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Seminar Report #3 Elly DeLaney

Seminar Report #3 Elly DeLaney . Yoon, J., Yoon C., Lim H., et al. 1999. Control of autoimmune diabetes in NOD mice by GAD expression or suppression in B cells. Background.

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Seminar Report #3 Elly DeLaney

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  1. Seminar Report #3Elly DeLaney Yoon, J., Yoon C., Lim H., et al. 1999. Control of autoimmune diabetes in NOD mice by GAD expression or suppression in B cells

  2. Background • Type I diabetes (insulin-dependent diabetes mellitus) results when the body’s own immune system attacks beta cells in the pancreas • It is unknown what triggers the destruction of beta cells in the pancreas, but it is believed that the presence of glutamic acid decarboxylase (GAD) in beta cells of humans and the NOD mouse, plays a role

  3. GAD Suppression • Tests were done to indicate how much of an effect beta cell expression of GAD has on diabetes. • To administer tests, GAD expression was selectively suppressed in diabetes prone NOD mice by producing NOD mice with antisense GAD transgene incorporated into their chromosomal DNA

  4. Results of GAD suppression • Beta cells were designated as : * H-AS-GAD-NOD (complete GAD suppression) * Hk-H-AS-GAD-NOD (complete GAD suppression) * M-AS-GAD-NOD (moderate GAD suppression) * Mk-AS-GAD-NOD (moderate GAD suppression) * L-AS-GAD-NOD (low GAD suppression) * Lk-AS-GAD-NOD (low GAD suppression)

  5. Determining if GAD Required for Diabetes • Disease development was monitored To determine whether GAD expression in beta cells was required for the development of autoimmune diabetes in NOD mice.

  6. Disease Development • 40 WEEKS OF AGE: developed diabetes * H-AS-GAD-NOD = 0 of 15 * M-AS-GAD-NOD = 12 of 18 (67%) * L-AS-GAD-NOD = 12 of 16 (75%) * Control = 17 of 21 (81%)

  7. Islet Histology at 20 Weeks of Age * H-AS-GAD-NOD = over 80% in tact * M-AS-GAD-NOD = most showed moderate to sever insulitis * L-AS-GAD-NOD = most showed moderate to sever insulitis * Control = most showed moderate to sever insulitis

  8. k-AS-GAD-NOD • Results were similar to AS-GAD-NOD except that 1 of 36 (2.8%) Hk- AS-GAD-NOD did develop diabetes. It is unknown whether this was due to a difference in gene susceptibility, or experimental error.

  9. Further tests • Antisense transgenic NOD mice were developed that expressed endogenous retroviral env protein, a beta cell auto antigen (not found in GOD-suppressed mice). DIABETES DEVELOPED * 15 of 19 (75%) * Control = 9 of 11 (82%) - This finding supports the view that diabetes prevention in AS-GAD-NOD mice is not due to a nonspecific effect of an antisense transgene incorporated into chromosomal DNA

  10. Salivary Gland Examination • Salivary glands of NOD mice were examined to determine whether beta cell specific suppression of GAD expression specifically affects beta cell specific autoimmunity because the salivary gland also shows lymphocytic infiltration in diabetes prone NOD mice. • Lymphocytic infiltration in the salivary gland of H-AS-GAD-NOD mice was not prevented, and sialitis was similar to that of the control group. • This indicates that GAD suppression does not effect auto-immunity in other tissues (besides pancreatic).

  11. Beta-cell Specific Diabetogenic T Cells • Researchers examined whether the suppression of GAD expression in the beta cells inhibits disease development by blocking the generation of beta cell specific diabetogenic T cells. • Splenocytes from 20 week old nondiabetic female H-AS-GAD-NOD and age matched nondiabetic controls were transfused into 6 to 8 week old NOD-severe combined deficiency disease mice

  12. No (0 of 8) recipients of splenocytes from H-AS-GAD-NOD mice developed diabetes 90% (9 f 10) recipients from the control group did develop diabetes 10 Weeks After Transfusion

  13. Significance • The generation of T cells capable of adoptively transferring diabetes is blocked in absence of GAD expression in beta cells • The generation of both diabetogenic CD4+ and CD8+ T cells was blocked in the absence of GAD expression in the beta cells

  14. Further studies done involving the suceptibility of GAD suppressed beta cells to attack by diabetogenic T cells derived from acutely diabetic NOD mice was evaluated. Low incidence of diabetes remained low in GAD suppressed NOD mice, suggesting that GAD suppressed beta cells aren’t susceptible to attack by diabetogenic T cells.

  15. Conclusion • Results from this study demonstrate that beta cell-specific suppression of GAD expression is sufficient to nearly completely prevent auto immune diabetes in NOD mice.

  16. References • Yoon, J., Yoon C., Lim H., et al. 1999. Control of autoimmune diabetes in NOD mice by GAD expression or suppression in B cells • The On-line Medical Dictionary. http://www.graylab.ac.uk/omd/

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