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D Fowell

Publications and source records attributed to D Fowell.

8 recordsLinked to original sources
PubMed1996

The thymus contains a high frequency of cells that prevent autoimmune diabetes on transfer into prediabetic recipients.

Rats of the PVG.RT1u strain develop autoimmune diabetes when thymectomized at 6 wk of age and are rendered relatively lymphopenic by a cumulative dose of 1,000 rads 137Cs gamma-irradiation given in four split doses. Previous studies have shown that the disease is prevented by the intravenous injection of 5 x 10(6) CD4+ CD45RC-TCR alpha beta+ RT6+ peripheral T cells from normal syngeneic donors. These cells have a memory phenotype and are presumably primed to some extrathymic antigen. However, we now report that the CD4+ CD8- population of mature thymocytes is a very potent source of cells, with the capacity to prevent diabetes in our lymphopenic animals. As few as 6 x 10(5) of these cells protect approximately 50% of recipients and the level of protection increases with cell dose. It appears that one characteristic of the intrathymic selection of the T cell repertoire is the generation of cells that regulate the autoimmune potential of peripheral T cells that have been neither clonally deleted intrathymically nor rendered irreversibly anergic in the periphery.

ADP Ribose Transferases↗
PubMed1995

The role of subsets of CD4+ T cells in autoimmunity.

It is generally considered that T cells which are reactive with self-antigens are effectively eliminated by two processes: clonal deletion and the induction of T cell anergy. More recently, it has been shown that some potentially autoreactive T cells remain unactivated because the self-antigens for which they are specific are not presented on competent antigen-presenting cells. All these mechanisms of self-tolerance may be regarded as passive in the sense that the autoreactive cells are either deleted or are intrinsically non-responsive. If this view of self-tolerance is adopted, then one would predict that rendering animals relatively lymphopoenic should not give rise to autoimmune disease. This prediction is not verified by experiment. Rats rendered relatively lymphopoenic by adult thymectomy followed by repeated low dose gamma-irradiation develop a high incidence of autoimmune diabetes. Furthermore, it has been shown that the reconstitution of these rats with a specific subset of CD4+ T cells from syngeneic donors prevents the development of this disease. The protective cells have the CD45RClow phenotype, they are resistant to adult thymectomy and the majority of them appear to be non-activated in the donor rats. In contrast, the CD45RChigh CD4+ subset does not provide protection from diabetes. Instead, on injection into athymic rats, it gives rise to pathological changes in a variety of organs: stomach, pancreas, liver, thyroid and lung. In addition, the CD45RClow CD4+ subset prevents these manifestations of autoimmunity in these circumstances. Recently, we have shown that CD4+ CD8- thymocytes are a highly potent source of cells that have the ability to control autoimmune diabetes in rats. It appears that the thymus has three distinct functions: positive selection; negative selection; and the generation of a population of cells that seem specialized for the control of autoimmunity.

Animals↗
PubMed1994

Antigenic determinants encoded by alternatively spliced exons of CD45 are determined by the polypeptide but influenced by glycosylation.

Antibodies recognising the products of alternatively spliced exons near the N-terminus of the leukocyte common antigen, CD45, have been widely used to distinguish populations of lymphocytes with different functional properties. These alternatively spliced regions contain a high content of serine and threonine residues (average 35%) and are heavily O-glycosylated. Despite evidence that the O-glycosylation contributes significantly to the antigenic character of this region of CD45, work with leukosialin and mucin glycoproteins leads to the prediction that the majority of epitopes in the N-terminal exons should be linear protein determinants. In this study the exons of CD45 were expressed in Escherichia coli as non-glycosylated proteins fused to glutathione S-transferase (GST). Fourteen out of 17 mAbs specific for human CD45R reacted with a fusion protein containing exons 4, 5 and 6 (ABC) of human CD45, and four out of six mAbs specific for rat CD45R reacted with an equivalent rat protein. mAbs recognising the product of rat exon B are reported for the first time. Kinetic analysis of MRC OX22 antibody binding to spleen CD45 and to GST fusion proteins showed that the carbohydrate affected the kinetics of binding of antibodies to the protein backbone. In conclusion, heterogeneity in the glycosylation of heavily O-glycosylated cell surface proteins can affect interactions of these proteins both directly through the carbohydrate and indirectly through effects on the protein backbone.

Alternative Splicing↗
PubMed1993

Evidence that the T cell repertoire of normal rats contains cells with the potential to cause diabetes. Characterization of the CD4+ T cell subset that inhibits this autoimmune potential.

Diabetes was induced in a normal nonautoimmune rat strain by rendering the animals relatively T cell deficient using a protocol of adult thymectomy and sublethal gamma irradiation. All male rats and 70% of females developed an acute syndrome with severe loss of weight and hyperglycemia. Diabetes in these lymphopoenic rats was associated with extensive insulitis involving CD4+ and CD8+ T cells and macrophages. The CD8+ T cells were essential for the development of diabetes but not insulitis. The autoimmune diabetes and insulitis were completely prevented by the injection of a particular CD4+ T cell subset, isolated from healthy syngeneic donors, of the phenotype CD45RClow T cell receptor alpha/beta+ RT6+ Thy-1- OX-40-. Cells of this protective phenotype, which make up about 5% of thoracic duct lymphocytes, were found to provide help for secondary antibody responses and produce interleukin 2 (IL-2) and IL-4, but no interferon gamma, on in vitro activation. These data provide evidence for the presence of autoreactive T cells in the normal immune system of the rat and reveal that in the intact animal these cells are prevented from expressing their autoreactive potential by other T cells.

Animals↗
PubMed1992

T-cell subsets in autoimmunity.

The demonstration that functionally different T-cell subsets can be defined by the isoforms of the leukocyte-common antigen, CD45, that they express, has prompted studies on the roles of these subsets in autoimmunity. The results have led to the identification of a particular subset of CD4+ T cells that have the ability to inhibit autoimmune disease. Further, it has been shown that diabetes in the B-B rat can be transferred by in vitro activation of T cells by Staphylococcal enterotoxin suggesting that superantigens may play a role in the pathogenesis of this disease. However, in this system too, it appears that a subset of T cells can inhibit the induction of autoaggressive cells. In other experimental autoimmune diseases there is evidence that CD8+ T cells can be protective and that these cells may mediate this protection by the synthesis of transforming growth factor-beta.

Animals↗