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

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

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ABSTRACT INSULIN-dependent diabetes mellitus (IDDM) is a disease with an autoimmune aetiology. The inbred non-obese diabetic (NOD) mouse strain provides a good animal model of the human disease1 and genetic analysis suggests that, as in man, at least one of the several genes controlling the development of IDDM is linked to the major histocompatibility complex2,3. The NOD mouse does not express I-E2 owing to a deletion in the promoter region of the I-E α-chain gene, and the sequence of NOD I-A β-chain in the first external domain is unique with His 56 and Ser 57 (ref. 4) replacing Pro and Asp, respectively, at these positions. There has been considerable interest in the role amino acid 57 might have in conferring susceptibility to autoimmune diseases, including IDDM. The presence of a charged residue (such as Asp) at this position might affect the conformation of the peptide binding groove5. But it could be assumed that Pro 56 gives rise to a different conformation of I-A β-chain than does His 56. We therefore constructed transgenic NOD mice in which the transgene encoded a modified Aβnod with Pro 56, and studied its effect on the development of IDDM in this mouse strain. Previous studies have suggested that NOD mice expressing I-E as a result of the introduction of an I-E α-chain (Eα) transgene are potected from the development of insulitis and hence IDDM6,7. To explore further the protective effect of this molecule we constructed a second class of transgenic NOD mouse carrying an Eαd transgene. Both transgenes protected the mice from IDDM, but this was not associated with a complete deletion of any T cells expressing commonly used T-cell receptor V β genes. Access through your institution Buy or subscribe This is a preview of subscription content, access via your institution ACCESS OPTIONS Access through your institution Subscribe to this journal Receive 51 print issues and online access $199.00 per year only $3.90 per issue Learn more Buy this article * Purchase on SpringerLink * Instant access to full article PDF Buy now Prices may be subject to local taxes which are calculated during checkout ADDITIONAL ACCESS OPTIONS: * Log in * Learn about institutional subscriptions * Read our FAQs * Contact customer support SIMILAR CONTENT BEING VIEWED BY OTHERS I-AG7 Β56/57 POLYMORPHISMS REGULATE NON-COGNATE NEGATIVE SELECTION TO CD4+ T CELL ORCHESTRATORS OF TYPE 1 DIABETES Article 20 February 2023 SYNGENEICALLY TRANSPLANTED INSULIN PRODUCING CELLS DIFFERENTIATED FROM ADIPOSE DERIVED STEM CELLS UNDERGO DELAYED DAMAGE BY AUTOIMMUNE RESPONSES IN NOD MICE Article Open access 07 April 2022 ISLET CELL REPLACEMENT AND TRANSPLANTATION IMMUNOLOGY IN A MOUSE STRAIN WITH INDUCIBLE DIABETES Article Open access 31 May 2022 REFERENCES * Makino, S. K. _et al._ _Exp. Anim._ 29, 1–13 (1980). Article  CAS  Google Scholar  * Hattori, M. _et al._ _Science_ 231, 733–735 (1986). Article  ADS  CAS  Google Scholar  * Wicker, L. S. _et al._ _J. exp. Med._ 165, 1639–1654 (1987). Article  CAS  Google Scholar  * Acha-Orbea, H. & McDevitt, H. O. _Proc. natn. Acad. Sci. U.S.A._ 84, 2435–2439 (1987). Article  ADS  CAS  Google Scholar  * Todd, J. A., Bell, J. I. & McDevitt, H. O. _Nature_ 329, 599–604 (1987). Article  ADS  CAS  Google Scholar  * Nishimoto, H., Kikutani, H., Yamamura, K. & Kishimoto, T. _Nature_ 328, 432–434 (1987). Article  ADS  CAS  Google Scholar  * Uehira, M. _et al._ _Int. Immun._ 1, 209–213 (1989). Article  CAS  Google Scholar  * Makino, S., Kurimoti, K., Mursaoka, Y. & Katagiri, K. _Exp. Anim._ 30, 137–140 (1981). Article  CAS  Google Scholar  * Harada, M. & Makino, S. _Diabetologia_ 27, 604–606 (1984). Article  CAS  Google Scholar  * Wicker, L. S., Miller, B. J. & Mullen, Y. _Diabetes_ 36, 855–860 (1986). Article  Google Scholar  * Tomonari, K. & Lovering, E. _Immunogenetics_ 28, 445–451 (1988). Article  CAS  Google Scholar  * Bill, J., Kanagawa, O., Woodland, D. L. & Palmer, E. _J. exp. Med._ 169, 1703–1719 (1989). Article  Google Scholar  * Reich, E. P., Sherwin, R. S., Kanagawa, O. & Janeway, C. A. _Nature_ 341, 326–328 (1989). Article  ADS  CAS  Google Scholar  * Haskins, K., Portas, M., Bergman, B., Lafferty, K. & Bradley, B. _Proc. natn. Acad. Sci. U.S.A._ 86, 8000–8004 (1989). Article  ADS  CAS  Google Scholar  * Barclay, A. N. _Immunology_ 44, 727–736 (1981). CAS  PubMed  PubMed Central  Google Scholar  * Hutchings, P. R. _et al._ _J. Autoimmunity_ 3, 101–109 (1990). Article  Google Scholar  * Grosveld, F. G. _et al._ _Nucleic Acid Res._ 10, 6715–6732 (1982). Article  CAS  Google Scholar  * Hyldig-Nielsen, J. J., Schenning, L., Hammerling, U. & Widmark, E. _Nucleic Acid Res._ 11, 5055–5072 (1983). Article  CAS  Google Scholar  * Larhammar, D. _et al._ _Cell._ 34, 179–188 (1983). Article  CAS  Google Scholar  * Chomczynski, P. & Sacchi, N. _Analyt. Biochem._ 162, 156–159 (1987). Article  CAS  Google Scholar  Download references AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * University College and Middlesex School of Medicine, 40-50 Tottenham Street, London, WIP 9PG, UK Torben Lund, Lorraine O'Reilly, Patricia Hutchings, Robert Gravely & Anne Cooke * Department of Pathology, Washington University, School of Medicine, 660 South Euclid Avenue, St Louis, Missouri, USA Osami Kanagawa * Clinical Research Centre, Watford Road, Harrow, Middlesex, HA1 3UJ, UK Elizabeth Simpson, Phillip Chandler, Julian Dyson, Jean K. Picard & Andrew Edwards * National Institute for Medical Research, The Ridgeway, Mill Hill, NW7 1AA, UK Dimitris Kioussis Authors * Torben Lund View author publications You can also search for this author inPubMed Google Scholar * Lorraine O'Reilly View author publications You can also search for this author inPubMed Google Scholar * Patricia Hutchings View author publications You can also search for this author inPubMed Google Scholar * Osami Kanagawa View author publications You can also search for this author inPubMed Google Scholar * Elizabeth Simpson View author publications You can also search for this author inPubMed Google Scholar * Robert Gravely View author publications You can also search for this author inPubMed Google Scholar * Phillip Chandler View author publications You can also search for this author inPubMed Google Scholar * Julian Dyson View author publications You can also search for this author inPubMed Google Scholar * Jean K. Picard View author publications You can also search for this author inPubMed Google Scholar * Andrew Edwards View author publications You can also search for this author inPubMed Google Scholar * Dimitris Kioussis View author publications You can also search for this author inPubMed Google Scholar * Anne Cooke View author publications You can also search for this author inPubMed Google Scholar RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Lund, T., O'Reilly, L., Hutchings, P. _et al._ 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 (1990). https://doi.org/10.1038/345727a0 Download citation * Received: 25 April 1990 * Accepted: 14 May 1990 * Issue Date: 21 June 1990 * DOI: https://doi.org/10.1038/345727a0 SHARE THIS ARTICLE Anyone you share the following link with will be able to read this content: Get shareable link Sorry, a shareable link is not currently available for this article. Copy to clipboard Provided by the Springer Nature SharedIt content-sharing initiative

ABSTRACT INSULIN-dependent diabetes mellitus (IDDM) is a disease with an autoimmune aetiology. The inbred non-obese diabetic (NOD) mouse strain provides a good animal model of the human


disease1 and genetic analysis suggests that, as in man, at least one of the several genes controlling the development of IDDM is linked to the major histocompatibility complex2,3. The NOD


mouse does not express I-E2 owing to a deletion in the promoter region of the I-E α-chain gene, and the sequence of NOD I-A β-chain in the first external domain is unique with His 56 and Ser


57 (ref. 4) replacing Pro and Asp, respectively, at these positions. There has been considerable interest in the role amino acid 57 might have in conferring susceptibility to autoimmune


diseases, including IDDM. The presence of a charged residue (such as Asp) at this position might affect the conformation of the peptide binding groove5. But it could be assumed that Pro 56


gives rise to a different conformation of I-A β-chain than does His 56. We therefore constructed transgenic NOD mice in which the transgene encoded a modified Aβnod with Pro 56, and studied


its effect on the development of IDDM in this mouse strain. Previous studies have suggested that NOD mice expressing I-E as a result of the introduction of an I-E α-chain (Eα) transgene are


potected from the development of insulitis and hence IDDM6,7. To explore further the protective effect of this molecule we constructed a second class of transgenic NOD mouse carrying an Eαd


transgene. Both transgenes protected the mice from IDDM, but this was not associated with a complete deletion of any T cells expressing commonly used T-cell receptor V β genes. Access


through your institution Buy or subscribe This is a preview of subscription content, access via your institution ACCESS OPTIONS Access through your institution Subscribe to this journal


Receive 51 print issues and online access $199.00 per year only $3.90 per issue Learn more Buy this article * Purchase on SpringerLink * Instant access to full article PDF Buy now Prices may


be subject to local taxes which are calculated during checkout ADDITIONAL ACCESS OPTIONS: * Log in * Learn about institutional subscriptions * Read our FAQs * Contact customer support


SIMILAR CONTENT BEING VIEWED BY OTHERS I-AG7 Β56/57 POLYMORPHISMS REGULATE NON-COGNATE NEGATIVE SELECTION TO CD4+ T CELL ORCHESTRATORS OF TYPE 1 DIABETES Article 20 February 2023


SYNGENEICALLY TRANSPLANTED INSULIN PRODUCING CELLS DIFFERENTIATED FROM ADIPOSE DERIVED STEM CELLS UNDERGO DELAYED DAMAGE BY AUTOIMMUNE RESPONSES IN NOD MICE Article Open access 07 April 2022


ISLET CELL REPLACEMENT AND TRANSPLANTATION IMMUNOLOGY IN A MOUSE STRAIN WITH INDUCIBLE DIABETES Article Open access 31 May 2022 REFERENCES * Makino, S. K. _et al._ _Exp. Anim._ 29, 1–13


(1980). Article  CAS  Google Scholar  * Hattori, M. _et al._ _Science_ 231, 733–735 (1986). Article  ADS  CAS  Google Scholar  * Wicker, L. S. _et al._ _J. exp. Med._ 165, 1639–1654 (1987).


Article  CAS  Google Scholar  * Acha-Orbea, H. & McDevitt, H. O. _Proc. natn. Acad. Sci. U.S.A._ 84, 2435–2439 (1987). Article  ADS  CAS  Google Scholar  * Todd, J. A., Bell, J. I. &


McDevitt, H. O. _Nature_ 329, 599–604 (1987). Article  ADS  CAS  Google Scholar  * Nishimoto, H., Kikutani, H., Yamamura, K. & Kishimoto, T. _Nature_ 328, 432–434 (1987). Article  ADS 


CAS  Google Scholar  * Uehira, M. _et al._ _Int. Immun._ 1, 209–213 (1989). Article  CAS  Google Scholar  * Makino, S., Kurimoti, K., Mursaoka, Y. & Katagiri, K. _Exp. Anim._ 30, 137–140


(1981). Article  CAS  Google Scholar  * Harada, M. & Makino, S. _Diabetologia_ 27, 604–606 (1984). Article  CAS  Google Scholar  * Wicker, L. S., Miller, B. J. & Mullen, Y.


_Diabetes_ 36, 855–860 (1986). Article  Google Scholar  * Tomonari, K. & Lovering, E. _Immunogenetics_ 28, 445–451 (1988). Article  CAS  Google Scholar  * Bill, J., Kanagawa, O.,


Woodland, D. L. & Palmer, E. _J. exp. Med._ 169, 1703–1719 (1989). Article  Google Scholar  * Reich, E. P., Sherwin, R. S., Kanagawa, O. & Janeway, C. A. _Nature_ 341, 326–328


(1989). Article  ADS  CAS  Google Scholar  * Haskins, K., Portas, M., Bergman, B., Lafferty, K. & Bradley, B. _Proc. natn. Acad. Sci. U.S.A._ 86, 8000–8004 (1989). Article  ADS  CAS 


Google Scholar  * Barclay, A. N. _Immunology_ 44, 727–736 (1981). CAS  PubMed  PubMed Central  Google Scholar  * Hutchings, P. R. _et al._ _J. Autoimmunity_ 3, 101–109 (1990). Article 


Google Scholar  * Grosveld, F. G. _et al._ _Nucleic Acid Res._ 10, 6715–6732 (1982). Article  CAS  Google Scholar  * Hyldig-Nielsen, J. J., Schenning, L., Hammerling, U. & Widmark, E.


_Nucleic Acid Res._ 11, 5055–5072 (1983). Article  CAS  Google Scholar  * Larhammar, D. _et al._ _Cell._ 34, 179–188 (1983). Article  CAS  Google Scholar  * Chomczynski, P. & Sacchi, N.


_Analyt. Biochem._ 162, 156–159 (1987). Article  CAS  Google Scholar  Download references AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * University College and Middlesex School of Medicine,


40-50 Tottenham Street, London, WIP 9PG, UK Torben Lund, Lorraine O'Reilly, Patricia Hutchings, Robert Gravely & Anne Cooke * Department of Pathology, Washington University, School


of Medicine, 660 South Euclid Avenue, St Louis, Missouri, USA Osami Kanagawa * Clinical Research Centre, Watford Road, Harrow, Middlesex, HA1 3UJ, UK Elizabeth Simpson, Phillip Chandler, 


Julian Dyson, Jean K. Picard & Andrew Edwards * National Institute for Medical Research, The Ridgeway, Mill Hill, NW7 1AA, UK Dimitris Kioussis Authors * Torben Lund View author


publications You can also search for this author inPubMed Google Scholar * Lorraine O'Reilly View author publications You can also search for this author inPubMed Google Scholar *


Patricia Hutchings View author publications You can also search for this author inPubMed Google Scholar * Osami Kanagawa View author publications You can also search for this author inPubMed


 Google Scholar * Elizabeth Simpson View author publications You can also search for this author inPubMed Google Scholar * Robert Gravely View author publications You can also search for


this author inPubMed Google Scholar * Phillip Chandler View author publications You can also search for this author inPubMed Google Scholar * Julian Dyson View author publications You can


also search for this author inPubMed Google Scholar * Jean K. Picard View author publications You can also search for this author inPubMed Google Scholar * Andrew Edwards View author


publications You can also search for this author inPubMed Google Scholar * Dimitris Kioussis View author publications You can also search for this author inPubMed Google Scholar * Anne Cooke


View author publications You can also search for this author inPubMed Google Scholar RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Lund, T.,


O'Reilly, L., Hutchings, P. _et al._ 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 (1990). https://doi.org/10.1038/345727a0 Download citation * Received: 25 April 1990 * Accepted: 14 May 1990 * Issue Date: 21 June 1990 * DOI:


https://doi.org/10.1038/345727a0 SHARE THIS ARTICLE Anyone you share the following link with will be able to read this content: Get shareable link Sorry, a shareable link is not currently


available for this article. Copy to clipboard Provided by the Springer Nature SharedIt content-sharing initiative