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International Immunology Advance Access originally published online on July 18, 2005
International Immunology 2005 17(9):1157-1165; doi:10.1093/intimm/dxh293
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© The Japanese Society for Immunology. 2005. All rights reserved. For permissions, please e-mail: journals.permissions@oupjournals.org

Stat4-null non-obese diabetic mice: protection from diabetes and experimental allergic encephalomyelitis, but with concomitant epitope spread

Rosemary J. Boyton1,2,*, Selina Davies1,*, Chloe Marden1, Cristina Fantino1, Catherine Reynolds2, Karina Portugal1, Hamlata Dewchand1 and Daniel M. Altmann2

1 Human Disease Immunogenetics Group, Department of Infectious Diseases and Transplantation Biology Group, Medical Research Council, Clinical Sciences Centre, Faculty of Medicine, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 ONN, UK
2 Lung Immunology Group, Department of Biological Sciences, Sir Alexander Fleming Building and National Heart and Lung Institute, Imperial College, London SW7 2AZ, UK

Correspondence to: D. M. Altmann; E-mail: d.altmann{at}ic.ac.uk

There is much interest in therapeutic manipulation of cytokine responses in autoimmunity, yet studies in mouse models have sometimes produced conflicting findings as to the role of particular mediators in disease. Examples include the contradictory findings regarding susceptibility to experimental allergic encephalomyelitis (EAE) or diabetes in knockout mice for various individual Th1 or Th2 cytokines or their receptors. An alternative approach to the analysis of Th1 and Th2 mechanisms in these diseases is to investigate strains carrying a null mutation for molecules involved in cytokine receptor signal transduction, signal transducer and activator of transcription (Stat4) and Stat6. Stat4 is pivotal in Th1 polarization, being activated when IL-12 binds the IL-12R and leading to the production of IFN{gamma}. We here report disease susceptibility in non-obese diabetic mice carrying a Stat4-null mutation. Knockout mice were almost completely protected from diabetes, only rarely showing pancreatic peri-islet infiltrates. Furthermore, there was near complete protection from the induction of EAE by either of the two encephalitogenic myelin epitopes. Despite this protection, Stat4-null mice showed clear epitope spread compared with controls during myelin oligodendrocyte glycoprotein-induced EAE as judged by T cell proliferation, although this was not associated with a strong Th1 response to the initial or spread epitope and, furthermore, there was no evidence of a switch to Th2 cytokines.

Keywords: antigens/peptides/epitopes, diabetes, EAE/MS, Th1/Th2 cells

* These authors contributed equally to the study

Transmitting editor: I. Pecht


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[Abstract] [Full Text] [PDF]


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