NIH Study Confirming Disease Reversal of Type I Diabetes and Sjogren’s Syndrome
Treatment Success and Regenerative Mechanisms Influenced by Age of NOD Mice and Target Organ of Autoimmune Attack
Tran SD 1, Kodama S 2, Lodde BM 3 and Mezey E 3 Diabetes 55, 283 (June, 2006)
(1) McGill University, Montreal, QC
(2) Brigham and Women’s Hospital, Boston, MA
(3) National Institutes of Health, Bethesda, MD ABSTRACT
The published literature of NOD mouse therapies to protect from autoimmune diabetes or Sjogren’s syndrome reveals treatment timing influences efficacy. The age of the host and stage of the disease influence disease-reversing mechanisms and may also influence how different target organs of auto-immunity recover. In this study, 3 institutions cooperated to test the reported efficacy of a therapy that reverses end-stage diabetes, in part with the brief exposure to induced TNF-α to cause CD8 autoreactive T cell death and MHC class I and self peptide re-education. Utilizing still normoglycemic 14-week-old NOD mice with adequate blood sugar control but greater than 50% loss of salivary function, treatment efficacy and mechanisms of disease reversal in 2 target organs of autoimmunity were evaluated. The 4 treatment criteria considered were: 1) protection from progression to diabetes; 2) evaluation of treatment cohorts for islet regeneration or rescue by lineage tracking; 3) reversal or halt of Sjogren’s syndrome by salivary flow; and, 4) evaluation of salivary glands for regeneration. The results of this study in mid-stage NOD mice shows: 1) type 1 diabetes is permanently halted in a higher percentage of NOD animals (100%) when therapy is administered in younger NOD mice than in end-stage NOD disease (85%); 2) lineage tracking methods confirm the halt of diabetic autoimmunity is facilitated by both islet rescue as well as islet regeneration; islet rescue dominates in earlier stage animals; 3) salivary gland function is dramatically restored by the therapy; and, 4) salivary gland function is recovered through both target tissue regeneration from endogenous and exogenously driven mechanisms. This NOD treatment has efficacy in both mid and late disease but reveals higher success rates in younger animals. Islet recovery occurs predominately by regeneration in older animals and islet rescue in mid-stage animals.
| METHODS
Animals: 13 female NOD mice: • with greater than 50% salivary function loss were monitored for ongoing gland destruction by stimulated salivary flow rates,(1) • were still normoglycemic at the start of therapy at approximately 14 weeks of age, • were randomized into two groups: untreated (n=5) versus treated (n=8) with CFA and male donor live spleen cells for 40 days.(2) |
| Histological Examination: • FISH detection of the Y chromosome of the male donor cells was combined with simultaneous immunohistochemical staining (IHC) for cytokeratin (marker for salivary epithelial cells).(3) •Similar lineage tracking methods (Y chromosome and insulin) were applied to the pancreatic sections of the treated and untreated NOD mice.(2, 4) |
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RESULTS Salivary Flow Rate: • Of the eight NOD mice treated with CFA and spleen cells, all continued to present with a decrease in salivary flow during the 40 days intervention followed by a remarkable 120 day time course of functional restoration of salivary flow (Fig 1A). • By 160 days after the start of therapy, the salivary flow of the treated NOD mice was restored to comparable salivary flow of age matched C57BL/6 mice (p=0.6434). • All untreated NOD mice showed a continuous decline in salivary flow both during the 40 days therapy and for an additional 40 days after therapy termination.
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| Hyperlycemia: • All untreated NOD cohorts died of severe hyperglycemia. • All treated NOD mice with reversal of Sjogren’s syndrome were similarly protected from diabetes to a significant degree (p=0.0002) (Fig. 1B).
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| Histological Examination: • Presence of Y-chromosome could be detected in a few salivary epithelial cells, exclusively in the treated NOD mice but not in control NOD mice or in control C57BL/6 mice (Fig. 2A-D). • Reappearance of large pancreatic islets free of invasive lymphoid infiltrates was observed (Fig 2E-G). • The number of Y chromosome positive salivary epithelial cells as well as Y chromosome positive pancreatic B cells was low, and most likely cannot be responsible for the functional recovery. • Instead, in the transplanted animals the autoimmune disease is suppressed and the host cells seem to be able to regenerate and the donor and host cells collaborate to restore function.
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| CONCLUSION This study establishes that a brief intervention (treatment with CFA and spleen cells) into autoimmune mice with advanced disease can stably reversed two forms of established autoimmune disease i.e. diabetes and Sjogren’s syndrome.
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| REFERENCES:
(1)M.R. Kok et al., J Gene Med 7, 432 (Apr, 2005). (2)S. Kodama, W. Kuhtreiber, S. Fujimura, E.A. Dale, D.L. Faustman, Science 302,1223 (Nov 14, 2003). (3)S.D. Tran et al., Lancet 361, 1084 (Mar 29, 2003). (4)E. Mezey et al., Science 290, 1779 (Dec 1, 2000). •This study is supported in part by the Sjogren’s Syndrome Foundation, NIH/NIDCR intramural program, CIHR and Canada Research Chair. |
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My dad has type 2 diabetes. He manages diabetes through Diet and Exercise and alo by taking food supplements like Alpha Lipoic acid which helps in preventing nerve damage. He also takes Chromium which helps in the regulation of blood sugar.