Anna-Lena, Gessler and Warncke, Max (2013) Master Thesis: Pathogenese und Keimzentrumsreaktion im Typ 1 Diabetes Mausmodell (Pathogenesis and germinal center reaction in the NOD T1D mouse model). University Freiburg.

Abstract

Type1 diabetes (T1D) is a chronic autoimmune disease leading to the destruction of
the insulin-producing β-cells of the pancreas, thereby causing a disturbance of
glucose homeostasis in the body. In industrialized countries T1D represents one of
the most common endocrine disorders. Interactions between T and B cells are critical
for the development of many autoimmune diseases (AID) and therapeutic
manipulation, for example by B-cell-depleting antibodies, is an effective treatment for
many AID. An important messenger in the T-B cell interaction is the cytokine IL-21,
which is crucial for the development of T1D in the NOD mouse model. Using the
NOD mouse, I wanted to find a correlation between disease progression, tissue
destruction and germinal center reactions in correlation to IL-21. On tissue sections
of the pancreas it could be demonstrated that the destruction of the islets progressing
from a state with intact insulin producing β-cells, without the presence of lymphocytes
over a stage of a peri-insulitis to destructive insulitis with the total loss of insulinproducing
cells. Using immunohistochemical staining it was shown that the disease is
accompanied by the presence of T and B cells and FDC. The presence of these cells
could be an indication for the formation of germinal center like structures at the site of
inflammation in the pancreas. Interestingly, numerous regulatory T cells could also
be found in the pancreas during fulminant inflammation. In secondary lymphoid
organs like spleen, lymph nodes and Peyer patches a slight tendency towards the
development of inflammation could be assessed in NOD mice with increasing age,
with a slight decrease in regulatory cells and the inverse rise of activated effector
cells. Overall, the highest immune response could be observed in the PP, suggesting
a continuous activation by the commensal flora. IL-21 expression of CD4 + cells was
induced by the stimulation via IL-6. However, the selected intracellular cytokine
staining showed IL-21 expression independently of IL-6 which is not compatible with
the literature.
In summary, several differences in the T-B cell interactions could be shown and the
further understanding of the interactions in the germinal center and the role of the
cytokines IL-6 and IL-21 in the induction of diabetes in the NOD model could possibly
provide new therapies for diabetes patients.

Item Type:	Book
Date Deposited:	15 Apr 2013 23:45
Last Modified:	15 Apr 2013 23:45
URI:	https://oak.novartis.com/id/eprint/9288