Nature Medicine
9, 198 - 205 (2003)
Published online: 21 January 2003; | doi:10.1038/nm818
Autoimmune islet destruction in spontaneous type 1 diabetes is not  -cell exclusiveShawn Winer1, 6, Hubert Tsui1, 6, Ambrose Lau1, Aihua Song1, Xiaomao Li2, Roy K. Cheung1, Anastazia Sampson1, Fatemeh Afifiyan1, Alisha Elford3, George Jackowski2, Dorothy J. Becker4, Pere Santamaria5, Pamela Ohashi3
& H -Michael Dosch11
Hospital For Sick Children, Research Institute and Departments of Pediatrics and Immunology, University of Toronto, Toronto, Ontario, Canada
2
Syn*X Pharma Inc., Toronto, Ontario, Canada
3
UHN, Ontario Cancer Institute, Departments of Medical Biophysics and Immunology, Toronto, Ontario, Canada
4
Department of Pediatrics, Children's Hospital and University of Pittsburgh, Pittsburgh, Pennsylvania, USA
5
Department of Microbiology and Infectious Diseases and Julia MacFarlane Diabetes Research Centre, Faculty of Medicine, Health Sciences Centre, University of Calgary, Calgary, Canada
6
S.W. and H.T. contributed equally to this study.
Correspondence should be addressed to H -Michael Dosch hmdosch@sickkids.caPancreatic islets of Langerhans are enveloped by peri-islet Schwann cells (pSC), which express glial fibrillary acidic protein (GFAP) and S100 . pSC-autoreactive T- and B-cell responses arise in 3- to 4-week-old diabetes-prone non-obese diabetic (NOD) mice, followed by progressive pSC destruction before detectable -cell death. Humans with probable prediabetes generate similar autoreactivities, and autoantibodies in islet-cell autoantibody (lCA) −positive sera co-localize to pSC. Moreover, GFAP-specific NOD T-cell lines transferred pathogenic peri-insulitis to NOD/severe combined immunodeficient (NOD/SCID) mice, and immunotherapy with GFAP or S100 prevented diabetes. pSC survived in rat insulin promoter Iymphocytic choriomeningitis virus (rip−LCMV) glycoprotein/CD8+ T-cell receptorgp double-transgenic mice with virus-induced diabetes, suggesting that pSC death is not an obligate consequence of local inflammation and -cell destruction. However, pSC were deleted in spontaneously diabetic NOD mice carrying the CD8+/8.3 T-cell receptor transgene, a T cell receptor commonly expressed in earliest islet infiltrates. Autoimmune targeting of pancreatic nervous system tissue elements seems to be an integral, early part of natural type 1 diabetes.
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-galactosylceramide treatment prevents the onset and recurrence of autoimmune Type 1 diabetes
