Weak Proinsulin Peptide–Major Histocompatibility Complexes Are Targeted in Autoimmune Diabetes in Mice

OBJECTIVE—Weak major histocompatibility complex (MHC) binding of self-peptides has been proposed as a mechanism that may contribute to autoimmunity by allowing for escape of autoreactive T-cells from the thymus. We examined the relationship between the MHC-binding characteristics of a β-cell antigen epitope and T-cell autoreactivity in a model of autoimmune diabetes

Islet-Specific CTL Cloned from a Type 1 Diabetes Patient Cause Beta-Cell Destruction after Engraftment into HLAA2 Transgenic NOD/SCID/IL2RG Null Mice

Despite increasing evidence that autoreactive CD8 T-cells are involved in both the initiation of type 1 diabetes (T1D) and the destruction of beta-cells, direct evidence for their destructive role in-vivo is lacking. To address a destructive role for autoreactive CD8 T-cells in human disease, we assessed the pathogenicity of a CD8 T-cell clone derived from a T1D donor and specific for an HLA-A2-restricted epitope of islet-specific glucose-6-phosphatase catalytic-subunit related protein (IGRP). HLA-A2/IGRP tetramer staining revealed a higher frequency of IGRP-specific CD8 T-cells in the peripheral blood of recent onset human individuals than of healthy donors. IGRP(265-273)-specific CD8 T-cells that were cloned from the peripheral blood of a recent onset T1D individual were shown to secrete IFNγ and Granzyme B after antigen-specific activation and lyse HLA-A2-expressing murine islets in-vitro. Lytic capacity was also demonstrated in-vivo by specific killing of peptide-pulsed target cells. Using the HLA-A2 NOD-scid IL2rγ(null) mouse model, HLA-A2-restricted IGRP-specific CD8 T-cells induced a destructive insulitis. Together, this is the first evidence that human HLA-restricted autoreactive CD8 T-cells target HLA-expressing beta-cells in-vivo, demonstrating the translational value of humanized mice to study mechanisms of disease and therapeutic intervention strategies

ION MICROPROBE STUDIES OF REACTIONS IN SQUEEZE-CAST ALUMINUM-ALLOY MATRIX COMPOSITES

An ion microprobe with high lateral resolution has been used to study the chemical reactions at the fibre/matrix interface of metal-matrix composites. During the squeeze-casting process, the Al-Si-Mg matrix reacts with the preform made of Saffil fibres (96% Al2O3, 4% SiO2). The reaction occurs mainly between the silica binder and Mg from the matrix according to SiO2 + 2Mg = 2MgO + Si. A continuous layer of MgO was formed around the fibres, even on surfaces that were not covered by the silica binder. Possible reasons are discussed for the formation of MgO in areas where binder coating was missing. In such areas, Mg reduces SiO2 that is contained in the fibre. However, the fibres (Al2O3) are not attacked by Mg. In the isolated case of fibres that were completely uncoated, no reaction products were observed at the interface. The presence of silica binder seems to be an essential requirement for this reaction to occur, When squeeze-casting is performed with sufficiently high melt temperature, Al from the matrix also reduces silica