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Replacing murine insulin 1 with human insulin protects NOD mice from diabetes


Autoři: Colleen M. Elso aff001;  Nicholas A. Scott aff001;  Lina Mariana aff001;  Emma I. Masterman aff001;  Andrew P. R. Sutherland aff001;  Helen E. Thomas aff001;  Stuart I. Mannering aff001
Působiště autorů: Immunology and Diabetes Unit, St. Vincent’s Institute of Medical Research, Fitzroy, Victoria, Australia aff001;  Department of Medicine, University of Melbourne, St. Vincent’s Hospital, Fitzroy, Victoria, Australia aff002
Vyšlo v časopise: PLoS ONE 14(12)
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pone.0225021

Souhrn

Type 1, or autoimmune, diabetes is caused by the T-cell mediated destruction of the insulin-producing pancreatic beta cells. Non-obese diabetic (NOD) mice spontaneously develop autoimmune diabetes akin to human type 1 diabetes. For this reason, the NOD mouse has been the preeminent murine model for human type 1 diabetes research for several decades. However, humanized mouse models are highly sought after because they offer both the experimental tractability of a mouse model and the clinical relevance of human-based research. Autoimmune T-cell responses against insulin, and its precursor proinsulin, play central roles in the autoimmune responses against pancreatic beta cells in both humans and NOD mice. As a first step towards developing a murine model of the human autoimmune response against pancreatic beta cells we set out to replace the murine insulin 1 gene (Ins1) with the human insulin gene (Ins) using CRISPR/Cas9. Here we describe a NOD mouse strain that expresses human insulin in place of murine insulin 1, referred to as HuPI. HuPI mice express human insulin, and C-peptide, in their serum and pancreata and have normal glucose tolerance. Compared with wild type NOD mice, the incidence of diabetes is much lower in HuPI mice. Only 15–20% of HuPI mice developed diabetes after 300 days, compared to more than 60% of unmodified NOD mice. Immune-cell infiltration into the pancreatic islets of HuPI mice was not detectable at 100 days but was clearly evident by 300 days. This work highlights the feasibility of using CRISPR/Cas9 to create mouse models of human diseases that express proteins pivotal to the human disease. Furthermore, it reveals that even subtle changes in proinsulin protect NOD mice from diabetes.

Klíčová slova:

Glucose tolerance – Insulin – Insulitis – Mammalian genomics – Mouse models – Protein sequencing – T cells


Zdroje

1. Mannering SI, Pathiraja V, Kay TW. The case for an autoimmune aetiology of type 1 diabetes. Clinical and experimental immunology. 2016;183(1):8–15. doi: 10.1111/cei.12699 26313217; PubMed Central PMCID: PMC4687512.

2. Pugliese A. Autoreactive T cells in type 1 diabetes. J Clin Invest. 2017;127(8):2881–91. Epub 2017/08/02. doi: 10.1172/JCI94549 28762987; PubMed Central PMCID: PMC5531393.

3. Zhang L, Gianani R, Nakayama M, Liu E, Kobayashi M, Baschal E, et al. Type 1 diabetes: chronic progressive autoimmune disease. Novartis Foundation symposium. 2008;292:85–94; discussion -8, 122–9, 202–3. Epub 2009/02/11. doi: 10.1002/9780470697405.ch7 19203094.

4. Makino S, Kunimoto K, Muraoka Y, Mizushima Y, Katagiri K, Tochino Y. Breeding of a non-obese, diabetic strain of mice. Jikken dobutsu Experimental animals. 1980;29(1):1–13. doi: 10.1538/expanim1978.29.1_1 6995140.

5. Pearson JA, Wong FS, Wen L. The importance of the Non Obese Diabetic (NOD) mouse model in autoimmune diabetes. J Autoimmun. 2016;66:76–88. Epub 2015/09/26. doi: 10.1016/j.jaut.2015.08.019 26403950; PubMed Central PMCID: PMC4765310.

6. Serreze DV, Leiter EH. Genetic and pathogenic basis of autoimmune diabetes in NOD mice. Current opinion in immunology. 1994;6(6):900–6. Epub 1994/12/01. doi: 10.1016/0952-7915(94)90011-6 7710714.

7. Roep BO, Peakman M. Antigen targets of type 1 diabetes autoimmunity. Cold Spring Harb Perspect Med. 2012;2(4):a007781. Epub 2012/04/05. doi: 10.1101/cshperspect.a007781 22474615; PubMed Central PMCID: PMC3312399.

8. Di Lorenzo TP, Peakman M, Roep BO. Translational Mini-Review Series on Type 1 Diabetes: Systematic analysis of T cell epitopes in autoimmune diabetes. Clinical and experimental immunology. 2007;148(1):1–16. doi: 10.1111/j.1365-2249.2006.03244.x 17349009.

9. Nakayama M, Abiru N, Moriyama H, Babaya N, Liu E, Miao D, et al. Prime role for an insulin epitope in the development of type 1 diabetes in NOD mice. Nature. 2005;435(7039):220–3. doi: 10.1038/nature03523 15889095; PubMed Central PMCID: PMC1364531.

10. Narendran P, Mannering SI, Harrison LC. Proinsulin-a pathogenic autoantigen in type 1 diabetes. Autoimmun Rev. 2003;2(4):204–10. Epub 2003/07/10. doi: 10.1016/s1568-9972(03)00009-0 12848947.

11. Delong T, Wiles TA, Baker RL, Bradley B, Barbour G, Reisdorph R, et al. Pathogenic CD4 T cells in type 1 diabetes recognize epitopes formed by peptide fusion. Science. 2016;351(6274):711–4. doi: 10.1126/science.aad2791 26912858

12. Pathiraja V, Kuehlich JP, Campbell PD, Krishnamurthy B, Loudovaris T, Coates PT, et al. Proinsulin-specific, HLA-DQ8, and HLA-DQ8-transdimer-restricted CD4+ T cells infiltrate islets in type 1 diabetes. Diabetes. 2015;64(1):172–82. Epub 2014/08/27. doi: 10.2337/db14-0858 25157096.

13. Michels AW, Landry LG, McDaniel KA, Yu L, Campbell-Thompson M, Kwok WW, et al. Islet-Derived CD4 T Cells Targeting Proinsulin in Human Autoimmune Diabetes. Diabetes. 2017;66(3):722–34. doi: 10.2337/db16-1025 27920090; PubMed Central PMCID: PMC5319719.

14. So M, Elso CM, Tresoldi E, Pakusch M, Pathiraja V, Wentworth JM, et al. Proinsulin C-peptide is an autoantigen in people with type 1 diabetes. Proceedings of the National Academy of Sciences of the United States of America. 2018;115(42):10732–7. Epub 2018/10/03. doi: 10.1073/pnas.1809208115 30275329; PubMed Central PMCID: PMC6196477.

15. Arif S, Tree TI, Astill TP, Tremble JM, Bishop AJ, Dayan CM, et al. Autoreactive T cell responses show proinflammatory polarization in diabetes but a regulatory phenotype in health. J Clin Invest. 2004;113(3):451–63. doi: 10.1172/JCI19585 14755342.

16. Wentworth BM, Schaefer IM, Villa-Komaroff L, Chirgwin JM. Characterization of the two nonallelic genes encoding mouse preproinsulin. J Mol Evol. 1986;23(4):305–12. Epub 1986/01/01. doi: 10.1007/bf02100639 3104603.

17. Deltour L, Leduque P, Blume N, Madsen O, Dubois P, Jami J, et al. Differential expression of the two nonallelic proinsulin genes in the developing mouse embryo. Proceedings of the National Academy of Sciences of the United States of America. 1993;90(2):527–31. Epub 1993/01/15. doi: 10.1073/pnas.90.2.527 8421685; PubMed Central PMCID: PMC45696.

18. Throsby M, Homo-Delarche F, Chevenne D, Goya R, Dardenne M, Pleau JM. Pancreatic hormone expression in the murine thymus: localization in dendritic cells and macrophages. Endocrinology. 1998;139(5):2399–406. Epub 1998/05/16. doi: 10.1210/endo.139.5.5989 9564851.

19. Heath VL, Moore NC, Parnell SM, Mason DW. Intrathymic expression of genes involved in organ specific autoimmune disease. J Autoimmun. 1998;11(4):309–18. Epub 1998/10/20. doi: 10.1006/jaut.1998.0210 9776708.

20. Moriyama H, Abiru N, Paronen J, Sikora K, Liu E, Miao D, et al. Evidence for a primary islet autoantigen (preproinsulin 1) for insulitis and diabetes in the nonobese diabetic mouse. Proceedings of the National Academy of Sciences of the United States of America. 2003;100(18):10376–81. doi: 10.1073/pnas.1834450100 12925730.

21. Thebault-Baumont K, Dubois-Laforgue D, Krief P, Briand JP, Halbout P, Vallon-Geoffroy K, et al. Acceleration of type 1 diabetes mellitus in proinsulin 2-deficient NOD mice. J Clin Invest. 2003;111(6):851–7. doi: 10.1172/JCI16584 12639991.

22. Roep BO, Buckner J, Sawcer S, Toes R, Zipp F. The problems and promises of research into human immunology and autoimmune disease. Nat Med. 2012;18(1):48–53. doi: 10.1038/nm.2626 22227672

23. Wekerle H, Flugel A, Fugger L, Schett G, Serreze D. Autoimmunity's next top models. Nat Med. 2012;18(1):66–70. doi: 10.1038/nm.2635 22227675.

24. 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(5):1712–24. doi: 10.2337/db13-1141 24478396

25. Tan S, Li Y, Xia J, Jin CH, Hu Z, Duinkerken G, et al. Type 1 diabetes induction in humanized mice. Proceedings of the National Academy of Sciences of the United States of America. 2017;114(41):10954–9. Epub 2017/09/07. doi: 10.1073/pnas.1710415114 28874533; PubMed Central PMCID: PMC5642714.

26. Racine JJ, Stewart I, Ratiu J, Christianson G, Lowell E, Helm K, et al. Improved Murine MHC-Deficient HLA Transgenic NOD Mouse Models for Type 1 Diabetes Therapy Development. Diabetes. 2018;67(5):923–35. Epub 2018/02/24. doi: 10.2337/db17-1467 29472249; PubMed Central PMCID: PMC5909999.

27. Verhagen J, Smith EL, Whettlock EM, Macintyre B, Peakman M. Proinsulin-mediated induction of type 1 diabetes in HLA-DR4-transgenic mice. Sci Rep. 2018;8(1):14106. Epub 2018/09/22. doi: 10.1038/s41598-018-32546-4 30237494; PubMed Central PMCID: PMC6148278.

28. Leiter EH. Mice with targeted gene disruptions or gene insertions for diabetes research: problems, pitfalls, and potential solutions. Diabetologia. 2002;45(3):296–308. Epub 2002/03/27. doi: 10.1007/s00125-001-0743-z 11914735.

29. Cong L, Ran FA, Cox D, Lin S, Barretto R, Habib N, et al. Multiplex genome engineering using CRISPR/Cas systems. Science. 2013;339(6121):819–23. doi: 10.1126/science.1231143 23287718; PubMed Central PMCID: PMC3795411.

30. Maruyama T, Dougan SK, Truttmann MC, Bilate AM, Ingram JR, Ploegh HL. Increasing the efficiency of precise genome editing with CRISPR-Cas9 by inhibition of nonhomologous end joining. Nature biotechnology. 2015;33(5):538–42. Epub 2015/03/24. doi: 10.1038/nbt.3190 25798939; PubMed Central PMCID: PMC4618510.

31. Trivedi PM, Graham KL, Scott NA, Jenkins MR, Majaw S, Sutherland RM, et al. Repurposed JAK1/JAK2 Inhibitor Reverses Established Autoimmune Insulitis in NOD Mice. Diabetes. 2017;66(6):1650–60. Epub 2017/03/16. doi: 10.2337/db16-1250 28292965.

32. Levisetti MG, Lewis DM, Suri A, Unanue ER. Weak Proinsulin Peptide–Major Histocompatibility Complexes Are Targeted in Autoimmune Diabetes in Mice. Diabetes. 2008;57(7):1852–60. doi: 10.2337/db08-0068 18398138

33. Weir GC, Bonner-Weir S. Islet beta cell mass in diabetes and how it relates to function, birth, and death. Annals of the New York Academy of Sciences. 2013;1281:92–105. doi: 10.1111/nyas.12031 23363033; PubMed Central PMCID: PMC3618572.

34. Luce S, Guinoiseau S, Gadault A, Letourneur F, Blondeau B, Nitschke P, et al. Humanized Mouse Model to Study Type 1 Diabetes. Diabetes. 2018;67(9):1816–29. Epub 2018/07/04. doi: 10.2337/db18-0202 29967002.

35. Noble JA. Immunogenetics of type 1 diabetes: A comprehensive review. J Autoimmun. 2015;64:101–12. Epub 2015/08/15. doi: 10.1016/j.jaut.2015.07.014 26272854.

36. Chen S, Sun S, Moonen D, Lee C, Lee AY, Schaffer DV, et al. CRISPR-READI: Efficient Generation of Knockin Mice by CRISPR RNP Electroporation and AAV Donor Infection. Cell Rep. 2019;27(13):3780–9 e4. Epub 2019/06/27. doi: 10.1016/j.celrep.2019.05.103 31242412; PubMed Central PMCID: PMC6693498.


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