La CDK11 i la seva implicació en la mort de la cèl·lula beta pancreàtica en el debut diabètic del ratolí NOD

Abstract

ABSTRACT Type 1 diabetes (T1D) is an autoimmune disease in which beta pancreatic cells producers of insulin are attacked by the self immune system leading to a deficiency of insulin production (insulinopenia) and the appearance of the disease. This thesis unveils one of the molecular targets involved in beta cell apoptosis caused by the lymphocytic attack. CDK11 expression is reduced in the endocrine cells of the islets of Langerhans during the autoimmune attack in the murine model NOD (Non Obese Diabetic) of T1D. CDK11 has two gen products in humans: p58 and p110 (p130 in mouse). CDK11p110 is involved in mRNA transcription and splicing and it is expressed ubiquitously during all the cell cycle. CDK11p58 is expressed only during mitosis (G2/M phase) and it is involved in apoptotic procedures. In front of these events, the causal relationship between CDK11 reduction and diabetes onset in the NOD mouse has been studied. The NODCDK11HTZ mouse, which had one CDK11 allele deleted, therefore it was CDK11 hemideficient, was produced. The HTZ mice had a reduced accumulative diabetes incidence compared with the WT mice, and this improvement on the accumulative diabetes incidence was determined by a resistance of beta pancreatic cells to apoptotic cell death induced by the lymphocytic infiltrate. Overall islet physiology did not seem to be altered by the hemideletion of CDK11 gene, because IPGTT and IPITT tests, as well as, intracellular calcium flux, were not modified in the HTZ mice. Moreover, the lymphocytic infiltrate populations presented the same number of T, B macrophages and DCs in both genotypes, as well as the same activation level. T regulatory cells ratios were neither modified as a consequence of CDK11 hemideletion. However, the protective effect against apoptosis by CDK11 hemideletion required the lymphocytic infiltrate, because NOD/SCID CDK11 HTZ and WT mice did not show different beta-cell apoptotic levels. Finally, pancreatic lymph node leucocytes diabetogenicity from HTZ mice was the same as WT mice when they were adoptively transferred to NOD/SCID mice. Bearing these results in mind, it can be concluded, that CDK11 hemideletion protects NOD mice from autoimmune diabetes in situ in an independent cell cycle manner, inhibiting beta cell death when the lymphocytic infiltrate attacks the islets of Langerhans of the NOD mice