The Role of NOD Mice in Type 1 Diabetes Research: Lessons from the Past and Recommendations for the Future

Yi-Guang Chen, Clayton E Mathews, John P Driver, Yi-Guang Chen, Clayton E Mathews, John P Driver

Abstract

For more than 35 years, the NOD mouse has been the primary animal model for studying autoimmune diabetes. During this time, striking similarities to the human disease have been uncovered. In both species, unusual polymorphisms in a major histocompatibility complex (MHC) class II molecule confer the most disease risk, disease is caused by perturbations by the same genes or different genes in the same biological pathways and that diabetes onset is preceded by the presence of circulating autoreactive T cells and autoantibodies that recognize many of the same islet antigens. However, the relevance of the NOD model is frequently challenged due to past failures translating therapies from NOD mice to humans and because the appearance of insulitis in mice and some patients is different. Nevertheless, the NOD mouse remains a pillar of autoimmune diabetes research for its usefulness as a preclinical model and because it provides access to invasive procedures as well as tissues that are rarely procured from patients or controls. The current article is focused on approaches to improve the NOD mouse by addressing reasons why immune therapies have failed to translate from mice to humans. We also propose new strategies for mixing and editing the NOD genome to improve the model in ways that will better advance our understanding of human diabetes. As proof of concept, we report that diabetes is completely suppressed in a knock-in NOD strain with a serine to aspartic acid substitution at position 57 in the MHC class II Aβ. This supports that similar non-aspartic acid substitutions at residue 57 of variants of the human class II HLA-DQβ homolog confer diabetes risk.

Keywords: NOD mouse; congenic; gene editing; genetics; preclinical; type 1 diabetes.

Figures

Figure 1
Figure 1
Differential staining of the major histocompatibility complex (MHC) class II molecule in wild-type NOD and NOD.Abg7-S57D mice. Total splenocytes were stained with anti-CD11c, anti-CD19, and the indicated I-Ab antibody clone at different titers. Shown is the I-Ab staining on B cells (CD19+ CD11c−) of NOD (dashed line) and NOD.Abg7-S57D (solid line) mice. The shaded area is the negative control staining using splenocytes isolated from I-Ab deficient NOD mice (NOD/ShiLtJ-H2-Ab1em1Ygch/J, JAX stock no. 027057). Similar results were obtained in two independent experiments.
Figure 2
Figure 2
NOD.Abg7-S57D mice are completely resistant to type 1 diabetes. NOD and NOD.Abg7-S57D mice were monitored for diabetes development weekly for 30 weeks by testing urine glucose. Diabetes onset was defined by two consecutive readings of >250 mg/dl.

References

    1. Melanitou E, Devendra D, Liu E, Miao D, Eisenbarth GS. Early and quantal (by litter) expression of insulin autoantibodies in the nonobese diabetic mice predict early diabetes onset. J Immunol (2004) 173:6603–10.10.4049/jimmunol.173.11.6603
    1. You S, Belghith M, Cobbold S, Alyanakian MA, Gouarin C, Barriot S, et al. Autoimmune diabetes onset results from qualitative rather than quantitative age-dependent changes in pathogenic T-cells. Diabetes (2005) 54:1415–22.10.2337/diabetes.54.5.1415
    1. Gregori S, Giarratana N, Smiroldo S, Adorini L. Dynamics of pathogenic and suppressor T cells in autoimmune diabetes development. J Immunol (2003) 171:4040–7.10.4049/jimmunol.171.8.4040
    1. Pugliese A. Autoreactive T cells in type 1 diabetes. J Clin Invest (2017) 127:2881–91.10.1172/JCI94549
    1. Regnell SE, Lernmark Å. Early prediction of autoimmune (type 1) diabetes. Diabetologia (2017) 60:1370–81.10.1007/s00125-017-4308-1
    1. Wester A, Skärstrand H, Lind A, Ramelius A, Carlsson A, Cedervall E, et al. An increased diagnostic sensitivity of truncated GAD65 autoantibodies in type 1 diabetes may be related to HLA-DQ8. Diabetes (2017) 66:735–40.10.2337/db16-0891
    1. Katsarou A, Gudbjörnsdottir S, Rawshani A, Dabelea D, Bonifacio E, Anderson BJ, et al. Type 1 diabetes mellitus. Nat Rev Dis Primers (2017) 3:17016.10.1038/nrdp.2017.16
    1. Mathews CE, Xue S, Posgai A, Lightfoot YL, Li X, Lin A, et al. Acute versus progressive onset of diabetes in NOD mice: potential implications for therapeutic interventions in type 1 diabetes. Diabetes (2015) 64:3885–90.10.2337/db15-0449
    1. DiLorenzo TP, Graser RT, Ono T, Christianson GJ, Chapman HD, Roopenian DC, et al. Major histocompatibility complex class I-restricted T cells are required for all but the end stages of diabetes development in nonobese diabetic mice and use a prevalent T cell receptor alpha chain gene rearrangement. Proc Natl Acad Sci U S A (1998) 95:12538–43.10.1073/pnas.95.21.12538
    1. Campbell-Thompson M, Fu A, Kaddis JS, Wasserfall C, Schatz DA, Pugliese A, et al. Insulitis and β-cell mass in the natural history of type 1 diabetes. Diabetes (2016) 65:719–31.10.2337/db15-0779
    1. Driver JP, Chen YG, Mathews CE. Comparative genetics: synergizing human and NOD mouse studies for identifying genetic causation of type 1 diabetes. Rev Diabet Stud (2012) 9:169–87.10.1900/RDS.2012.9.169
    1. Uchigata Y, Okada T, Gong JS, Yamada Y, Iwamoto Y, Tanaka M. A mitochondrial genotype associated with the development of autoimmune-related type 1 diabetes. Diabetes Care (2002) 25:2106.10.2337/diacare.25.11.2106
    1. Mathews CE, Leiter EH, Spirina O, Bykhovskaya Y, Gusdon AM, Ringquist S, et al. mt-Nd2 Allele of the ALR/Lt mouse confers resistance against both chemically induced and autoimmune diabetes. Diabetologia (2005) 48:261–7.10.1007/s00125-004-1644-8
    1. Onengut-Gumuscu S, Chen WM, Burren O, Cooper NJ, Quinlan AR, Mychaleckyj JC, et al. Fine mapping of type 1 diabetes susceptibility loci and evidence for colocalization of causal variants with lymphoid gene enhancers. Nat Genet (2015) 47:381–6.10.1038/ng.3245
    1. Vijayakrishnan L, Slavik JM, Illes Z, Greenwald RJ, Rainbow D, Greve B, et al. An autoimmune disease-associated CTLA-4 splice variant lacking the B7 binding domain signals negatively in T cells. Immunity (2004) 20:563–75.10.1016/S1074-7613(04)00110-4
    1. Ueda H, Howson JM, Esposito L, Heward J, Snook H, Chamberlain G, et al. Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease. Nature (2003) 423:506–11.10.1038/nature01621
    1. Araki M, Chung D, Liu S, Rainbow DB, Chamberlain G, Garner V, et al. Genetic evidence that the differential expression of the ligand-independent isoform of CTLA-4 is the molecular basis of the Idd5.1 type 1 diabetes region in nonobese diabetic mice. J Immunol (2009) 183:5146–57.10.4049/jimmunol.0802610
    1. Lin X, Pelletier S, Gingras S, Rigaud S, Maine CJ, Marquardt K, et al. CRISPR-Cas9-mediated modification of the NOD mouse genome with Ptpn22R619W mutation increases autoimmune diabetes. Diabetes (2016) 65:2134–8.10.2337/db16-0061
    1. Winkler C, Krumsiek J, Lempainen J, Achenbach P, Grallert H, Giannopoulou E, et al. A strategy for combining minor genetic susceptibility genes to improve prediction of disease in type 1 diabetes. Genes Immun (2012) 13:549–55.10.1038/gene.2012.36
    1. Howson JM, Cooper JD, Smyth DJ, Walker NM, Stevens H, She JX, et al. Evidence of gene-gene interaction and age-at-diagnosis effects in type 1 diabetes. Diabetes (2012) 61:3012–7.10.2337/db11-1694
    1. Grant CW, Moran-Paul CM, Duclos SK, Guberski DL, Arreaza-Rubín G, Spain LM. Testing agents for prevention or reversal of type 1 diabetes in rodents. PLoS One (2013) 8:e72989.10.1371/journal.pone.0072989
    1. 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) 346:1685–91.10.1056/NEJMoa012350
    1. Skyler JS, Krischer JP, Wolfsdorf J, Cowie C, Palmer JP, Greenbaum C, et al. Effects of oral insulin in relatives of patients with type 1 diabetes: the diabetes prevention trial – type 1. Diabetes Care (2005) 28:1068–76.10.2337/diacare.28.5.1068
    1. Näntö-Salonen K, Kupila A, Simell S, Siljander H, Salonsaari T, Hekkala A, et al. Nasal insulin to prevent type 1 diabetes in children with HLA genotypes and autoantibodies conferring increased risk of disease: a double-blind, randomised controlled trial. Lancet (2008) 372:1746–55.10.1016/S0140-6736(08)61309-4
    1. Sherry NA, Chen W, Kushner JA, Glandt M, Tang Q, Tsai S, et al. Exendin-4 improves reversal of diabetes in NOD mice treated with anti-CD3 monoclonal antibody by enhancing recovery of beta-cells. Endocrinology (2007) 148:5136–44.10.1210/en.2007-0358
    1. Gill RG, Pagni PP, Kupfer T, Wasserfall CH, Deng S, Posgai A, et al. A preclinical consortium approach for assessing the efficacy of combined anti-CD3 plus IL-1 blockade in reversing new-onset autoimmune diabetes in NOD mice. Diabetes (2016) 65:1310–6.10.2337/db15-0492
    1. Herold KC, Gitelman SE, Masharani U, Hagopian W, Bisikirska B, Donaldson D, 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) 54:1763–9.10.2337/diabetes.54.6.1763
    1. Herold KC, Hagopian W, Auger JA, Poumian-Ruiz E, Taylor L, Donaldson D, et al. Anti-CD3 monoclonal antibody in new-onset type 1 diabetes mellitus. N Engl J Med (2002) 346:1692–8.10.1056/NEJMoa012864
    1. Keymeulen B, Vandemeulebroucke E, Ziegler AG, Mathieu C, Kaufman L, Hale G, et al. Insulin needs after CD3-antibody therapy in new-onset type 1 diabetes. N Engl J Med (2005) 352:2598–608.10.1056/NEJMoa043980
    1. Haller MJ, Gitelman SE, Gottlieb PA, Michels AW, Rosenthal SM, Shuster JJ, et al. Anti-thymocyte globulin/G-CSF treatment preserves β cell function in patients with established type 1 diabetes. J Clin Invest (2015) 125:448–55.10.1172/JCI78492
    1. Haller MJ, Gitelman SE, Gottlieb PA, Michels AW, Perry DJ, Schultz AR, et al. Antithymocyte globulin plus G-CSF combination therapy leads to sustained immunomodulatory and metabolic effects in a subset of responders with established type 1 diabetes. Diabetes (2016) 65:3765–75.10.2337/db16-0823
    1. Xue S, Posgai A, Wasserfall C, Myhr C, Campbell-Thompson M, Mathews CE, et al. Combination therapy reverses hyperglycemia in NOD mice with established type 1 diabetes. Diabetes (2015) 64:3873–84.10.2337/db15-0164
    1. Atkinson MA. Evaluating preclinical efficacy. Sci Transl Med (2011) 3:96cm22.10.1126/scitranslmed.3002757
    1. Wicker LS, Todd JA, Prins JB, Podolin PL, Renjilian RJ, Peterson LB. Resistance alleles at two non-major histocompatibility complex-linked insulin-dependent diabetes loci on chromosome 3, Idd3 and Idd10, protect nonobese diabetic mice from diabetes. J Exp Med (1994) 180:1705–13.10.1084/jem.180.5.1705
    1. Lord CJ, Bohlander SK, Hopes EA, Montague CT, Hill NJ, Prins JB, et al. Mapping the diabetes polygene Idd3 on mouse chromosome 3 by use of novel congenic strains. Mamm Genome (1995) 6:563–70.10.1007/BF00352359
    1. Podolin PL, Denny P, Lord CJ, Hill NJ, Todd JA, Peterson LB, et al. Congenic mapping of the insulin-dependent diabetes (Idd) gene, Idd10, localizes two genes mediating the Idd10 effect and eliminates the candidate Fcgr1. J Immunol (1997) 159:1835–43.
    1. Todd JA, Aitman TJ, Cornall RJ, Ghosh S, Hall JR, Hearne CM, et al. Genetic analysis of autoimmune type 1 diabetes mellitus in mice. Nature (1991) 351:542–7.10.1038/351542a0
    1. Hill NJ, Lyons PA, Armitage N, Todd JA, Wicker LS, Peterson LB. NOD Idd5 locus controls insulitis and diabetes and overlaps the orthologous CTLA4/IDDM12 and NRAMP1 loci in humans. Diabetes (2000) 49:1744–7.10.2337/diabetes.49.10.1744
    1. Cornall RJ, Prins JB, Todd JA, Pressey A, DeLarato NH, Wicker LS, et al. Type 1 diabetes in mice is linked to the interleukin-1 receptor and Lsh/Ity/Bcg genes on chromosome 1. Nature (1991) 353:262–5.10.1038/353262a0
    1. Garchon HJ, Bedossa P, Eloy L, Bach JF. Identification and mapping to chromosome 1 of a susceptibility locus for periinsulitis in non-obese diabetic mice. Nature (1991) 353:260–2.10.1038/353260a0
    1. Hunter K, Rainbow D, Plagnol V, Todd JA, Peterson LB, Wicker LS. Interactions between Idd5.1/Ctla4 and other type 1 diabetes genes. J Immunol (2007) 179:8341–9.10.4049/jimmunol.179.12.8341
    1. Rodrigues NR, Cornall RJ, Chandler P, Simpson E, Wicker LS, Peterson LB, et al. Mapping of an insulin-dependent diabetes locus, Idd9, in NOD mice to chromosome 4. Mamm Genome (1994) 5:167–70.10.1007/BF00352349
    1. Lyons PA, Hancock WW, Denny P, Lord CJ, Hill NJ, Armitage N, et al. The NOD Idd9 genetic interval influences the pathogenicity of insulitis and contains molecular variants of Cd30, Tnfr2, and Cd137. Immunity (2000) 13:107–15.10.1016/S1074-7613(00)00012-1
    1. Brodnicki TC, McClive P, Couper S, Morahan G. Localization of Idd11 using NOD congenic mouse strains: elimination of Slc9a1 as a candidate gene. Immunogenetics (2000) 51:37–41.10.1007/s002510050006
    1. Hamilton-Williams EE, Rainbow DB, Cheung J, Christensen M, Lyons PA, Peterson LB, et al. Fine mapping of type 1 diabetes regions Idd9.1 and Idd9.2 reveals genetic complexity. Mamm Genome (2013) 24:358–75.10.1007/s00335-013-9466-y
    1. Lin B, Ciecko AE, MacKinney E, Serreze DV, Chen YG. Congenic mapping identifies a novel Idd9 subregion regulating type 1 diabetes in NOD mice. Immunogenetics (2017) 69:193–8.10.1007/s00251-016-0957-3
    1. Ridgway WM, Peterson LB, Todd JA, Rainbow DB, Healy B, Burren OS, et al. Gene-gene interactions in the NOD mouse model of type 1 diabetes. Adv Immunol (2008) 100:151–75.10.1016/S0065-2776(08)00806-7
    1. Fraser HI, Dendrou CA, Healy B, Rainbow DB, Howlett S, Smink LJ, et al. Nonobese diabetic congenic strain analysis of autoimmune diabetes reveals genetic complexity of the Idd18 locus and identifies Vav3 as a candidate gene. J Immunol (2010) 184:5075–84.10.4049/jimmunol.0903734
    1. Morin J, Boitard C, Vallois D, Avner P, Rogner UC. Mapping of the murine type 1 diabetes locus Idd20 by genetic interaction. Mamm Genome (2006) 17:1105–12.10.1007/s00335-006-0076-9
    1. Hollis-Moffatt JE, Hook SM, Merriman TR. Colocalization of mouse autoimmune diabetes loci Idd21.1 and Idd21.2 with IDDM6 (human) and Iddm3 (rat). Diabetes (2005) 54:2820–5.10.2337/diabetes.54.9.2820
    1. Rogner UC, Boitard C, Morin J, Melanitou E, Avner P. Three loci on mouse chromosome 6 influence onset and final incidence of type I diabetes in NOD.C3H congenic strains. Genomics (2001) 74:163–71.10.1006/geno.2001.6508
    1. Driver JP, Serreze DV, Chen YG. Mouse models for the study of autoimmune type 1 diabetes: a NOD to similarities and differences to human disease. Semin Immunopathol (2011) 33:67–87.10.1007/s00281-010-0204-1
    1. Lundholm M, Motta V, Löfgren-Burström A, Duarte N, Bergman ML, Mayans S, et al. Defective induction of CTLA-4 in the NOD mouse is controlled by the NOD allele of Idd3/IL-2 and a novel locus (Ctex) telomeric on chromosome 1. Diabetes (2006) 55:538–44.10.2337/diabetes.55.02.06.db05-1240
    1. Lin X, Hamilton-Williams EE, Rainbow DB, Hunter KM, Dai YD, Cheung J, et al. Genetic interactions among Idd3, Idd5.1, Idd5.2, and Idd5.3 protective loci in the nonobese diabetic mouse model of type 1 diabetes. J Immunol (2013) 190:3109–20.10.4049/jimmunol.1203422
    1. Wang N, Elso CM, Mackin L, Mannering SI, Strugnell RA, Wijburg OL, et al. Congenic mice reveal genetic epistasis and overlapping disease loci for autoimmune diabetes and listeriosis. Immunogenetics (2014) 66:501–6.10.1007/s00251-014-0782-5
    1. Hermann R, Lipponen K, Kiviniemi M, Kakko T, Veijola R, Simell O, et al. Lymphoid tyrosine phosphatase (LYP/PTPN22) Arg620Trp variant regulates insulin autoimmunity and progression to type 1 diabetes. Diabetologia (2006) 49:1198–208.10.1007/s00125-006-0225-4
    1. Smyth DJ, Cooper JD, Howson JM, Walker NM, Plagnol V, Stevens H, et al. PTPN22 Trp620 explains the association of chromosome 1p13 with type 1 diabetes and shows a statistical interaction with HLA class II genotypes. Diabetes (2008) 57:1730–7.10.2337/db07-1131
    1. Steck AK, Liu SY, McFann K, Barriga KJ, Babu SR, Eisenbarth GS, et al. Association of the PTPN22/LYP gene with type 1 diabetes. Pediatr Diabetes (2006) 7:274–8.10.1111/j.1399-5448.2006.00202.x
    1. Stolp J, Chen YG, Cox SL, Henck V, Zhang W, Tsaih SW, et al. Subcongenic analyses reveal complex interactions between distal chromosome 4 genes controlling diabetogenic B cells and CD4 T cells in nonobese diabetic mice. J Immunol (2012) 189:1406–17.10.4049/jimmunol.1200120
    1. Silveira PA, Chapman HD, Stolp J, Johnson E, Cox SL, Hunter K, et al. Genes within the Idd5 and Idd9/11 diabetes susceptibility loci affect the pathogenic activity of B cells in nonobese diabetic mice. J Immunol (2006) 177:7033–41.10.4049/jimmunol.177.10.7033
    1. Chen YG, Scheuplein F, Osborne MA, Tsaih SW, Chapman HD, Serreze DV. Idd9/11 genetic locus regulates diabetogenic activity of CD4 T-cells in nonobese diabetic (NOD) mice. Diabetes (2008) 57:3273–80.10.2337/db08-0767
    1. Waldner H, Sobel RA, Price N, Kuchroo VK. The autoimmune diabetes locus Idd9 regulates development of type 1 diabetes by affecting the homing of islet-specific T cells. J Immunol (2006) 176:5455–62.10.4049/jimmunol.176.9.5455
    1. Hamilton-Williams EE, Wong SB, Martinez X, Rainbow DB, Hunter KM, Wicker LS, et al. Idd9.2 and Idd9.3 protective alleles function in CD4+ T-cells and nonlymphoid cells to prevent expansion of pathogenic islet-specific CD8+ T-cells. Diabetes (2010) 59:1478–86.10.2337/db09-1801
    1. Yamanouchi J, Puertas MC, Verdaguer J, Lyons PA, Rainbow DB, Chamberlain G, et al. Idd9.1 locus controls the suppressive activity of FoxP3+CD4+CD25+ regulatory T-cells. Diabetes (2010) 59:272–81.10.2337/db09-0648
    1. Ueno A, Wang J, Cheng L, Im JS, Shi Y, Porcelli SA, et al. Enhanced early expansion and maturation of semi-invariant NK T cells inhibited autoimmune pathogenesis in congenic nonobese diabetic mice. J Immunol (2008) 181:6789–96.10.4049/jimmunol.181.10.6789
    1. Hill NJ, Stotland A, Solomon M, Secrest P, Getzoff E, Sarvetnick N. Resistance of the target islet tissue to autoimmune destruction contributes to genetic susceptibility in type 1 diabetes. Biol Direct (2007) 2:5.10.1186/1745-6150-2-5
    1. Ghosh S, Palmer SM, Rodrigues NR, Cordell HJ, Hearne CM, Cornall RJ, et al. Polygenic control of autoimmune diabetes in nonobese diabetic mice. Nat Genet (1993) 4:404–9.10.1038/ng0893-404
    1. Rogner UC, Lepault F, Gagnerault MC, Vallois D, Morin J, Avner P, et al. The diabetes type 1 locus Idd6 modulates activity of CD4+CD25+ regulatory T-cells. Diabetes (2006) 55:186–92.10.2337/diabetes.55.01.06.db05-0598
    1. Robles DT, Eisenbarth GS, Dailey NJ, Peterson LB, Wicker LS. Insulin autoantibodies are associated with islet inflammation but not always related to diabetes progression in NOD congenic mice. Diabetes (2003) 52:882–6.10.2337/diabetes.52.3.882
    1. Pomerleau DP, Bagley RJ, Serreze DV, Mathews CE, Leiter EH. Major histocompatibility complex-linked diabetes susceptibility in NOD/Lt mice: subcongenic analysis localizes a component of Idd16 at the H2-D end of the diabetogenic H2(g7) complex. Diabetes (2005) 54:1603–6.10.2337/diabetes.54.5.1603
    1. Grattan M, Mi QS, Meagher C, Delovitch TL. Congenic mapping of the diabetogenic locus Idd4 to a 5.2-cM region of chromosome 11 in NOD mice: identification of two potential candidate subloci. Diabetes (2002) 51:215–23.10.2337/diabetes.51.1.215
    1. Serreze DV, Bridgett M, Chapman HD, Chen E, Richard SD, Leiter EH. Subcongenic analysis of the Idd13 locus in NOD/Lt mice: evidence for several susceptibility genes including a possible diabetogenic role for beta 2-microglobulin. J Immunol (1998) 160:1472–8.
    1. Reed JC, Herold KC. Thinking bedside at the bench: the NOD mouse model of T1DM. Nat Rev Endocrinol (2015) 11:308–14.10.1038/nrendo.2014.236
    1. Yamanouchi J, Rainbow D, Serra P, Howlett S, Hunter K, Garner VE, et al. Interleukin-2 gene variation impairs regulatory T cell function and causes autoimmunity. Nat Genet (2007) 39:329–37.10.1038/ng1958
    1. Kachapati K, Adams DE, Wu Y, Steward CA, Rainbow DB, Wicker LS, et al. The B10 Idd9.3 locus mediates accumulation of functionally superior CD137(+) regulatory T cells in the nonobese diabetic type 1 diabetes model. J Immunol (2012) 189:5001–15.10.4049/jimmunol.1101013
    1. McGuire HM, Vogelzang A, Hill N, Flodström-Tullberg M, Sprent J, King C. Loss of parity between IL-2 and IL-21 in the NOD Idd3 locus. Proc Natl Acad Sci U S A (2009) 106:19438–43.10.1073/pnas.0903561106
    1. Fraser HI, Howlett S, Clark J, Rainbow DB, Stanford SM, Wu DJ, et al. Ptpn22 and Cd2 variations are associated with altered protein expression and susceptibility to type 1 diabetes in nonobese diabetic mice. J Immunol (2015) 195:4841–52.10.4049/jimmunol.1402654
    1. Long SA, Rieck M, Sanda S, Bollyky JB, Samuels PL, Goland R, et al. Rapamycin/IL-2 combination therapy in patients with type 1 diabetes augments Tregs yet transiently impairs β-cell function. Diabetes (2012) 61:2340–8.10.2337/db12-0049
    1. Grinberg-Bleyer Y, Baeyens A, You S, Elhage R, Fourcade G, Gregoire S, et al. IL-2 reverses established type 1 diabetes in NOD mice by a local effect on pancreatic regulatory T cells. J Exp Med (2010) 207:1871–8.10.1084/jem.20100209
    1. Lowe CE, Cooper JD, Brusko T, Walker NM, Smyth DJ, Bailey R, et al. Large-scale genetic fine mapping and genotype-phenotype associations implicate polymorphism in the IL2RA region in type 1 diabetes. Nat Genet (2007) 39:1074–82.10.1038/ng2102
    1. Todd JA, Walker NM, Cooper JD, Smyth DJ, Downes K, Plagnol V, et al. Robust associations of four new chromosome regions from genome-wide analyses of type 1 diabetes. Nat Genet (2007) 39:857–64.10.1038/ng2068
    1. Lyons PA, Armitage N, Argentina F, Denny P, Hill NJ, Lord CJ, et al. Congenic mapping of the type 1 diabetes locus, Idd3, to a 780-kb region of mouse chromosome 3: identification of a candidate segment of ancestral DNA by haplotype mapping. Genome Res (2000) 10:446–53.10.1101/gr.10.4.446
    1. Barrett JC, Clayton DG, Concannon P, Akolkar B, Cooper JD, Erlich HA, et al. Genome-wide association study and meta-analysis find that over 40 loci affect risk of type 1 diabetes. Nat Genet (2009) 41(6):703–7.10.1038/ng.381
    1. Morahan G, Mehta M, James I, Chen WM, Akolkar B, Erlich HA, et al. Tests for genetic interactions in type 1 diabetes: linkage and stratification analyses of 4,422 affected sib-pairs. Diabetes (2011) 60:1030–40.10.2337/db10-1195
    1. Rubinson DA, Dillon CP, Kwiatkowski AV, Sievers C, Yang L, Kopinja J, et al. A lentivirus-based system to functionally silence genes in primary mammalian cells, stem cells and transgenic mice by RNA interference. Nat Genet (2003) 33:401–6.10.1038/ng1117
    1. Tiscornia G, Singer O, Ikawa M, Verma IM. A general method for gene knockdown in mice by using lentiviral vectors expressing small interfering RNA. Proc Natl Acad Sci U S A (2003) 100:1844–8.10.1073/pnas.0437912100
    1. Rao DD, Vorhies JS, Senzer N, Nemunaitis J. siRNA vs. shRNA: similarities and differences. Adv Drug Deliv Rev (2009) 61:746–59.10.1016/j.addr.2009.04.004
    1. Joseph J, Bittner S, Kaiser FM, Wiendl H, Kissler S. IL-17 silencing does not protect nonobese diabetic mice from autoimmune diabetes. J Immunol (2012) 188:216–21.10.4049/jimmunol.1101215
    1. Zheng P, Kissler S. PTPN22 silencing in the NOD model indicates the type 1 diabetes-associated allele is not a loss-of-function variant. Diabetes (2012) 62:896–904.10.2337/db12-0929
    1. Gerold KD, Zheng P, Rainbow DB, Zernecke A, Wicker LS, Kissler S. The soluble CTLA-4 splice variant protects from type 1 diabetes and potentiates regulatory T-cell function. Diabetes (2011) 60:1955–63.10.2337/db11-0130
    1. Schuster C, Gerold KD, Schober K, Probst L, Boerner K, Kim MJ, et al. The autoimmunity-associated gene CLEC16A modulates thymic epithelial cell autophagy and alters T cell selection. Immunity (2015) 42:942–52.10.1016/j.immuni.2015.04.011
    1. Caballero-Franco C, Kissler S. The autoimmunity-associated gene RGS1 affects the frequency of T follicular helper cells. Genes Immun (2016) 17:228–38.10.1038/gene.2016.16
    1. Kissler S, Stern P, Takahashi K, Hunter K, Peterson LB, Wicker LS. In vivo RNA interference demonstrates a role for Nramp1 in modifying susceptibility to type 1 diabetes. Nat Genet (2006) 38:479–83.10.1038/ng1766
    1. Nowakowska DJ, Kissler S. Ptpn22 modifies regulatory T cell homeostasis via GITR upregulation. J Immunol (2016) 196:2145–52.10.4049/jimmunol.1501877
    1. Jacob HJ, Lazar J, Dwinell MR, Moreno C, Geurts AM. Gene targeting in the rat: advances and opportunities. Trends Genet (2010) 26:510–8.10.1016/j.tig.2010.08.006
    1. Urnov FD, Rebar EJ, Holmes MC, Zhang HS, Gregory PD. Genome editing with engineered zinc finger nucleases. Nat Rev Genet (2010) 11:636–46.10.1038/nrg2842
    1. Geurts AM, Moreno C. Zinc-finger nucleases: new strategies to target the rat genome. Clin Sci (2010) 119:303–11.10.1042/CS20100201
    1. Geurts AM, Cost GJ, Remy S, Cui X, Tesson L, Usal C, et al. Generation of gene-specific mutated rats using zinc-finger nucleases. Methods Mol Biol (2010) 597:211–25.10.1007/978-1-60327-389-3_15
    1. Geurts AM, Cost GJ, Freyvert Y, Zeitler B, Miller JC, Choi VM, et al. Knockout rats via embryo microinjection of zinc-finger nucleases. Science (2009) 325:433.10.1126/science.1172447
    1. Cui X, Ji D, Fisher DA, Wu Y, Briner DM, Weinstein EJ. Targeted integration in rat and mouse embryos with zinc-finger nucleases. Nat Biotechnol (2011) 29:64–7.10.1038/nbt.1731
    1. Chen YG, Forsberg MH, Khaja S, Ciecko AE, Hessner MJ, Geurts AM. Gene targeting in NOD mouse embryos using zinc-finger nucleases. Diabetes (2014) 63:68–74.10.2337/db13-0192
    1. Cannons JL, Chamberlain G, Howson J, Smink LJ, Todd JA, Peterson LB, et al. Genetic and functional association of the immune signaling molecule 4-1BB (CD137/TNFRSF9) with type 1 diabetes. J Autoimmun (2005) 25:13–20.10.1016/j.jaut.2005.04.007
    1. Forsberg MH, Ciecko AE, Bednar KJ, Itoh A, Kachapati K, Ridgway WM, et al. CD137 plays both pathogenic and protective roles in Type 1 diabetes development in NOD mice. J Immunol (2017) 198:3857–68.10.4049/jimmunol.1601851
    1. Acha-Orbea H, McDevitt HO. The first external domain of the nonobese diabetic mouse class II I-A beta chain is unique. Proc Natl Acad Sci U S A (1987) 84:2435–9.10.1073/pnas.84.8.2435
    1. Todd JA, Acha-Orbea H, Bell JI, Chao N, Fronek Z, Jacob CO, et al. A molecular basis for MHC class II-associated autoimmunity. Science (1988) 240:1003–9.10.1126/science.3368786
    1. Lund T, O’Reilly L, Hutchings P, Kanagawa O, Simpson E, Gravely R, et al. Prevention of insulin-dependent diabetes mellitus in non-obese diabetic mice by transgenes encoding modified I-A beta-chain or normal I-E alpha-chain. Nature (1990) 345:727–9.10.1038/345727a0
    1. Quartey-Papafio R, Lund T, Chandler P, Picard J, Ozegbe P, Day S, et al. Aspartate at position 57 of nonobese diabetic I-Ag7 beta-chain diminishes the spontaneous incidence of insulin-dependent diabetes mellitus. J Immunol (1995) 154:5567–75.
    1. Singer SM, Tisch R, Yang XD, Sytwu HK, Liblau R, McDevitt HO. Prevention of diabetes in NOD mice by a mutated I-Ab transgene. Diabetes (1998) 47:1570–7.10.2337/diabetes.47.10.1570
    1. Harrison MM, Jenkins BV, O’Connor-Giles KM, Wildonger J. A CRISPR view of development. Genes Dev (2014) 28:1859–72.10.1101/gad.248252.114
    1. Qin W, Dion SL, Kutny PM, Zhang Y, Cheng AW, Jillette NL, et al. Efficient CRISPR/Cas9-mediated genome editing in mice by Zygote electroporation of nuclease. Genetics (2015) 200:423–30.10.1534/genetics.115.176594
    1. Ratiu JJ, Racine JJ, Hasham MG, Wang Q, Branca JA, Chapman HD, et al. Genetic and small molecule disruption of the AID/RAD51 axis similarly protects nonobese diabetic mice from type 1 diabetes through expansion of regulatory B lymphocytes. J Immunol (2017) 198:4255–67.10.4049/jimmunol.1700024
    1. Zemmour D, Pratama A, Loughhead SM, Mathis D, Benoist C. Flicr, a long noncoding RNA, modulates Foxp3 expression and autoimmunity. Proc Natl Acad Sci U S A (2017) 114:E3472–80.10.1073/pnas.1700946114
    1. Bottini N, Peterson EJ. Tyrosine phosphatase PTPN22: multifunctional regulator of immune signaling, development, and disease. Annu Rev Immunol (2014) 32:83–119.10.1146/annurev-immunol-032713-120249
    1. Pugliese A, Yang M, Kusmarteva I, Heiple T, Vendrame F, Wasserfall C, et al. The juvenile diabetes research foundation network for pancreatic organ donors with diabetes (nPOD) program: goals, operational model and emerging findings. Pediatr Diabetes (2014) 15:1–9.10.1111/pedi.12097
    1. Wallet MA, Santostefano KE, Terada N, Brusko TM. Isogenic cellular systems model the impact of genetic risk variants in the pathogenesis of type 1 diabetes. Front Endocrinol (2017) 8:276.10.3389/fendo.2017.00276
    1. Millman JR, Xie C, Van Dervort A, Gurtler M, Pagliuca FW, Melton DA. Generation of stem cell-derived beta-cells from patients with type 1 diabetes. Nat Commun (2016) 7:11463.10.1038/ncomms11463
    1. Sugimura R, Jha DK, Han A, Soria-Valles C, da Rocha EL, Lu YF, et al. Haematopoietic stem and progenitor cells from human pluripotent stem cells. Nature (2017) 545:432–8.10.1038/nature22370
    1. Kudva YC, Rajagopalan G, Raju R, Abraham RS, Smart M, Hanson J, et al. Modulation of insulitis and type 1 diabetes by transgenic HLA-DR3 and DQ8 in NOD mice lacking endogenous MHC class II. Hum Immunol (2002) 63:987–99.10.1016/S0198-8859(02)00435-4
    1. Marron MP, Graser RT, Chapman HD, Serreze DV. Functional evidence for the mediation of diabetogenic T cell responses by HLA-A2.1 MHC class I molecules through transgenic expression in NOD mice. Proc Natl Acad Sci U S A (2002) 99:13753–8.10.1073/pnas.212221199
    1. Elliott JF, Liu J, Yuan ZN, Bautista-Lopez N, Wallbank SL, Suzuki K, et al. Autoimmune cardiomyopathy and heart block develop spontaneously in HLA-DQ8 transgenic IAbeta knockout NOD mice. Proc Natl Acad Sci U S A (2003) 100:13447–52.10.1073/pnas.2235552100
    1. Antal Z, Baker JC, Smith C, Jarchum I, Babad J, Mukherjee G, et al. Beyond HLA-A*0201: new HLA-transgenic nonobese diabetic mouse models of type 1 diabetes identify the insulin C-peptide as a rich source of CD8+ T cell epitopes. J Immunol (2012) 188:5766–75.10.4049/jimmunol.1102930
    1. Takaki T, Marron MP, Mathews CE, Guttmann ST, Bottino R, Trucco M, et al. HLA-A*0201-restricted T cells from humanized NOD mice recognize autoantigens of potential clinical relevance to type 1 diabetes. J Immunol (2006) 176:3257–65.10.4049/jimmunol.176.5.3257
    1. Niens M, Grier AE, Marron M, Kay TW, Greiner DL, Serreze DV. Prevention of “humanized” diabetogenic CD8 T-cell responses in HLA-transgenic NOD mice by a multipeptide coupled-cell approach. Diabetes (2011) 60:1229–36.10.2337/db10-1523
    1. Shultz LD, Brehm MA, Garcia-Martinez JV, Greiner DL. Humanized mice for immune system investigation: progress, promise and challenges. Nat Rev Immunol (2012) 12:786–98.10.1038/nri3311
    1. Unger WW, Pearson T, Abreu JR, Laban S, van der Slik AR, der Kracht SM, et al. Islet-specific CTL cloned from a type 1 diabetes patient cause beta-cell destruction after engraftment into HLA-A2 transgenic NOD/scid/IL2RG null mice. PLoS One (2012) 7:e49213.10.1371/journal.pone.0049213
    1. Viehmann Milam AA, Maher SE, Gibson JA, Lebastchi J, Wen L, Ruddle NH, et al. A humanized mouse model of autoimmune insulitis. Diabetes (2014) 63:1712–24.10.2337/db13-1141
    1. Whitfield-Larry F, Young EF, Talmage G, Fudge E, Azam A, Patel S, et al. HLA-A2-matched peripheral blood mononuclear cells from type 1 diabetic patients, but not nondiabetic donors, transfer insulitis to NOD-scid/gammac(null)/HLA-A2 transgenic mice concurrent with the expansion of islet-specific CD8+ T cells. Diabetes (2011) 60:1726–33.10.2337/db10-1287
    1. Wen L, Ley RE, Volchkov PY, Stranges PB, Avanesyan L, Stonebraker AC, et al. Innate immunity and intestinal microbiota in the development of type 1 diabetes. Nature (2008) 455:1109–13.10.1038/nature07336
    1. Markle JG, Frank DN, Mortin-Toth S, Robertson CE, Feazel LM, Rolle-Kampczyk U, et al. Sex differences in the gut microbiome drive hormone-dependent regulation of autoimmunity. Science (2013) 339:1084–8.10.1126/science.1233521
    1. Yurkovetskiy L, Burrows M, Khan AA, Graham L, Volchkov P, Becker L, et al. Gender bias in autoimmunity is influenced by microbiota. Immunity (2013) 39:400–12.10.1016/j.immuni.2013.08.013
    1. Endesfelder D, zu Castell W, Ardissone A, Davis-Richardson AG, Achenbach P, Hagen M, et al. Compromised gut microbiota networks in children with anti-islet cell autoimmunity. Diabetes (2014) 63:2006–14.10.2337/db13-1676
    1. Alkanani AK, Hara N, Gottlieb PA, Ir D, Robertson CE, Wagner BD, et al. Alterations in intestinal microbiota correlate with susceptibility to type 1 diabetes. Diabetes (2015) 64:3510–20.10.2337/db14-1847
    1. Kostic AD, Gevers D, Siljander H, Vatanen T, Hyotylainen T, Hamalainen AM, et al. The dynamics of the human infant gut microbiome in development and in progression toward type 1 diabetes. Cell Host Microbe (2015) 17:260–73.10.1016/j.chom.2015.01.001
    1. Vatanen T, Kostic AD, d’Hennezel E, Siljander H, Franzosa EA, Yassour M, et al. Variation in microbiome LPS immunogenicity contributes to autoimmunity in humans. Cell (2016) 165:842–53.10.1016/j.cell.2016.04.007
    1. Hansen CH, Krych L, Nielsen DS, Vogensen FK, Hansen LH, Sorensen SJ, et al. Early life treatment with vancomycin propagates Akkermansia muciniphila and reduces diabetes incidence in the NOD mouse. Diabetologia (2012) 55:2285–94.10.1007/s00125-012-2564-7
    1. Peng J, Narasimhan S, Marchesi JR, Benson A, Wong FS, Wen L. Long term effect of gut microbiota transfer on diabetes development. J Autoimmun (2014) 53:85–94.10.1016/j.jaut.2014.03.005
    1. Candon S, Perez-Arroyo A, Marquet C, Valette F, Foray AP, Pelletier B, et al. Antibiotics in early life alter the gut microbiome and increase disease incidence in a spontaneous mouse model of autoimmune insulin-dependent diabetes. PLoS One (2015) 10:e0125448.10.1371/journal.pone.0125448
    1. Hu Y, Peng J, Tai N, Hu C, Zhang X, Wong FS, et al. Maternal antibiotic treatment protects offspring from diabetes development in nonobese diabetic mice by generation of tolerogenic APCs. J Immunol (2015) 195:4176–84.10.4049/jimmunol.1500884

Source: PubMed

Patrocinadores e Colaboradores

Condições médicas

Intervenções de drogas

3
Se inscrever