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

Down selecting adjuvanted vaccine formulations: a comparative method for harmonized evaluation.

The need for rapid and accurate comparison of panels of adjuvanted vaccine formulations and subsequent rational down selection, presents several challenges for modern vaccine development. Here we describe a method which may enable vaccine and adjuvant developers to compare antigen/adjuvant combinations in a harmonized fashion. Three reference antigens: Plasmodium falciparum apical membrane antigen 1 (AMA1), hepatitis B virus surface antigen (HBsAg), and Mycobacterium tuberculosis antigen 85A (Ag85A), were selected as model antigens and were each formulated with three adjuvants: aluminium oxyhydroxide, squalene-in-water emulsion, and a liposome formulation mixed with the purified saponin fraction QS21. The nine antigen/adjuvant formulations were assessed for stability and immunogenicity in mice in order to provide benchmarks against which other formulations could be compared, in order to assist subsequent down selection of adjuvanted vaccines. Furthermore, mouse cellular immune responses were analyzed by measuring IFN-γ and IL-5 production in splenocytes by ELISPOT, and humoral responses were determined by antigen-specific ELISA, where levels of total IgG, IgG1, IgG2b and IgG2c in serum samples were determined. The reference antigens and adjuvants described in this study, which span a spectrum of immune responses, are of potential use as tools to act as points of reference in vaccine development studies. The harmonized methodology described herein may be used as a tool for adjuvant/antigen comparison studies

Variable BCG efficacy in rhesus populations: Pulmonary BCG provides protection where standard intra-dermal vaccination fails

Pathogenesis and treatment of chronic pulmonary disease

Acute stress syndrome of the yellow European eel (Anguilla anguilla Linnaes) when exposed to a graded swimming-load

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