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A G Baxter

Publications and source records attributed to A G Baxter.

At least 19 recordsLinked to original sources
PubMed2001

Identification of the Gasa3 and Gasa4 autoimmune gastritis susceptibility genes using congenic mice and partitioned, segregative and interaction analyses.

BALB/c mice thymectomized on their third day of life develop a high incidence of experimental autoimmune gastritis (EAG) which closely resembles human chronic atrophic (type A, autoimmune) gastritis. Linkage analysis of (BALB/cCrSlcxC57BL/6)F2 mice previously demonstrated that the Gasa1 and Gasa2 genes on distal Chromosome (Chr) 4 have major effects on the development of EAG in this murine model, while other loci displayed a trend towards linkage. Here, we implemented partitioned chi(2)-analysis in order to develop a better understanding of the genotypes contributing to susceptibility and resistance at each linkage region. This approach revealed that linkage of Gasa1 and Gasa2 to EAG was due to codominant and recessive BALB/cCrSlc alleles, respectively. To identify additional EAG susceptibility genes, separate linkage studies were performed on Gasa1 heterozygotes and Gasa2 C57BL/6 homozygotes plus heterozygotes so as to minimize the effects of these disease genes. The enhanced sensitivity of these analyses confirmed the existence of a third EAG susceptibility gene (designated Gasa3) on Chr 6. Epistatic interactions between the Gasa2 EAG susceptibility gene and the H2 were also identified, and the presence of an H2-linked susceptibility gene (Gasa4) confirmed by analysis of H2 congenic mice.

Animals↗
PubMed2001

Clonal cytotoxic T cells are expanded in myeloma and reside in the CD8(+)CD57(+)CD28(-) compartment.

The occurrence of clonal T cells in multiple myeloma (MM), as defined by the presence of rearrangements in the T-cell receptor (TCR)-beta chains detected on Southern blotting, is associated with an improved prognosis. Recently, with the use of specific anti-TCR-variable-beta (anti-TCRV(beta)) antibodies, the presence in MM patients of expanded populations of T cells expressing particular V(beta) regions was reported. The majority of these T-cell expansions have the phenotype of cytotoxic T cells (CD8(+)CD57(+) and perforin positive). Since V(beta) expansions can result from either a true clonal population or a polyclonal response, the clonality of CD8(+)TCRV(beta)(+) T cells was tested by TCRV(beta) complementarity-determining region 3 length analysis and DNA sequencing of the variable region of the TCR. In this report, the CD57(+) and CD57(-) subpopulations within expanded TCRV(beta)(+)CD8(+) cell populations are compared, and it is demonstrated that the CD57(+) subpopulations are generally monoclonal or biclonal, whereas the corresponding CD57(-) cells are frequently polyclonal. The oligoclonality of CD57(+) expanded CD8(+) T cells but not their CD57(-) counterparts was also observed in age-matched controls, in which the T-cell expansions were mainly CD8(-). The CD8(+)CD57(+) clonal T cells had a low rate of turnover and expressed relatively lower levels of the apoptotic marker CD95 than their CD57(-) counterparts. Taken together, these findings demonstrate that MM is associated with CD57(+)CD8(+) T-cell clones, raising the possibility that the expansion and accumulation of activated clonal CD8(+) T cells in MM may be the result of persistent stimulation by tumor-associated antigens, combined with a reduced cellular death rate secondary to reduced expression of the apoptosis-related molecule CD95.

Adult↗
PubMed2001

CD1d-restricted NKT cells: an interstrain comparison.

CD1d-restricted Valpha14-Jalpha281 invariant alphabetaTCR(+) (NKT) cells are well defined in the C57BL/6 mouse strain, but they remain poorly characterized in non-NK1.1-expressing strains. Surrogate markers for NKT cells such as alphabetaTCR(+)CD4(-)CD8(-) and DX5(+)CD3(+) have been used in many studies, although their effectiveness in defining this lineage remains to be verified. Here, we compare NKT cells among C57BL/6, NK1.1-congenic BALB/c, and NK1.1-congenic nonobese diabetic mice. NKT cells were identified and compared using a range of approaches: NK1.1 expression, surrogate phenotypes used in previous studies, labeling with CD1d/alpha-galactosylceramide tetramers, and cytokine production. Our results demonstrate that NKT cells and their CD4/CD8-defined subsets are present in all three strains, and confirm that nonobese diabetic mice have a numerical and functional deficiency in these cells. We also highlight the hazards of using surrogate phenotypes, none of which accurately identify NKT cells, and one in particular (DX5(+)CD3(+)) actually excludes these cells. Finally, our results support the concept that NK1.1 expression may not be an ideal marker for CD1d-restricted NKT cells, many of which are NK1.1-negative, especially within the CD4(+) subset and particularly in NK1.1-congenic BALB/c mice.

Animals↗
PubMed2001

Modelling the effects of genetic and environmental factors on the risk of autoimmune disease.

The presence or absence of autoimmune disease is a qualitative outcome resulting from the combined influences of genetic, environmental and stochastic factors that interact in complex ways. Because of the nature of these interactions, the effects of risk factors that contribute to the aetiology of disease cannot be adequately assessed individually. Here, I propose an approach to multiparameter modelling of autoimmune disease that incorporates Falconer's concept of liability in a generalized linear model. Specifically, a logistic model, allied to that used to assess the influence of genetic risk factors, is suggested. The limits of modelling autoimmune disease and the requirements for data collection are also briefly discussed.

Autoimmune Diseases↗
PubMed2001

Louis Pasteur's beer of revenge.

Although by the mid-nineteenth century evidence existed for an association between micoorganisms and disease, it was the combined efforts of Louis Pasteur and Robert Koch that created the germ theory of disease--the theory that specific microbes cause specific diseases. Surprisingly, the relationship between the two founders of microbiology and immunology was far from friendly.

Allergy and Immunology↗
PubMed2001

Cytometric and functional analyses of NK and NKT cell deficiencies in NOD mice.

Defects in NK and NKT cell activities have been implicated in the etiology of type 1 (autoimmune) diabetes in NOD mice on the basis of experiments performed using surrogate phenotypes for the identification of these lymphocyte subsets. Here, we have generated a congenic line of NOD mice (NOD.b-Nkrp1(b)) which express the allelic NK1.1 marker, enabling the direct study of NK and NKT cells in NOD mice. Major deficiencies in both populations were identified when NOD.b-Nkrp1(b) mice were compared with C57BL/6 and BALB.B6-Cmv1(r) mice by flow cytometry. The decrease in numbers of peripheral NK cells was associated with an increase in their numbers in the bone marrow, suggesting that a defect in NK cell export may be involved. In contrast, the most severe deficiency of NKT cells found was in the thymus, indicating that defects in thymic production were probably responsible. The deficiencies in NK cell activity in NOD mice could only partly be accounted for by the reduced numbers of NK cells, and fewer NKT cells from NOD mice produced IL-4 following stimulation, suggesting that NK and NKT cells from NOD mice shared functional deficiencies in addition to their numerical deficiencies. Despite the relative lack of IL-4 production by NOD NKT cells, adoptive transfer of alpha beta TCR(+)NK1.1(+) syngeneic NKT cells into 3-week-old NOD recipients successfully prevented the onset of spontaneous diabetes. As both NK and NKT cells play roles in regulating immune responses, we postulate that the synergistic defects reported here contribute to the susceptibility of NOD mice to autoimmune disease.

Animals↗
PubMed2001

The NOD mouse as a model of SLE.

In addition to developing a high incidence of type 1 diabetes caused by a specific autoimmune response against pancreatic beta cells in the islets of Langerhans, NOD mice also demonstrate spontaneous autoimmunity to other targets including the thymus, adrenal gland, salivary glands, thyroid, testis, nuclear components and red blood cells. Moreover, treatment of pre-diabetic NOD mice with an intravenous dose of heat killed Mycobacterium bovis (M. bovis; bacillus Calmette-Guèrin (BCG)) protects them from developing type 1 diabetes, but instead precipitates an autoimmune rheumatic disease similar to systemic lupus erythematosus (SLE), characterised by accelerated and increased incidence of haemolytic anaemia (HA), anti-nuclear autoantibody (ANA) production, exacerbation of sialadenitis, and the appearance of immune complex-mediated glomerulonephritis (GN). The reciprocal switching between the two phenotypes by a single environmental trigger (mycobacterial exposure) raised the possibility that genetic susceptibility for type 1 diabetes and SLE may be conferred by a single collection of genes in the NOD mouse. This review will focus on the genetic components predisposing NOD mice to SLE induced by BCG treatment and compare them to previously determined diabetes susceptibility genes in this strain and SLE susceptibility genes in the BXSB, MRL and the New Zealand mouse strains.

Animals↗
PubMed2000

Linkage analysis of systemic lupus erythematosus induced in diabetes-prone nonobese diabetic mice by Mycobacterium bovis.

Systemic lupus erythematosus induced by Mycobacterium bovis in diabetes-prone nonobese diabetic mice was mapped in a backcross to the BALB/c strain. The subphenotypes-hemolytic anemia, antinuclear autoantibodies, and glomerular immune complex deposition-did not cosegregate, and linkage analysis for each trait was performed independently. Hemolytic anemia mapped to two loci: Bah1 at the MHC on chromosome 17 and Bah2 on distal chromosome 16. Antinuclear autoantibodies mapped to three loci: Bana1 at the MHC on chromosome 17, Bana2 on chromosome 10, and Bana3 on distal chromosome 1. Glomerular immune complex deposition did not show significant linkage to any genomic region. Mapping of autoantibodies (Coombs' or antinuclear autoantibodies) identified two loci: Babs1 at the MHC and Babs2 on distal chromosome 1. It has previously been reported that genes conferring susceptibility to different autoimmune diseases map nonrandomly to defined regions of the genome. One possible explanation for this clustering is that some alleles at loci within these regions confer susceptibility to multiple autoimmune diseases-the "common gene" hypothesis. With the exception of the H2, this study failed to provide direct support for the common gene hypothesis, because the loci identified as conferring susceptibility to systemic lupus erythematosus did not colocalize with those previously implicated in diabetes. However, three of the four regions identified had been previously implicated in other autoimmune diseases.

Anemia, Hemolytic↗
PubMed2000

NKT cells: facts, functions and fallacies.

The proposed roles of NK1.1(+) T (NKT) cells in immune responses range from suppression of autoimmunity to tumor rejection. Heterogeneity of these cells contributes to the controversy surrounding their development and function. This review aims to provide an update on NKT cell biology and, whenever possible, to compare what is known about NKT-cell subsets.

Animals↗
PubMed1999

Multiple deficiencies underlie NK cell inactivity in lymphotoxin-alpha gene-targeted mice.

We have evaluated the NK cell antitumor activity in lymphotoxin (LT)-deficient mice. Both NK cell-mediated tumor rejection and protection from experimental metastases were significantly compromised in LT-alpha-deficient mice. Analysis of LT-alpha-deficient mice revealed that the absolute number of alphabetaTCR- NK1.1+ NK cells was reduced in bone marrow and thymus, but with overall proportional decreases in other hemopoietic organs. In addition, the antitumor potential of alphabetaTCR- NK1.1+ cells, as determined by their lytic capacity and perforin expression, was reduced 1.5- to 3-fold in LT-alpha-deficient mice, as compared with wild-type mice. Combined defects in NK cell development and effector function contribute to compromised NK cell antitumor function in LT-alpha-deficient mice.

Animals↗
PubMed1999

A major linkage region on distal chromosome 4 confers susceptibility to mouse autoimmune gastritis.

Although much is known about the pathology of human chronic atrophic (type A, autoimmune) gastritis, its cause is poorly understood. Mouse experimental autoimmune gastritis (EAG) is a CD4+ T cell-mediated organ-specific autoimmune disease of the stomach that is induced by neonatal thymectomy of BALB/c mice. It has many features similar to human autoimmune gastritis. To obtain a greater understanding of the genetic components predisposing to autoimmune gastritis, a linkage analysis study was performed on (BALB/cCrSlc x C57BL/6)F2 intercross mice using 126 microsatellite markers covering 95% of the autosomal genome. Two regions with linkage to EAG were identified on distal chromosome 4 and were designated Gasa1 and Gasa2. The Gasa1 gene maps within the same chromosomal segment as the type 1 diabetes and systemic lupus erythematosus susceptibility genes Idd11 and Nba1, respectively. Gasa2 is the more telomeric of the two genes and was mapped within the same chromosomal segment as the type 1 diabetes susceptibility gene Idd9. In addition, there was evidence of quantitative trait locus controlling autoantibody titer within the telomeric segment of chromosome 4. The clustering of genes conferring susceptibility to EAG with those conferring susceptibility to type 1 diabetes is consistent with the coinheritance of gastritis and diabetes within human families. This is the first linkage analysis study of autoimmune gastritis in any organism and as such makes an important and novel contribution to our understanding of the etiology of this disease.

Animals↗
PubMed1999

NKT cells are phenotypically and functionally diverse.

NK1.1(+)alpha betaTCR(+) (NKT) cells have several important roles including tumor rejection and prevention of autoimmune disease. Although both CD4(+) and CD4(-)CD8(-) double-negative (DN) subsets of NKT cells have been identified, they are usually described as one population. Here, we show that NKT cells are phenotypically, functionally and developmentally heterogeneous, and that three distinct subsets (CD4(+), DN and CD8(+)) are differentially distributed in a tissue-specific fashion. CD8(+) NKT cells are present in all tissues but the thymus, and are highly enriched for CD8alpha(+)beta(-) cells. These subsets differ in their expression of a range of cell surface molecules (Vbeta8, DX5, CD69, CD45RB, Ly6C) and in their ability to produce IL-4 and IFN-gamma, with splenic NKT cell subsets producing lower levels than thymic NKT cells. Developmentally, most CD4(+) and DN NKT cells are thymus dependent, in contrast to CD8(+) NKT cells, and are also present amongst recent thymic emigrants in spleen and liver. TCR Jalpha281-deficient mice show a dramatic deficiency in thymic NKT cells, whereas a significant NKT cell population (enriched for the DN and CD8(+) subsets) is still present in the periphery. Taken together, this study reveals a far greater level of complexity within the NKT cell population than previously recognized.

Animals↗
PubMed1998

An essential role for tumor necrosis factor in natural killer cell-mediated tumor rejection in the peritoneum.

Natural killer (NK) cells are thought to provide the first line of defence against tumors, particularly major histocompatibility complex (MHC) class I- variants. We have confirmed in C57BL/6 (B6) mice lacking perforin that peritoneal growth of MHC class I- RMA-S tumor cells in unprimed mice is controlled by perforin-dependent cytotoxicity mediated by CD3(-) NK1.1(+) cells. Furthermore, we demonstrate that B6 mice lacking tumor necrosis factor (TNF) are also significantly defective in their rejection of RMA-S, despite the fact that RMA-S is insensitive to TNF in vitro and that spleen NK cells from B6 and TNF-deficient mice are equally lytic towards RMA-S. NK cell recruitment into the peritoneum was abrogated in TNF-deficient mice challenged with RMA-S or RM-1, a B6 MHC class I- prostate carcinoma, compared with B6 or perforin-deficient mice. The reduced NK cell migration to the peritoneum of TNF-deficient mice correlated with the defective NK cell response to tumor in these mice. By contrast, a lack of TNF did not affect peptide-specific cytotoxic T lymphocyte-mediated rejection of tumor from the peritoneum of preimmunized mice. Overall, these data show that NK cells delivering perforin are the major effectors of class I- tumor rejection in the peritoneum, and that TNF is specifically critical for their recruitment to the peritoneum.

Animals↗
PubMed1998

alpha/beta-T cell receptor (TCR)+CD4-CD8- (NKT) thymocytes prevent insulin-dependent diabetes mellitus in nonobese diabetic (NOD)/Lt mice by the influence of interleukin (IL)-4 and/or IL-10.

We have previously shown that nonobese diabetic (NOD) mice are selectively deficient in alpha/beta-T cell receptor (TCR)+CD4-CD8- NKT cells, a defect that may contribute to their susceptibility to the spontaneous development of insulin-dependent diabetes mellitus (IDDM). The role of NKT cells in protection from IDDM in NOD mice was studied by the infusion of thymocyte subsets into young female NOD mice. A single intravenous injection of 10(6) CD4-/lowCD8- or CD4-CD8- thymocytes from female (BALB/c x NOD)F1 donors protected intact NOD mice from the spontaneous onset of clinical IDDM. Insulitis was still present in some recipient mice, although the cell infiltrates were principally periductal and periislet, rather than the intraislet pattern characteristic of insulitis in unmanipulated NOD mice. Protection was not associated with the induction of "allogenic tolerance" or systemic autoimmunity. Accelerated IDDM occurs after injection of splenocytes from NOD donors into irradiated adult NOD recipients. When alpha/beta-TCR+ and alpha/beta-TCR- subsets of CD4-CD8- thymocytes were transferred with diabetogenic splenocytes and compared for their ability to prevent the development of IDDM in irradiated adult recipients, only the alpha/beta-TCR+ population was protective, confirming that NKT cells were responsible for this activity. The protective effect in the induced model of IDDM was neutralized by anti-IL-4 and anti-IL-10 monoclonal antibodies in vivo, indicating a role for at least one of these cytokines in NKT cell-mediated protection. These results have significant implications for the pathogenesis and potential prevention of IDDM in humans.

Animals↗