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Biomedical subjects

A G Baxter

Publications and source records attributed to A G Baxter.

At least 37 records · Page 2Linked to original sources
PubMed1998

Factors influencing the effects of murine cytomegalovirus on the pancreas.

BACKGROUND: As human cytomegalovirus (HCMV) infections are implicated in insulin-dependent diabetes mellitus (IDDM), the effects of murine (M)CMV infection of inbred mice on the pancreas are of interest. RESULTS: Inflammation and periacinar oedema peaked on day 3 and were replaced by a focal inflammation, but infected cells were rare. The islets were spared in C57BL mice. Insulitis normally seen in non-obese diabetic (NOD) mice was accelerated, but infected NOD mice did not become glycosuric. Isotypes of total and autoreactive antibodies suggested a shift to a Th 1 response (IgG2a) in all MCMV-infected mice. MCMV-induced pancreatitis was not affected by MHC genes but was similar or less severe in BALB/c mice. As these lack the Cmv1 gene, which provides a protective natural killer (NK) cell response in C57BL congenic mice, the C57BL background may carry a pancreatitis susceptibility gene able to counter NK-mediated restriction of viral replication. Consistently, congenic mice expressing Cmvl on a BALB/c background did not display pancreatitis, unless depleted of NK cells. In vivo treatment with soluble cytokine receptors suggested that interleukin 1 (IL-1) and/or tumour necrosis factor alpha contribute to acinar necrosis in C57BL mice.

Animals↗
PubMed1998

Characterization and specificity of B-cell responses in lupus induced by Mycobacterium bovis in NOD/Lt mice.

A single dose of pasteurized Mycobacterium bovis administered intravenously to prediabetic non-obese diabetic (NOD) mice prevented the onset of type 1 diabetes but precipitated a systemic 'autoimmune rheumatic disease' (ARD) similar to systemic lupus erythematosus. This syndrome was characterized by haemolytic anaemia, anti-dsDNA and anti-Smith antigen (Sm) antinuclear autoantibodies, increased severity of sialadenitis and glomerular immune complex deposition. Here, we examine the specificity of the autoantibody responses in M. bovis-treated NOD mice. Large amounts of antibody were detected to the Sm/ribonucleoprotein (RNP) complex, of which the 28 000 MW polypeptide appeared to be immunodominant. The IgG subclass involved in the anti-Sm response was primarily IgG2a. Antibodies against dsDNA were also detected, but the subclass of this response was mixed, with IgG2a and IgG2b being present in equal amounts. Together, these findings argue against a role for immune deviation towards T helper type 2 (Th2) responses in pathogenesis of the disease. The anti-dsDNA and anti-Sm reactivities were not mediated by polyreactive antibodies since neither antigen could cross-compete plasma antibody binding to the other in competitive enzyme-linked immunosorbent assay. The role of polyclonal B-cell activation was examined by measuring total gamma-globulin as well as IgG reactive with other nuclear antigens including Ro60, Ro52 and La, which although not a major component of the autoantibody responses in these mice, did show small but significant increases following immunization with M. bovis. Thus polyclonal stimulation, while likely to be occurring, was not directly responsible for production of anti-Sm antibodies.

Animals↗
PubMed1997

Flow cytometric study of T cell development in NOD mice reveals a deficiency in alphabetaTCR+CDR-CD8- thymocytes.

As a result of failed induction of T cell tolerance to pancreatic B cells, non-obese diabetic (NOD) mice develop spontaneous autoimmune insulin-dependent diabetes mellitus (IDDM). The thymic stroma, which plays a crucial role in thymic T cell maturation, undergoes extensive premature disorganization in NOD mice, so it is of interest to examine NOD T cell development. In this study, both major and minor developmental populations of thymocytes of NOD/Lt mice were studied and compared to those of BALB/c, C57BL/6 and CBA mice by multiparameter flow cytometry (FACS). These results are described in detail and reveal that most thymocyte subsets were normally represented, including alphaTcR-CD4-CD8- (triple negative; TN), alphabetaTcR-CD4+CD8- and alphabetaTcR-CD4-CD8+ (immature single positive; ISP), alphabetaTcR-/lowCD4+CD8+ (double positive; DP) and alphabetaTcR+CD4+CD8- and alphabetaTcR+CD4-CD8+ (mature single positive; SP) as well as gammadelta T cells. However, NOD mice exhibited a marked deficiency of thymic alphabetaTcR+CD4-CD8- (alphabeta+DN) T cells. alphabeta+DN T cells, which are included among NK1+ T cells in C57BL/6 mice, produce large amounts of IL-4 on primary stimulation. Given the potential significance of NKT cells in immunoregulation, it is possible that the scarcity of these cells in NOD mice plays a role in the pathogenesis of IDDM.

Animals↗
PubMed1997

Association between alphabetaTCR+CD4-CD8- T-cell deficiency and IDDM in NOD/Lt mice.

NOD mice develop spontaneous IDDM as a result of T-cell-mediated autoimmune destruction of pancreatic beta-cells. It is not known why these T-cells become autoreactive, nor is it clear whether the breakdown in self-tolerance reflects a general problem in T-cell development or a selective defect in an as yet undefined regulatory cell population. In this study, we showed that NOD mice, although relatively normal with regard to most thymocyte subsets, exhibit a marked deficiency in alphabetaTCR+CD4-CD8- (alphabeta+DN) T-cells in the thymus and, to a lesser extent, in the periphery. These T-cells have been termed NKT cells (NK1.1+-like T-cells) because they share some cell surface markers with conventional natural killer (NK) cells. To examine the role of these cells in the pathogenesis of IDDM, semiallogeneic or syngeneic double-negative (DN) thymocytes, enriched for NKT cells, were transferred into intact 4-week-old NOD recipients; the onset of diabetes was then monitored over the ensuing 30 weeks. Mice receiving NKT-enriched thymocytes did not develop diabetes, whereas mice receiving unfractionated thymocytes or phosphate-buffered saline developed diabetes at the normal rate. NKT cells represent a distinct T-cell lineage that has been shown to play a role in immunoregulation in vivo. The deficiency of these cells observed in NOD mice may therefore contribute to destruction of pancreatic islet cells by conventional T-cells.

Adoptive Transfer↗
PubMed1997

Immunogenetics and the cause of autoimmune disease.

Autoimmune disease results from the action of environmental factors on a predisposed genotype. In this review, the role of genetic susceptibility in the aetiology of autoimmune disease is examined. As the genetics of autoimmune diabetes has been studied more intensively than that of other autoimmune diseases, supporting evidence is drawn principally from that example. Autoimmune diseases are not inherited as entities but as constitutions which confer an increased probability of developing disease. It is proposed that there are two components to autoimmune disease susceptibility. One confers susceptibility to autoimmunity per se, while the other determines tissue specificity. In this review, the concept of liability is introduced as a tool used in quantitative genetics and is applied to the analysis of autoimmune diabetes by considering a threshold model. In this example, empirically derived incidence figures are used to calculate heritability which is a relative measure of the influence of genetics and environmental factors. The validity of applying the concept of liability to diabetes is confirmed by examining the values of heritability calculated from empirical data obtained from different kindred relationships, and by confirming that the assumptions on which liability is based are supported by recent gene mapping data. Finally, the physiological significance of liability is considered and its significance to the cause of autoimmunity discussed.

Animals↗
PubMed1996

Regulation of autoimmune diabetes: characteristics of non-islet-antigen specific therapies.

Non-islet-antigen specific treatments have been shown to alter the natural history of insulin dependent diabetes in both the non-obese diabetic (NOD) mouse and in recently diagnosed patients. However concerns have been raised regarding the possibility that non-islet-antigen specific therapy may trade cell mediated autoimmunity for antibody dependent autoimmunity. Female NOD mice at approximately 70 days of age were treated with the non-islet-antigen specific agents complete Freund's adjuvant (CFA) and Bacillus Calmette-Guerin (BCG) and assayed for the development of antibody mediated autoimmunity at 300 days of age. Autoantibodies to red cells were not detected in any of the BCG (n = 19) or CFA (n = 15) treated animals, while 2 of 13 age-matched NOD animals had autoantibodies to red cells, shown by a positive direct Coomb's test. Anti-nuclear autoantibodies and complement deposition in the renal glomeruli were not significantly increased in the treated animals as compared to age-matched non-diabetic mice. The relative effectiveness of CFA and BCG treatment was examined in terms of the ability of these agents to preserve insulin containing islets. Complete Freund's adjuvant treatment was found to be more effective in preserving insulin containing islets when compared to BCG treatment. This study demonstrates that it is possible to inhibit the development of autoimmune diabetes without increasing the probability that treated animals will develop antibody dependent autoimmunity.

Animals↗
PubMed1994

Genetic polymorphisms of the non-obese diabetic (NOD) mouse.

The non-obese diabetic (NOD) mouse is a polygenic model of insulin-dependent diabetes. To better understand the biology, immunology and genetics of this mouse strain NOD mice were typed for RFLP at 29 loci and microsatellite variation at a further nine loci. Mice were also typed for the expression of lymphocyte differentiation antigens. Comparisons were made with two non-diabetic strains, C57BL/6 and SJL, for these markers. A number of restriction fragment length polymorphisms (RFLP) were defined: seven between C57BL/6 and NOD; five between SJL and NOD; and four in which both C57BL/6 and SJL differed from NOD. Previously reported microsatellite results were extended by defining the SJL alleles at these loci, finding five loci at which NOD differed from B6 alone, and four loci at which NOD differed from both B6 and SJL. In addition, the NOD Igh allotype and alleles for a number of lymphocyte differentiation antigens were defined for the first time. The expression of uncommon alleles of these antigens suggests candidates whose role in the diabetogenic process can be tested.

Alleles↗
PubMed1994

Mycobacteria precipitate autoimmune rheumatic disease in NOD mice via an adjuvant-like activity.

NOD mice spontaneously develop organ-specific autoimmunity and are widely used as a model for diabetes. NOD mice also exhibit some features of non-organ specific autoimmune rheumatic disease such as thymocytotoxic and anti-nuclear autoantibodies and they develop haemolytic anaemia in senescence. A single dose of 2.6 x 10(7) heat-killed Bacillus Calmette-Guerin (BCG) i.v. in 8-week-old NOD mice prevented diabetes but precipitated a syndrome similar to systemic lupus erythematosus (SLE), in which treated mice rapidly developed haemolytic anaemia, high titre anti-DNA and anti-Sm antinuclear autoantibodies, perivascular lymphocytic infiltration in the kidneys and glomerular immune complex deposition. Here, we examined the mechanism of action by which BCG precipitated rheumatic autoimmune disease in NOD mice. Two weeks after injection, reticuloendothelial cell function was dramatically increased in BCG-treated NOD mice. By 4 weeks, treated mice had a three- to four-fold increase in Mac-1+ and class-II+, B220-negative splenocytes and in vitro antigen-presentation capacity was enhanced two- to four-fold. In vivo responses to SRBC confirmed enhancement of DTH 4 weeks after BCG injection, consistent with an adjuvant-like activity.

Adjuvants, Immunologic↗
PubMed1994

Mycobacteria precipitate an SLE-like syndrome in diabetes-prone NOD mice.

Non-obese diabetic (NOD) mice spontaneously develop organ-specific autoimmunity and are widely used as a model for diabetes. Aged NOD mice also exhibit some features of non-organ-specific autoimmune rheumatic disease such as anti-nuclear antibodies and late-onset haemolytic anaemia. Here, we report that a single dose of 2.6 x 10(7) heat-killed bacillus Calmette-Guérin (BCG) i.v. in 8-week-old NOD mice prevented diabetes but precipitated a syndrome similar to systemic lupus erythematosus (SLE). Treated mice developed haemolytic anaemia, anti-DNA and anti-Sm anti-nuclear autoantibodies and an increased severity of sialadenitis. Perivascular lymphocytic infiltration in the kidneys and glomerular immune complex deposition were also found. The action of BCG appeared to be mediated by an adjuvant-like activity as treated mice showed a substantial increase in reticuloendothelial cell function and enhanced antigen presentation capacity.

Anemia, Hemolytic, Autoimmune↗
PubMed1993

Genetic basis for diabetes resistance in NOD/Wehi mice.

The basis for diabetes resistance in low diabetes incidence NOD/Wehi mice was examined in a breeding study. NOD/Wehi mice were crossed with high diabetes incidence NOD/Lt mice producing F1 hybrid mice which expressed a low incidence of diabetes. To distinguish between genetic and environmental causes for diabetes resistance, these F1 mice were backcrossed to NOD/Lt mice resulting in BC1 hybrid mice which expressed an intermediate incidence of diabetes. Similar results were obtained by examining the severity of insulitis in the hybrid mice. As both the incidence of diabetes and severity of insulitis in the hybrid mice were consistent with a single dominant gene mediating diabetes resistance, an attempt to localize this gene was made. Although over 140 loci which display polymorphism amongst inbred strains were typed in both parental lines, only a single locus, D8Mit9, was found to differ. As heterozygotes at D8Mit9 were not over represented amongst 45 diabetic BC1 hybrid mice examined, it was concluded that a resistance gene was not linked to this locus.

Alleles↗
PubMed1993

Complement lytic activity has no role in the pathogenesis of autoimmune diabetes in NOD mice.

The NOD mouse is widely used as a model of organ-specific autoimmunity because it develops specific autoimmune destruction of pancreatic beta-cells. Although it is clear that T-cells and monocytes are necessary for beta-cell destruction, humoral factors, such as antibodies and complement, may also contribute to tissue damage. Attempts to cure diabetes in experimental models by immunoisolation of transplanted islets has raised the need to protect the islets from the relatively small components of the complement cascade. In this study, we report that NOD mice have no complement lytic activity and that the exclusion of complement is unnecessary in this model. Sera from young NOD mice were unable to lyse sheep red blood cells coated with rabbit antibody. Lytic activity of NOD sera was reconstituted by mixing with C4-deficient CBA sera, but not C5-deficient DBA/2 sera, indicating the presence of C4, but the absence of C5 activity in NOD sera. Lytic activity of NOD sera could be reconstituted with human C5 electrofocused in polyacrylamide gel. The polymerase chain reaction was used to amplify fragments from genomic DNA corresponding to the region of Hc (the gene encoding C5) in DBA/2 mice, which carries a 2-base pair deletion responsible for the lack of C5 protein expression in these mice. DBA/2 and NOD mice from several colonies produced a fragment 2 bases shorter than that generated from the wild-type allele in BALB/c mice.(ABSTRACT TRUNCATED AT 250 WORDS)

Alleles↗
PubMed1991

Hemolytic anemia in non-obese diabetic mice.

The non-obese diabetic mouse (NOD mouse) is widely used as a model of organ-specific autoimmunity because it develops specific autoimmune destruction of pancreatic beta cells mediated by T cells and culminating in insulin-dependent diabetes mellitus. Here, we report that the NOD mouse also develops Coombs'-positive hemolytic anemia, a B cell-mediated autoimmune disease. Aged NOD mice were found to have splenomegaly and jaundice predominantly due to raised unconjugated serum bilirubin. Their hematocrits were markedly lowered, and there was a reciprocal increase in the reticulocyte count. Red blood cells (RBC) from anemic mice showed a normal lytic response to hypotonicity. RBC from non-anemic mice had normal half lives in non-anemic, non-diabetic NOD mice by 51Cr labeling but, dramatically shortened half lives in anemic mice. Similar results were obtained with RBC from anemic mice. Hemolysis could be transferred with serum from anemic mice resulting in reticulocytosis. The antibody-mediated nature of the anemia was confirmed with the direct Coombs' test. Anemia was found only in mice aged greater than 200 days and was more common in diabetic (4/8) than non-diabetic (1/16) mice at 300 days. However, by 550 days, 14/17 non-diabetic mice were affected.

Anemia, Hemolytic↗
PubMed1991

Accelerated diabetes in non-obese diabetic (NOD) mice differing in incidence of spontaneous disease.

The NOD mouse is an established model of autoimmune diabetes mellitus. Various lines of NOD mice differ in their incidence of spontaneous diabetes, e.g. 93% of female NOD/Lt mice compared with 46% of female NOD/Wehi mice develop diabetes by 250 days. These two lines were studied under conditions which greatly accelerate the onset of hyperglycaemia. It was hoped that their responses to these manipulations would reveal characteristic differences which would increase our understanding of diabetes resistance in the low incidence NOD/Wehi line. One dose of 300 mg/kg of cyclophosphamide (CP) produced hyperglycaemia in 50% of NOD mice within 2 weeks in both lines. They were also equally susceptible to diabetes induced by splenocyte transfer at 21 days of age from prediabetic 150-day-old NOD/Lt or NOD/Wehi females. Five daily 40 mg/kg doses of streptozotocin (STZ) resulted in a severity of diabetes in the NOD mice greater than in C57BL or SJL/mice. While the incidence and severity of diabetes induced in the two NOD lines were similar, this appeared to be principally due to sensitivity to the toxic effects of STZ rather than its ability to exacerbate autoimmune beta cell destruction. It has previously been shown that it is possible to prevent diabetes in susceptible NOD mice with simple, relatively benign therapies and here we show that it is possible to induce diabetes in resistant animals at a rate indistinguishable from fully predisposed individuals. It therefore appears that the prediabetic NOD mouse is poised in an immunologically precarious state with the onset of disease being highly dependent on factors which exacerbate or moderate autoimmune destruction.

Animals↗
PubMed1991

High and low diabetes incidence nonobese diabetic (NOD) mice: origins and characterisation.

The Nonobese Diabetic mouse (NOD mouse) is an established model of autoimmune diabetes mellitus. While all colonies of NOD mice are derived from a single diabetic female detected during the breeding of a cataract-prone strain of mice, some of the dispersed colonies have been separated for many generations and express varying levels of diabetes. It is unclear to what extent this is due to environmental factors such as diet factor or a result of the varied origins of the colonies. Here we compare the incidence of diabetes and severity of insulitis in two divergent lines of NOD mice that differ in incidence of disease, but are maintained in the same environment. F1 crosses were performed and the progeny found to express the disease incidence of the low incidence line. This finding is consistent with either a dominant resistance gene(s) being responsible for reduced penetrance of disease or a transmissible environmental agent reducing the severity of the autoimmune process.

Animals↗
PubMed1989

Comparison of high- and low-diabetes-incidence NOD mouse strains.

The nonobese diabetic (NOD) mouse is a model of insulin-dependent diabetes mellitus. These mice develop insulinopenia and hyperglycemia secondary to beta-cell destruction, which is associated with insulitis and autoantibody production. We have two strains of NOD mice: a low-incidence strain (NOD/Wehi), in which less than 10% females and less than 1% males develop diabetes by 150 days despite intense insulitis, and a high-incidence strain (NOD/Lt), in which most females and many males develop diabetes by 150 days. This phenotypic difference has been maintained for 24 mo despite identical housing in our specific pathogen-free unit. Reciprocal skin grafting and allozyme electrophoresis have not identified a difference between the strains. Mixed-lymphocyte cultures were performed with splenic T-lymphocytes cultured with equal numbers of irradiated stimulator splenocytes for 3-6 days. NOD/Wehi mice demonstrated a heightened syngeneic mixed-lymphocyte response (SMLR), averaging 19% of the allogeneic response to CBA/CaHWehi cells. The response to NOD/Lt stimulator cells was not significantly different from the syngeneic response. In contrast, NOD/Lt mice had an SMLR similar to that of BALB/cAnBradleyWehi control mice, averaging 5% of the allogeneic response. NOD/Lt cells also responded similarly to NOD/Wehi stimulator cells and briskly to allogeneic cells. The heightened SMLR in NOD/Wehi mice may reflect active generation of suppressor function, and this may account for the low incidence of diabetes.

Alleles↗