The non-obese diabetic (NOD) mouse is a model for the study of insulin-dependent diabetes mellitus (IDDM). Recently transgenic NOD mice have been derived (NOD-E) that express the major histocompatibility complex (MHC) class II I-E molecule. NOD-E do not become diabetic and show negligible pancreatic insulitis. The possibility pertained that NOD-E mice are protected from disease by a process of T-cell deletion or anergy. This paper describes our attempts to discover whether this was so, by comparing NOD and NOD-E mouse T-cell receptor V beta usage. Splenocytes and lymph node cells were therefore tested for their ability to proliferate in response to monoclonal anti-V beta antibodies. We were unable to show any consistent differences between NOD and NOD-E responses to the panel of antibodies used. Previously proposed V beta were shown to be unlikely candidates for deletion or anergy. T cells present at low frequency (V beta 5+) in both NOD and NOD-E mice were shown to be as capable of expansion in response to antigenic stimulation as were more frequently expressed V beta. Our data therefore do not support deletion or anergy as mechanisms which could account for the observed disease protection in NOD-E mice.
Soluble bovine or ovine insulin given intravenously to female NOD mice shortly after weaning had a downregulating effect on several autoimmune parameters associated with insulin-dependent diabetes. The titer of spontaneous anti-insulin antibodies was reduced, insulitis was delayed and less severe, and only 25% of treated mice were diabetic at 30 weeks compared with 70% of untreated mice. An interesting paradox occurred in that bovine insulin, although poorly immunogenic in NOD mice and ineffective as a tolerogen for complete Freund's adjuvant–induced cellular and humoral responses to ovine insulin, was nearly as effective as immunogenic ovine insulin in protecting against diabetes and better than ovine insulin at downregulating spontaneous autoantibodies to insulin. Bovine and ovine insulins differ by only one amino acid on the A-chain loop, but whereas modulation of the induced response to ovine insulin appeared to be sheep-specific, modulation of the induced and spontaneous autoimmunity was achieved almost equally well by bovine or ovine insulin. We suggest therefore that modulation of the induced and spontaneous responses are dependent on different T-cell epitopes and that modulation of spontaneous autoimmunity appears to be governed by an epitope common to both insulins.
Type 1 diabetes is caused by the destruction of insulin producing beta cells by the immune system. The p110δ isoform of PI3K is expressed primarily in cells of haematopoietic origin and the catalytic activity of p110δ is important for the activation of these cells. Targeting of this pathway offers an opportunity to reduce immune cell activity without unwanted side effects. We have explored the effects of a specific p110δ isoform inhibitor, IC87114, on diabetogenic T cells both in vitro and in vivo, and find that although pharmacological inhibition of p110δ has a considerable impact on the production of pro-inflammatory cytokines, it does not delay the onset of diabetes after adoptive transfer of diabetogenic cells. Further, we demonstrate that combination treatment with CTLA4-Ig does not improve the efficacy of treatment, but instead attenuates the protective effects seen with CTLA4-Ig treatment alone. Our results suggest that decreased IL-10 production by Foxp3+ CD4+ T cells in the presence of IC87114 negates individual anti-inflammatory effects of IC8114 and CTLA4-Ig.
Trainees tell us that the majority of their learning occurs during placement experience within the NHS. We briefly describe a project to meaningfully integrate the views of service users and carers into this learning context. In a separate article, trainees tell you of their experiences within the project.
Dietary iodine has long been known to influence the development of human autoimmune thyroid disease. In nonobese diabetic (NOD) and NOD-H2h4 mice elevated dietary iodine has been shown to induce autoimmune thyroid disease. Immune responses to thyroid antigens can be detected in these mouse strains, including T cell responses in the NOD-H2h4 mouse to thyroid peroxidase. Cell transfer studies and antibody depletion experiments reveal a requirement for both CD4+ T cells and CD8+ T cells in the development of thyroid autoimmunity. Histological analyses of the thyroids show that following 1 week of iodine administration MHC class I expression is elevated on thyroid follicular cells and CD4+ and CD8+ T cells have begun to infiltrate the gland. Although MHC class II expression on thyroid epithelial cells was also elevated, the tempo of expression was slower and the extent of expression was far less than that for MHC class I. Depletion of CD8+ T cells at early stages of disease induction inhibited not only thyroid infiltration and autoantibody production but also reduced the levels of MHC expression in the thyroid, suggesting that cytokine production by infiltrating lymphocytes was responsible for the increased MHC expression.
Abstract Infection with Schistosoma mansoni ( S. mansoni ) or exposure to eggs from this helminth inhibits the development of type 1 diabetes in NOD mice. In this study we show that soluble extracts of S. mansoni worm or egg completely prevent onset of type 1 diabetes in these mice but only if injection is started at 4 weeks of age. T cells from diabetes‐protected mice make IL‐10 in recall responses to parasite antigens. These cells are furthermore impaired in their ability to transfer diabetes to NOD‐SCID recipients. Bone marrow dendritic cells derived from NOD mice are found to make more IL‐10 and less IL‐12 following culture with S. mansoni soluble egg antigens in conjunction with lipopolysaccharides. NOD mice are deficient in NKT cells. Soluble worm and egg antigens increase the numbers of Vα14 i NKT cells in NOD mice. These effects of schistosome antigens on the innate immune system provide a mechanism for their ability to prevent type 1 diabetes in NOD mice.
'%3e%3cpath fill='%23012169' d='M0 0v30h60V0z'/%3e%3cpath stroke='%23fff' stroke-width='6' d='m0 0 60 30m0-30L0 30'/%3e%3cpath stroke='%23C8102E' stroke-width='4' d='m0 0 60 30m0-30L0 30' clip-path='url(%23b)'/%3e%3cpath stroke='%23fff' stroke-width='10' d='M30 0v30M0 15h60'/%3e%3cpath stroke='%23C8102E' stroke-width='6' d='M30 0v30M0 15h60'/%3e%3c/g%3e%3c/svg%3e)
