Regulation of Pancreatic Cytokines by Fas Ligand in Autoimmune Diabetes Prone Mice

Type 1 diabetes (T1D) results from autoimmune destruction of pancreatic insulin-producing-ß-cells. Autoreactive T cells are activated by islet autoantigens in pancreatic lymph nodes (PLN) and infiltrate pancreatic islets of Langerhans to cause insulitis and ß-cell destruction. Within the normal repertoire of healthy individuals, such autoreactive T cells are kept on check by suppressive cytokines and specialized subsets of regulatory cells. In disease-susceptible individuals and the widely used Non-Obese Diabetic (NOD) mouse model for T1D, these immunoregulatory mechanisms fail thereby permitting diabetogenic T cells to infiltrate pancreatic islets, cause insulitis, and destroy ß-cells. What causes these mechanisms to fail and how the failures can be avoided/rectified are current questions of paramount scientific and clinical significance. A poorly understood question in the pathogenesis of the disease is how the loss-of-function mutation in Fas ligand (gld mutation) completely prevents the disease in the NOD mice. Because the Fas pathway is not critical for host defense, understanding how its modulation protects from T1D can lead to new therapy that does not cause immune suppression. An increase in anti-inflammatory and decrease in proinflammatory cytokines were observed in gld/+ NOD mice via Flowcytomix. FACs analysis will further confirm these cytokine regulatory differences and show whether T-Cells, B-Cells, macrophages, or granulocytes are responsible for the differences in cytokine regulation. Differential cytokine regulation in gld/+ compared to the WT model will provide further insight on how a gld mutation in the Fas/FasL pathway promotes complete resistance against developing T1D.