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N J Davidson

Publications and source records attributed to N J Davidson.

12 recordsLinked to original sources
PubMed1998

IL-12, but not IFN-gamma, plays a major role in sustaining the chronic phase of colitis in IL-10-deficient mice.

IL-10-deficient (IL-10(-/-)) mice develop chronic enterocolitis mediated by CD4+ Th1 cells producing IFN-gamma. Because IL-12 can promote Th1 development and IFN-gamma production, the ability of neutralizing anti-IL-12 mAb to modulate colitis in IL-10(-/-) mice was investigated. Anti-IL-12 mAb treatment completely prevented disease development in young IL-10(-/-) mice. Treatment of adult mice resulted in significant amelioration of established disease accompanied by reduced numbers of mesenteric lymph node and colonic CD4+ T cells and of mesenteric lymph node T cells spontaneously producing IFN-gamma. In contrast, anti-IFN-gamma mAb had minimal effect on disease reversal, despite a significant preventative effect in young mice. These findings suggested that IL-12 sustains colitis by supporting the expansion of differentiated Th1 cells that mediate disease independently of their IFN-gamma production. This conclusion was supported by the finding that anti-IL-12 mAb greatly diminished the ability of a limited number of CD4+ T cells expressing high levels of CD45RB from diseased IL-10(-/-) mice to expand and cause colitis in recombination-activating gene-2(-/-) recipients, while anti-IFN-gamma mAb had no effect. Furthermore, IL-12 could support pathogenic IL-10(-/-) T cells stimulated in vitro in the absence of IL-2. While these studies show that IL-12 plays an important role in sustaining activated Th1 cells during the chronic phase of disease, the inability of anti-IL-12 mAb to abolish established colitis or completely prevent disease transfer by Thl cells suggests that additional factors contribute to disease maintenance.

Adoptive Transfer↗
PubMed1997

Studies with IL-10-/- mice: an overview.

Our studies have elucidated, in part, the mechanism whereby persistent stimulation by normal enteric antigens leads to the development of chronic enterocolitis in interleukin 10-deficient (IL-10-/-) mice. This disease is mediated by IL-10-/- CD4+ T cells as evidenced by their ability to transfer colitis to immunodeficient RAG-2-/- mice. Furthermore, the CD4+ T cells recovered from the affected colons of IL-10-/- mice consisted of a highly polarized Th1-like population because they produced interferon-gamma (IFN-gamma) but not IL-4. We found that enterocolitis could be prevented if 3-week-old mutants were treated for 6-8 weeks with either anti-IL-12 or anti-IFN-gamma monoclonal antibodies (mAb). These results were consistent with the findings of in vitro studies suggesting that IFN-gamma and, in particular, IL-12 direct the differentiation of naive T cells toward a Th1 phenotype. Apparently, the uncontrolled production of IL-12 and IFN-gamma by accessory cells and T cells, respectively, in IL-10-/- mice ultimately resulted in the excessive generation and activation of Th1 cells, hence, immunopathology. IL-10-/- mice have also been used to evaluate the importance of IL-10 in regulating immune responses outside of the gastrointestinal (GI) tract. In these studies, IL-10-/- mice were challenged with a variety of foreign antigens using different routes of administration. In general, the results repeatedly demonstrated that a major function of IL-10 is to protect the host from the harmful side effects of an overly zealous immune-inflammatory response. However, other studies have confirmed speculations that the potent immunosuppressive activities of IL-10 may, under certain circumstances, increase the host's susceptibility to infection with certain types of pathogenic organisms.

Animals↗
PubMed1996

T helper cell 1-type CD4+ T cells, but not B cells, mediate colitis in interleukin 10-deficient mice.

Mice rendered deficient in the production of interleukin 10 (IL-10-/-) develop a chronic inflammatory bowel disease (IBD) that predominates in the colon and shares histopathological features with human IBD. Our aim was to identify which cell type(s) can mediate colitis in IL-10-/- mice. We detected an influx of immunoglobulin-positive cells into the colon and the presence of colon-reactive antibodies in the serum of IL-10-/- mice. To assess a pathogenic role for B cells, we generated a B cell-deficient (B-/-) strain of IL-10-/- mice. B-/-IL-10-/- mice acquired a severe colitis analogous to that IL-10-/- mice, implying that B cells were not the primary mediator of IBD in this model. A series of cell transfer experiments was performed to assess a pathogenic role for T cells. When IL-10-/- T cell-enriched lamina propria lymphocytes (LPL) or intraepithelial lymphocytes (IEL) were transferred into immunodeficient recombinase-activating gene (RAG)-2-/- recipients, a mild to severe colitis developed, depending on the cell number transferred. Lymphocytes recovered from the colon of transplanted RAG-2-/- mice with colitis were predominantly alpha beta TCR+CD4+, including a large proportion of CD4+CD8 alpha + cells. These cells were also CD45RB-/low and CD44+, indicative of an activated/memory population. Individual populations of CD4+CD8 alpha-, CD4+CD8 alpha + and CD4-CD8 alpha + T cells were then isolated from the lamina propria compartment of IL-10-/- mice and transferred into RAG-2-/- recipients. Only IL-10-/- CD4-expressing LPL, including both the CD4+CD8 alpha- and CD4+CD8 alpha + populations, induced colitis in recipient mice. Interferon-gamma, but little to no IL-4, was produced by CD4+CD8 alpha- and CD4+CD8 alpha + LPL recovered from the inflamed colons of RAG-2-/- recipients implicating alpha T helper cell 1 (TH1)-mediated response. We thus conclude that colitis in IL-10-/- mice is predominantly mediated by TH1-type alpha beta TCR+ T cells expressing CD4 alone, or in combination with the CD8 alpha molecule.

Animals↗
PubMed1995

Interleukin 10 but not interleukin 4 is a natural suppressant of cutaneous inflammatory responses.

We have examined the role of endogenously produced interleukin (IL) 4 and IL-10 in the regulation of inflammatory and immune reactions in the skin. In these experiments, irritant and contact hypersensitivity (CH) responses were elicited in mice with targeted disruptions of the IL-4 (IL-4T) or IL-10 (IL-10T) gene. Our study showed that IL-4T and wild-type (wt) mice exhibited equivalent responses to the irritant croton oil. In contrast, the response of IL-10T mice challenged with croton oil was abnormally increased. When IL-10T mice were exposed to a higher dose of irritant, irreversible tissue damage occurred. By comparison, any treatment of wt mice with croton oil resulted in far less tissue damage and resolution of inflammation. Neutralizing antibody studies demonstrated that the necrosis that occurred in IL-10T mice was due to the overproduction of tumor necrosis factor. The anti-tumor necrosis factor antibody treatment of IL-10T mice did not significantly reduce the edema or the influx of inflammatory cells, suggesting that these changes were due to the uncontrolled production of other proinflammatory cytokines. T cell-dependent immune responses were also evaluated using the contact sensitizer oxazolone. The response of IL-4T mice did not differ from wt mice. In contrast, IL-10T mice mounted an exaggerated CH response, increased in both magnitude and duration as compared with wt mice. Based on these studies, we have concluded that IL-10, but not IL-4, is a natural suppressant of irritant responses and of CH, and it limits immunopathologic damage in the skin.

Animals↗
PubMed1993

Phenotypic mapping of the chicken embryonic thymic microenvironment developing within an organ culture system.

The chicken thymic microenvironment, as it developed in an embryonic thymus organ culture system, was phenotypically mapped using a panel of mAb defining both epithelial and nonepithelial stromal cell antigens. We have previously reported that thymocyte proliferation and differentiation with proceed for up to 6-8 days in thymus organ culture, hence demonstrating the functional integrity of the thymic microenvironment in vitro. During this time, the stromal component reflected that of the normal embryo with cortical and medullary epithelial areas readily identifiable by both morphology and surface-antigen expression. An abundance of subcapsular and cortical epithelial antigens was detected in the cultured thymus, particularly those normally expressed by the epithelium lining the capsule, trabeculae, and vascular regions (type I epithelium) in the adult and embryonic thymus. Medullary epithelial antigens developed in organ culture, although were present in lower frequency than observed in the age-matched embryonic thymus. MHC class II expression by both epithelial and nonepithelial cells was maintained at high levels throughout the culture period. With increasing time in culture, the ratio of epithelial to nonepithelial cells decreased, concurrent with a decrease in thymocyte frequency and suggestive of a bidirectional interaction between these two cell types. Thus, a functionally intact thymic microenvironment appears to be maintained in embryonic thymus organ culture, a model that is currently being exploited to assess the role of stromal antigens, as defined by our mAb, in the process of thymopoiesis.

Animals↗
PubMed1992

Kinetics of chicken embryonic thymocyte development in ovo and in organ culture.

Thymocyte development was monitored in an embryonic thymus organ culture system to establish a model in the chicken in which the functional nature of the thymic microenvironment could be assessed. Thymus lobes were removed from 10-day-old embryos and cultured for 2-10 days. Cell yield increased to a maximum in 4-8 days of culture with a corresponding decrease in average cell size. An initial thymocyte population of predominantly CD3-CD4-CD8- cells gave rise to all CD3/CD4/CD8-defined subpopulations in vitro, maintaining high levels of CD3-CD4-CD8+ and CD3+CD4-CD8+ cells and a low representation of CD3-CD4+CD8-, CD3+CD4+CD8-, CD3-CD4+CD8+ and CD3+CD4+CD8+ thymocytes. This is the first observation of a CD3-CD4+CD8- population in the chicken. Developmental kinetics of CD3+ cells were similar to that in the embryo, suggesting that the in vitro environment is sufficient to promote and maintain thymocyte maturation. Thymocytes of both the gamma delta and alpha beta T cell receptor (TcR) lineages developed in that order, confirming in ovo data and the lineage potential of the first wave of thymocyte precursors. One unusual finding was a relative accumulation of gamma delta TcR+ thymocytes in culture, incorporating all CD4/CD8 subsets, including a previously undetected population, CD4+CD8-. This may indicate a favorable developmental environment or simply a lack of normal cellular emigration. A detailed comparison with T cell development in the embryo demonstrated that the chicken thymus organ culture system reflects thymic events in ovo during a limited time period and thus should prove useful in the identification of functionally relevant thymic molecules.

Animals↗
PubMed1992

Delineation of chicken thymocytes by CD3-TCR complex, CD4 and CD8 antigen expression reveals phylogenically conserved and novel thymocyte subsets.

To further define the relationship between thymocyte subsets and their developmental sequence, multi-parameter flow cytometry was used to determine the distribution of the CD3-TCR complex and the accessory molecules CD4 and CD8 on chicken thymocytes. As in mammals, adult thymocytes could be subdivided into CD3-, CD3lo, and CD3hi staining populations. CD4 and CD8 distribution on such populations revealed the presence of CD3-CD4+CD8- and CD3-CD4-CD8+ thymocytes, putative precursors to CD4+CD8+ cells, detectable in the adult and at high frequency during ontogeny. Of particular interest was the existence of CD3lo expression on CD4+CD8- and CD4-CD8+, and in some instances, on CD4-CD8- thymocytes. Such phenotypes are not easily detectable in the mammalian thymus but were readily observed in both adult and embryonic chicken thymus from 16 days of embryogenesis. Further analysis of the TCR lineage of these CD3lo cells revealed that they were essentially all of the alpha beta TCR type. Mature CD3hi thymocytes were found within the CD4+CD8+ and CD4+CD8- and CD4-CD8+ subsets. Both alpha beta and gamma delta TCR lineage thymocytes were detected within all CD4- and CD8-defined subsets, thus identifying novel thymocyte subsets in the chicken thymus, namely alpha beta TCR+CD4-CD8- and gamma delta TCR+ CD4+CD8- cells. Hence, this analysis of chicken thymocytes, while confirming the phylogenically conserved nature of the thymus, has revealed novel T cell subsets, providing further insight into the complexity of mainstream thymocyte maturation pathways.

Animals↗
PubMed1992

Phenotypic analysis of the chicken thymic microenvironment during ontogenic development.

The development of monoclonal antibodies (mAb) reactive with the thymic microenvironment has identified distinct subpopulations within the stromal component, but the function of these subregions in intrathymic T-cell differentiation remains essentially an enigma. In this study, we have used such a panel of mAb to examine the chicken thymus during ontogenic development to gain insight into the contributions of these thymic regions to the distinct phases of T-cell development and to further characterize the development of this organ. Our reagents have demonstrated the complex differentiation of the primitive endodermal epithelium into more specialized structures and the development of other thymic stromal components from mesectodermal cells. We also describe molecules localized to the subcapsular and perivascular regions, which have an ontogenic expression corresponding to the early localization and stimulation of thymic precursors and another molecule on the medullary vasculature expressed corresponding to the exit of mature cells from the thymus. In addition, two markers of distinct medullary epithelial clusters are initially expressed corresponding to the appearance of T-cell receptor-1 (TcR-1) and TcR-2 positive cells in the medulla, respectively. These mAb potentially represent excellent reagents for further definition of the thymic modulation of T-cell differentiation.

Age Factors↗
PubMed1984

Defective phagocytosis in insulin controlled diabetics: evidence for a reaction between glucose and opsonising proteins.

Neutrophils from diabetic patients controlled with insulin showed impaired phagocytosis of a yeast, Candida guilliermondii. The defect was detected by measuring the initial rate of phagocytosis at optimal concentrations of phagocytes and organisms in autologous plasma. By mixing normal neutrophils in diabetic plasma and vice versa both cellular and plasma abnormalities were shown. The defect was reproduced by incubating normal plasma at a D-glucose concentration of 15 mmol/l for 3 h or for shorter periods at higher concentrations of glucose. The data suggest that defective phagocytosis is partly due to a reaction between glucose and the plasma proteins concerned with opsonisation. Defective phagocytosis may be important not only in coping with infections but also in other diabetic complications as plasma proteins are concerned with the removal of damaged or effete cells as well as foreign antigens.

Blood Glucose↗