–627

    Article  CAS  PubMed  Google Scholar 

  5. Aly TA, Ide A, Jahromi MM, Barker JM, Fernando MS et al (2006) Extreme genetic risk for type 1A diabetes. Proc Natl Acad Sci U S A 103:14074–14079

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Erlich H, Valdes AM, Noble J, Carlson JA, Varney M et al (2008) HLA DR-DQ haplotypes and genotypes and type 1 diabetes risk: analysis of the type 1 diabetes genetics consortium families. Diabetes 57:1084–1092

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Hanson MS, Cetkovic-Cvrlje M, Ramiya VK, Atkinson MA, MacLaren NK et al (1996) Quantitative thresholds of MHC class II I-E expressed on hematopoietically derived APC in transgenic NOD/Lt mice determine level of diabetes resistance and indicate mechanism of protection. J Immunol 157:1279–1287

    CAS  PubMed  Google Scholar 

  8. Lund T, O’Reilly L, Hutchings P, Kanagawa O, Simpson E et al (1990) Prevention of insulin-dependent diabetes mellitus in non-obese diabetic mice by transgenes encoding modified I-A β-chain or normal I-E α-chain. Nature 345:727–729

    Article  CAS  PubMed  Google Scholar 

  9. Miyazaki T, Uno M, Uehira M, Kikutani H, Kishimoto T et al (1990) Direct evidence for the contribution of the unique I-Anod to the development of insulitis in non-obese diabetic mice. Nature 345:722–724

    Article  CAS  PubMed  Google Scholar 

  10. Singer SM, Tisch R, Yang X-D, McDevitt HO (1993) An Abd transgene prevents diabetes in nonobese diabetic mice by inducing regulatory T cells. Proc Natl Acad Sci U S A 90:9566–9570

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Slattery RM, Kjer-Nielsen L, Allison J, Charlton B, Mandel T et al (1990) Prevention of diabetes in non-obese diabetic I-Ak transgenic mice. Nature 345:724–726

    Article  CAS  PubMed  Google Scholar 

  12. Christianson SW, Shultz LD, Leiter EH (1993) Adoptive transfer of diabetes into immunodeficient NOD-scid/scid mice: relative contributions of CD4+ and CD8+ T lymphocytes from diabetic versus prediabetic NOD.NON-Thy 1 a donors. Diabetes 42:44–55

    Article  CAS  PubMed  Google Scholar 

  13. Zijlstra M, Bix M, Simister NE, Loring JM, Raulet DH et al (1990) β2-microglobulin deficient mice lack CD4-8+ cytolytic T cells. Nature 344:742–746

    Article  CAS  PubMed  Google Scholar 

  14. Koller BH, Marrack P, Kappler JW, Smithes O (1990) Normal development of mice deficient in b2m, MHC class I proteins, and CD8+ T cells. Science 248:1227–1230

    Article  CAS  PubMed  Google Scholar 

  15. Serreze DV, Leiter EH, Christianson GJ, Greiner D, Roopenian DC (1994) MHC class I deficient NOD-B2m null mice are diabetes and insulitis resistant. Diabetes 43:505–509

    Article  CAS  PubMed  Google Scholar 

  16. Wicker LS, Leiter EH, Todd JA, Renjilian RJ, Peterson E et al (1994) β2-microglobulin-deficient NOD mice do not develop insulitis or diabetes. Diabetes 43:500–504

    Article  CAS  PubMed  Google Scholar 

  17. Sumida T, Furukawa M, Sakamoto A, Namekawa T, Maeda T et al (1994) Prevention of insulitis and diabetes in beta(2)-microglobulin-deficient non-obese diabetic mice. Int Immunol 6:1445–1449

    Article  CAS  PubMed  Google Scholar 

  18. Serreze DV, Choisy-Rossi C-M, Grier A, Holl TM, Chapman HD et al (2008) Through regulation of TCR expression levels, an Idd7 region gene(s) interactively contributes to the impaired thymic deletion of autoreactive diabetogenic CD8 T-cells in NOD mice. J Immunol 180:3250–3259

    Article  CAS  PubMed  Google Scholar 

  19. Nejentsev S, Howson JMM, Walker NM, Szeszko J, Field SF et al (2007) Localization of type 1 diabetes susceptibility to the MHC class I genes HLA-B and HLA-A. Nature 450:887–892

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Demaine AG, Hibberd ML, Mangles D, Millward BA (1995) A new marker in the HLA class I region is associated with the age at onset of IDDM. Diabetologia 38:622–628

    Article  Google Scholar 

  21. Fennessy M, Metcalfe K, Hitman GA, Niven M, Biro PA et al (1994) A gene in the HLA class I region contributes to susceptibility to IDDM in the Finnish population. Diabetologia 37:937–944

    Article  CAS  PubMed  Google Scholar 

  22. Honeyman MC, Harrison LC, Drummond B, Colman PG, Tait BD (1995) Analysis of families at risk for insulin-dependent diabetes mellitus reveals that HLA antigens influence progression to clinical disease. Mol Med 1:576–582

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Mizota M, Uchigata Y, Moriyama S, Tokunaga K, Matsuura N et al (1996) Age dependent association of HLA-A24 in Japanese IDDM patients. Diabetologia 39:371–373

    Article  CAS  PubMed  Google Scholar 

  24. Nakanishi K, Kobayashi T, Murase T, Naruse T, Nose Y et al (1999) Human leukocyte antigen-A24 and-DQA1*0301 in Japanese insulin-dependent diabetes mellitus: independent contributions to susceptibility to the disease and additive contributions to acceleration of beta-cell destruction. J Clin Endocrinol Metab 84:3721–3725

    CAS  PubMed  Google Scholar 

  25. Nejentsev S, Reijonen H, Adojaan B, Kovalchuk L, Sochnevs A et al (1997) The effect of HLA-B allele on the IDDM risk defined by DRB1*04 subtypes and DQB1*0302. Diabetes 46:1888–1892

    Article  CAS  PubMed  Google Scholar 

  26. Nejentsev S, Gombos Z, Laine A-P, Veijola R, Knip M et al (2000) Non-class II HLA gene associated with type 1 diabetes maps to the 240-kb region near HLA-B. Diabetes 49:2217–2221

    Article  CAS  PubMed  Google Scholar 

  27. Robles DT, Eisenbarth GS, Wang T, Erlich HA, Bugawan TL et al (2002) Identification of children with early onset and high incidence of anti-islet autoantibodies. Clin Immunol 102:217–224

    Article  CAS  PubMed  Google Scholar 

  28. Tait BD, Colman PG, Morahan G, Marchinovska L, Dore E et al (2003) HLA genes associated with autoimmunity and progression to disease in type 1 diabetes. Tissue Antigens 61:146–153

    Article  CAS  PubMed  Google Scholar 

  29. Undlien DE, Lie BA, Thorsby E (2001) HLA complex genes in type 1 diabetes and other autoimmune diseases. Which genes are involved? Trends Genet 17:93–100

    Article  CAS  PubMed  Google Scholar 

  30. Geluk A, van Meijgaarden KE, Fraken KLMC, Drijfhout JW, D’Souza S et al (2000) Identification of major epitopes of Mycobacterium tuberculosis AG85B that are recognized by HLA-A0201 restricted CD8+ T cells in HLA-transgenic mice and humans. J Immunol 165:6463–6471

    Article  CAS  PubMed  Google Scholar 

  31. Shirai M, Arichi T, Nishioka M, Nomura T, Ikeda K et al (1995) CTL responses of HLA-A2.1-transgenic mice specific for Hepatitis C viral peptides predict epitopes for CTL of humans carrying HLA-2.1. J Immunol 154:2733–2742

    CAS  PubMed  Google Scholar 

  32. Serreze DV, Chapman HD, Varnum DS, Hanson MS, Reifsnyder PC et al (1996) B lymphocytes are essential for the initiation of T cell mediated autoimmune diabetes: analysis of a new “speed congenic” stock of NOD.Igμ null mice. J Exp Med 184:2049–2053

    Article  CAS  PubMed  Google Scholar 

  33. Wang B, Andre I, Gonzalez A, Katz JD, Aguet M et al (1997) Interferon-γ impacts at multiple points during progression of autoimmune diabetes. Proc Natl Acad Sci U S A 94:13844–13849

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Kanagawa O, Xu G, Tevaarwerk A, Vaupel BA (2000) Protection of nonobese diabetic mice from diabetes by gene(s) closely linked to IFN-γ receptor loci. J Immunol 164:3919–3923

    Article  CAS  PubMed  Google Scholar 

  35. Leiter EH (1997) The NOD mouse: a model for insulin-dependent diabetes mellitus. Curr Protoc Immunol 24:15.19.11–15.19.23

    Google Scholar 

  36. Nagy A, Gertsenstein M, Vintersten K, Behringer R (2003) Manipulating the mouse embryo: a laboratory manual, 3rd edn. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY

    Google Scholar 

  37. Marron MP, Graser RT, Chapman HD, Serreze DV (2002) Functional evidence for the mediation of diabetogenic T cell responses by human HLA-A2.1 MHC class I molecules through transgenic expression in NOD mice. Proc Natl Acad Sci U S A 99:13753–13758

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Takaki T, Marron MP, Mathews CE, Guttman ST, Bottino R et al (2006) HLA-A*0201-restricted T cells from humanized NOD mice recognize autoantigens of potential clinical relevance to type 1 diabetes. J Immunol 176:3257–3265

    Article  CAS  PubMed  Google Scholar 

  39. Irwin MJ, Heath WR, Sherman LA (1989) Species-restricted interactions between CD8 and the alpha 3 domain of class I influence the magnitude of the xenogeneic response. J Exp Med 170:1091–1101

    Article  CAS  PubMed  Google Scholar 

  40. Lieberman SM, Takaki T, Han B, Santamaria P, Serreze DV et al (2004) Individual nonobese diabetic mice exhibit unique patterns of CD8 T cell reactivity to three islet antigens including the newly identified widely expressed dystrophia myotonica kinase. J Immunol 173:6727–6734

    Article  CAS  PubMed  Google Scholar 

  41. Jarchum I, Baker JC, Yamada T, Takaki T, Marron MP et al (2007) In vivo cytotoxicity of insulin specific CD8+ T cells in HLA-A*0201 transgenic NOD mice. Diabetes 56:2551–2560

    Article  CAS  PubMed  Google Scholar 

  42. Mallone R, Martinuzzi E, Blancou P, Novelli G, Afonzo G et al (2007) CD8+ T cell responses identify β-cell autoimmunity in human type 1 diabetes. Diabetes 56:613–621

    Article  CAS  PubMed  Google Scholar 

  43. Ouyang Q, Standifer NE, Qin H, Gottlieb PA, Verchere CB et al (2006) Recognition of HLA-class I restricted β-cell epitopes in type 1 diabetes. Diabetes 55:3068–3074

    Article  CAS  PubMed  Google Scholar 

  44. Panagiotopoulos C, Qin H, Tan R, Verchere CB (2003) Identification of a β cell specific HLA class I restricted epitope in type 1 diabetes. Diabetes 52:2647–2651

    Article  CAS  PubMed  Google Scholar 

  45. Pinske GGM, Tysma OHM, Bergen CAM, Kester MGD, Ossendorp F et al (2005) Autoreactive CD8 T cells associated with β cell destruction in type 1 diabetes. Proc Natl Acad Sci U S A 102:18425–18430

    Article  Google Scholar 

  46. Standifer NE, Ouyang Q, Panagiotopoulos C, Verchere CB, Tan R et al (2006) Identification of novel HLA-A*0201-restricted epitopes in recent onset type 1 diabetic subjects and antibody positive relatives. Diabetes 55:3061–3067

    Article  CAS  PubMed  Google Scholar 

  47. Toma A, Haddouk S, Briand JP, Camoin L, Gahery H et al (2005) Recognition of a subregion of human proinsulin by class I restricted T cells in type 1 diabetic patients. Proc Natl Acad Sci U S A 102:10581–10586

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Han B, Serra P, Amrani A, Yamanouchi J, Maree AF et al (2005) Prevention of diabetes by manipulation of anti-IGRP autoimmunity: high efficiency of a low affinity peptide. Nat Med 11:645–652

    Article  CAS  PubMed  Google Scholar 

  49. Krishnamurthy B, Dudek N, McKenzie MD, Purcell AW, Brooks AG et al (2006) Responses against islet antigens in NOD mice are prevented by tolerance to proinsulin but not IGRP. J Clin Invest 116:3258–3265

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Jaeckel E, Lipes MA, von Boehmer H (2004) Recessive tolerance to preproinsulin 2 reduces but does not abolish type 1 diabetes. Nat Immunol 5:1028–1035

    Article  CAS  PubMed  Google Scholar 

  51. Nakayama T, Abiru N, Moriyama H, Babaya N, Liu E et al (2005) Prime role for an insulin epitope in the development of type 1 diabetes in NOD mice. Nature 435:220–223

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Mukhopadhaya A, Hanafusa T, Jarchum I, Chen YG, Iwai Y et al (2008) Selective delivery of beta cell antigen to dendritic cells in vivo leads to deletion and tolerance of autoreactive CD8+ T cells in NOD mice. Proc Natl Acad Sci U S A 105:6374–6379

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Chen Y-G, Silveira P, Osborne MA, Chapman HD, Serreze DV (2007) Cellular expression requirements for inhibition of type 1 diabetes by a dominantly protective major histocompatibility complex haplotype. Diabetes 56:424–430

    Article  CAS  PubMed  Google Scholar 

  54. Ikehara S, Ohtsuki H, Good RA, Asamoto H, Nakamura T et al (1985) Prevention of type 1 diabetes in nonobese diabetic mice by allogeneic bone marrow transplantation. Proc Natl Acad Sci U S A 82:7743–7747

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Ildstad ST, Chilton PM, Xu H, Domenick MA, Ray MB (2005) Preconditioning of NOD mice with anti-CD8 mAb and co-stimulatory blockade enhances chimerism and tolerance and prevents diabetes while depletion of aβ TCR+ and CD4 T cells negates the effect. Blood 105:2577–2584

    Article  CAS  PubMed  Google Scholar 

  56. LaFace DW, Peck AB (1989) Reciprocal allogeneic bone marrow transplantation between NOD mice and diabetes-nonsusceptible mice associated with transfer and prevention of autoimmune diabetes. Diabetes 38:894–901

    Article  CAS  PubMed  Google Scholar 

  57. Li H, Kaufman CL, Boggs SS, Johnson PC, Patrene KD et al (1996) Mixed allogeneic chimerism induced by a sublethal approach prevents autoimmune diabetes and reverses insulitis in nonobese diabetic (NOD) mice. J Immunol 156:380–388

    CAS  PubMed  Google Scholar 

  58. Mathieu C, Castells K, Bouillon R, Waer M (1997) Protection against autoimmune diabetes in mixed bone marrow chimeras. J Immunol 158:1453–1457

    CAS  PubMed  Google Scholar 

  59. Nikolic B, Takeuchi Y, Leykin I, Fudaba Y, Smith RN et al (2004) Mixed hematopoietic chimerism allows cure of autoimmune diabetes through allogeneic tolerance and reversal of autoimmunity. Diabetes 53:376–383

    Article  CAS  PubMed  Google Scholar 

  60. Serreze DV, Leiter EH (1991) Development of diabetogenic T cells from NOD/Lt marrow is blocked when an allo-H-2 haplotype is expressed on cells of hematopoietic origin, but not on thymic epithelium. J Immunol 147:1222–1229

    CAS  PubMed  Google Scholar 

  61. Serreze DV, Osborne MA, Chen Y-G, Chapman HD, Pearson T et al (2006) Partial versus full allogeneic hemopoietic chimerization is a preferential means to inhibit type 1 diabetes as the latter induces generalized immunosuppression. J Immunol 177:6675–6684

    Article  CAS  PubMed  Google Scholar 

  62. Seung E, Iwakoshi N, Woda BA, Markees TG, Mordes JP et al (2000) Allogeneic hematopoietic chimerism in mice treated with sublethal myeloablation and anti-CD154 antibody: absence of graft-versus-host disease, induction of skin allograft tolerance, and prevention of recurrent autoimmunity in islet-allografted NOD/Lt mice. Blood 95:2175–2182

    CAS  PubMed  Google Scholar 

  63. Serreze DV, Holl TM, Marron MP, Graser RT, Johnson EA et al (2004) MHC class II molecules play a role in the selection of autoreactive class I restricted CD8 T cells that are essential contributors to type 1 diabetes development in NOD mice. J Immunol 172:871–879

    Article  CAS  PubMed  Google Scholar 

  64. Shultz LD, Ishikawa F, Greiner DL (2007) Humanized mice in translational biomedical research. Nat Rev Immunol 7:118–130

    Article  CAS  PubMed  Google Scholar 

  65. King M, Pearson T, Shultz LD, Leif J, Bottino R et al (2008) A new Hu-PBL model for the study of human islet alloreactivity based on NOD-scid mice bearing a targeted mutation in the IL-2 receptor gamma chain gene. Clin Immunol 126:303–314

    Article  CAS  PubMed  Google Scholar 

  66. Ishikawa F, Yasukawa M, Lyons B, Yoshida S, Miyamoto T et al (2005) Development of functional human blood and immune systems in NOD/SCID/IL2 γ chainnull mice. Blood 106:1565–1573

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. The Jackson Laboratory, 600 Main Street, Bar Harbor, ME, 04609, USA

    David V. Serreze, Marijke Niens & John Kulik

  2. Department of Microbiology & Immunology, Albert Einstein College of Medicine, Bronx, NY, 10461, USA

    Teresa P. DiLorenzo

  3. Division of Endocrinology, Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, 10461, USA

    Teresa P. DiLorenzo

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  1. David V. Serreze
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  2. Marijke Niens
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  3. John Kulik
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  4. Teresa P. DiLorenzo
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Correspondence to David V. Serreze .

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  1. Takeda Pharmaceutical Company, Cambridge, Massachusetts, USA

    Gabriele Proetzel

  2. The Jackson Laboratory, Bar Harbor, Maine, USA

    Michael V. Wiles

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Serreze, D.V., Niens, M., Kulik, J., DiLorenzo, T.P. (2016). Bridging Mice to Men: Using HLA Transgenic Mice to Enhance the Future Prediction and Prevention of Autoimmune Type 1 Diabetes in Humans. In: Proetzel, G., Wiles, M. (eds) Mouse Models for Drug Discovery. Methods in Molecular Biology, vol 1438. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-3661-8_9

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  • DOI: https://doi.org/10.1007/978-1-4939-3661-8_9

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