The role of CD4(+) cells in vivo on the induction of the immune response to Porphyromonas gingivalis in mice

Background: It has previously been suggested that CD4(+) T cells play a pivotal role in regulating the immune response to periodontal pathogens. The aim of the present study therefore was to determine delayed type hypersensitivity (DTH), spleen cell proliferation, serum and splenic anti-Porphyromonas gingivalis antibody levels, and lesion sizes following challenge with viable P. gingiualis in CD4-depleted BALB/c mice immunized with P. gingiualis outer membrane proteins (OMP). Methods: Four groups of BALB/c mice were used. Groups 1 and 2 were injected intraperitoneally (ip) with saline for 3 consecutive days and then weekly throughout the experiment. Groups 3 and 4 were injected ip with rat immunoglobulin and a monoclonal rat anti-mouse CD4 antibody, respectively. Two days later, group 1 mice were injected ip with saline only, while all the other groups were immunized ip with P. gingiualis OMP weekly for 3 weeks. One week later following the last immunization of OMP, 3 separate experiments were conducted to determine: 1) the DTH response to P. gingiualis OMP by measuring footpad swelling; 2) the levels of antibodies to P. gingiualis in serum samples and spleen cell cultures using an enzyme-linked immunosorbent assay, as well as spleen cell proliferation after stimulation with OMP; and 3) the lesion sizes after a subcutaneous challenge with viable P. gingiualis cells. Results: In CD4(+) T-cell-depleted mice (group 4), the DTH response and antigen-stimulated cell proliferation were significantly suppressed when compared to groups 2 and 3. Similarly, the levels of serum and splenic IgM, IgG, and all IgG subclass antibodies to P. gingiualis OMP were depressed. Delayed healing of P. gingivalis-induced lesions was also observed in the CD4(+) T-cell-depleted group. Conclusions: This study has shown that depletion of CD4(+) T cells prior to immunization with P. gingiualis OMP led to the suppression of both the humoral and cell-mediated immune response to this microorganism and that this was associated with delayed healing. These results suggest that the induction of the immune response to P. gingiualis is a CD4(+) T-cell-dependent mechanism and that CD4(+) T cells are important in the healing process.

Nature and specificity of the required protective immune response that develops postchallenge in mice vaccinated with the 19-kilodalton fragment of Plasmodium yoelii merozoite surface protein 1

Immunity induced by the 19-kDa fragment of Plasmodium yoelii merozoite surface protein 1 (MSP1(19)) is dependent on high titers of specific antibodies present at the time of challenge and a continuing active immune response postinfection. However, the specificity of the active immune response postinfection has not been defined. In particular, it is not known whether anti-MSP1(19) antibodies that arise following infection alone are sufficient for protection. We developed systems to investigate whether an MSP1(19)-specific antibody response alone both prechallenge and postchallenge is sufficient for protection. We were able to exclude antibodies with other specificities, as well as any contribution of MSP1(19)-specific CD4(+) T cells acting independent of antibody, and we concluded that an immune response focused solely on MSP1(19)-specific antibodies is sufficient for protection. The data imply that the ability of natural infection to boost an MSPI,g-specific antibody response should greatly improve vaccine efficacy.

Immune correlate study on human Schistosoma japonicum in a well-defined population in Leyte, Philippines: I. Assessment of 'resistance' versus 'susceptibility' to S-japonicum infection

This study describes the categorical classification of 155 individuals living in an endemic village in Macanip, Leyte, Philippines as 'resistant' or 'susceptible' to Schistosoma japonicum infection using available exposure, infection and reinfection data collected from a 3-year water contact (WC) study. Epidemiological parameters including age, sex, and infection intensities in relation to observed reinfection patterns are also described. This classification was used in subsequent immunological studies described in two accompanying papers to identify protective immune mechanisms among resistant individuals induced by defined candidate vaccine molecules for S. japonicum. The study suggests that individuals who were most vulnerable to rapid reinfection were children belonging to the 5-14 age group. A drop in incidence at age group 15-19 and decreased intensity of infection starting at this age group and older (15+) suggests development of immunity. Controlling for the effect of the other variables, a multivariate analysis showed significant association for sex, in that females were more likely to be resistant. This implies that other than acquired immunity to infection, some age-dependent host factors may also play an important role in the overall changes of reinfection patterns seen in schistosomiasis japonica in this population. Crown Copyright (C) 2002 Published by Elsevier Science B.V. All rights reserved.

T cell regulation of the immune response to infection in periodontal diseases

Although T cells have been implicated in the pathogenesis and are considered to be central both in progression and control of the chronic inflammatory periodontal diseases, the precise contribution of T cells to the regulation of tissue destruction has not been fully elucidated. Current dogma suggests that immunity to infection is controlled by distinct T helper 1 (Th1) and T helper 2 (Th2) subsets of T cells classified on the basis of their cytokine profile. Further, a subset of T cells with immunosuppressive function and cytokine profile distinct from Th1 or Th2 has been described and designated as regulatory T cells. Although these regulatory T cells have been considered to maintain self-tolerance resulting in the suppression of auto-immune responses, recent data suggest that these cells may also play a role in preventing infection-induced immunopathology. In this review, the role of functional and regulatory T cells in chronic inflammatory periodontal diseases will be summarized. This should not only provide an insight into the relationship between the immune response to periodontopathic bacteria and disease but should also highlight areas of development for potentially new therapeutic modalities.

Antigen-specific suppression of a primed immune response by dendritic cells mediated by regulatory T cells secreting interleukin-10

Antigen-specific suppression of a previously primed immune response is a major challenge for immunotherapy of autoimmune disease. ReIB activation is required for myeloid DC differentiation. Here, we show that antigen-exposed DCs in which ReIB function is inhibited lack cell surface CD40, prevent priming of immunity, and suppress previously primed immune responses. DCs generated from CD40-deficient mice similarly confer suppression. Regulatory CD4(+) T cells induced by the DCs transfer antigen-specific Infectious tolerance to primed recipients in an interleukin10-dependent fashion. Thus CD40, regulated by ReIB activity, determines the consequences of antigen presentation by myeloid DCs. These observations have significance for autoimmune immunotherapy and suggest a mechanism by which peripheral tolerance might be constitutively maintained by RelB(-) CD40(-) DCs.

Greater replication and differentiation of preadipocytes in inherited corticosteroid-binding globulin deficiency

Glucocorticoids are pivotal for adipose tissue development. Rodent studies suggest that corticosteroid-binding globulin (CBG) modulates glucocorticoid action in adipose tissue. In humans, both genetic CBG deficiency and suppressed CBG concentrations in hyperinsulinemic states are associated with obesity. We hypothesized that CBG deficiency in humans modulates the response of human preadipocytes to glucocorticoids, predisposing them to obesity. We compared normal preadipocytes with subcultured preadipocytes from an individual with the first ever described complete deficiency of CBG due to a homozygous null mutation. CBG-negative preadipocytes proliferated more rapidly and showed greater peroxisome proliferator-activated receptor-gamma-mediated differentiation than normal preadipocytes. CBG was not expressed in normal human preadipocytes. Glucocorticoid receptor number and binding characteristics and 11beta-hydroxysteroid dehydrogenase activity were similar for CBG-negative and normal preadipocytes. We propose that the increased proliferation and enhanced differentiation of CBG-negative preadipocytes may promote adipose tissue deposition and explain the obesity seen in individuals with genetic CBG deficiency. Furthermore, these observations may be relevant to obesity occurring with suppressed CBG concentrations associated with hyperinsulinemia.

Plasma zinc and immune markers in runners in response to a moderate increase in training volume

Changes in plasma zinc concentration and markers of immune function were examined in a group of 10 male runners (n = 10) following a moderate increase in training over four weeks. Seven sedentary males acted as controls. Fasting blood samples were taken at rest, before (T0) and after T4) four weeks of increased (+ 16 %) training and after two weeks of reduced (- 31 %) training (W. Blood was analysed for plasma zinc concentration, differential leucocyte counts, lymphocyte subpopulations and lymphocyte proliferation using incorporation of H-3-thymidine. The runners increased their training volume by 16 % over the four weeks. When compared with the nonathletes, the runners had lower concentrations of plasma zinc (p = 0.012), CD3(+) (p = 0.042) and CD19(+) lymphocytes (p = 0.010) over the four weeks. Lymphocyte proliferation in response to Concanavalin A stimulation was greater in the runners (p = 0.0090). Plasma zinc concentration and immune markers remained constant during the study. Plasma zinc concentration correlated with total leucocyte counts in the athletes at T6 (r = -0.72, p < 0.05) and with Pokeweed mitogen stimulation in the nonathletes at T6 (r = -0.92, p < 0.05). Therefore, athletes are unlikely to benefit from zinc supplementation during periods of moderately increased training volume.