11 research outputs found
Defects in Antigen-Presenting Cells in the BB-DP Rat Model of Diabetes
Type-1 diabetes is the result of a T cell mediated
immune response against the insulin-producing β cells in the islet of
Langerhans. In humans, until now, the disease is only clearly
detectable at the onset of the disease. Therefore studies to identify
initial factors involved in the etio-pathogenesis are impossible in
humans prone to develop diabetes. In order to study the early,
prodromal phases of type-1 diabetes we used a spontaneous rodent
animal model of the disease, the Biobreeding-Diabetes Prone (BB-DP)
rat. This rat develops diabetes, because it is in particular defective
for a population of regulatory T cells, the ART2+ regulatory T cells
and because it possesses the disease-prone MHC haplotype RT1u (iddm1).
We investigated (Chapter 2) the myeloid dendritic cells (DC) in this
animal model, since DC, the antigen-presenting cells par excellence,
are able to elicit immune responses from naïve T cells and are known
to be involved in autoimmune responses because they are capable of
modulating immunity versus tolerance. We studied bone-marrow precursor
derived myeloid DC of three BB-DP rat sub-lines (Worcester, Groningen,
Seattle) to identify defects in these DC, which could be responsible
for the defective tolerance induction towards diabetes-associated
islet autoantigens in this rat model. We found that the myeloid DC
generated from bone-marrow precursors were defective in these three BB-
DP rat sub-lines, showing an immature, more macrophage-like phenotype,
a low MHC class II expression on their surface, a reduced T cell
stimulatory capacity, a reduced capability to differentiate
into fully mature DC and a reduced production of the immunosuppressive
cytokine IL-10 as compared to two control rat strains (Wistar, F344).
We assume that such DC defects contribute to the decreased tolerance
towards islet autoantigens in the autoimmune diabetes of the BB-DP
rat, since such defective DC are in particular defective to stimulate
ART2+ regulatory T cells sufficiently.
We
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Aberrancies in the differentiation and maturation of dendritic cells from bone-marrow precursors are linked to various genes on chromosome 4 and other chromosomes of the BB-DP rat
Low-density cells isolated from the rat thymus resemble branched cortical macrophages and have a reduced capability of rescuing double-positive thymocytes from apoptosis in the BB-DP rat
Defects in differentiation of bone-marrow derived dendritic cells of the BB rat are partly associated with IDDM2 (the lyp gene) and partly associated with other genes in the BB rat background
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Tumorimmunolog