Selective blockade of the inhibitory Fcgamma receptor (FcgammaRIIB) in human dendritic cells and monocytes induces a type I interferon response program.

The ability of dendritic cells (DCs) to activate immunity is linked to their maturation status. In prior studies, we have shown that selective antibody-mediated blockade of inhibitory FcgammaRIIB receptor on human DCs in the presence of activating immunoglobulin (Ig) ligands leads to DC maturation and enhanced immunity to antibody-coated tumor cells. We show that Fcgamma receptor (FcgammaR)-mediated activation of human monocytes and monocyte-derived DCs is associated with a distinct gene expression pattern, including several inflammation-associated chemokines, as well as type 1 interferon (IFN) response genes, including the activation of signal transducer and activator of transcription 1 (STAT1). FcgammaR-mediated STAT1 activation is rapid and requires activating FcgammaRs. However, this IFN response is observed without a detectable increase in the expression of type I IFNs themselves or the need to add exogenous IFNs. Induction of IFN response genes plays an important role in FcgammaR-mediated effects on DCs, as suppression of STAT1 by RNA interference inhibited FcgammaR-mediated DC maturation. These data suggest that the balance of activating/inhibitory FcgammaRs may regulate IFN signaling in myeloid cells. Manipulation of FcgammaR balance on DCs and monocytes may provide a novel approach to regulating IFN-mediated pathways in autoimmunity and human cancer.

Harnessing the immune system against human glioma.

Our studies are directed toward immune resistance to glial tumors, particularly in children. Initial experiments indicate that it is possible to boost both innate natural killer T lymphocytes and adaptive CD4+ and CD8+ T cells by targeting the appropriate antigens to dendritic cells. Our hypothesis is that optimal vaccination approaches against cancer will need to recruit both innate and adaptive defense mechanisms.

Humor in systemic lupus erythematosus.

OBJECTIVE: Humor has neurophysiological effects influencing the release of cortisol, which may have a direct impact on the immune system. Laughter is associated with a decreased production of inflammatory cytokines both in the general population and in rheumatoid arthritis (RA). Our objective was to explore the effects of humor on serum cytokines [particularly interleukin-6 (IL-6)] and cortisol levels in systemic lupus erythematosus (SLE), after a standard intervention (120 min of visual comedy). MATERIAL AND METHODS: We enrolled 58 females with SLE from consecutive patients assessed in the Montreal General Hospital lupus clinic. The subjects who consented to participate were randomized in a 1:1 ratio to the intervention (watching 120 min of comedy) or control group (watching a 120 min documentary). Measurements of cytokine and serum cortisol levels as well as 24-h urine cortisol were taken before, during, and after the interventions. We compared serum cytokine levels and serum and 24-h urine cortisol levels in the humor and control groups and performed regression analyses of these outcomes, adjusting for demographics and the current use of prednisone. RESULTS: There were no significant differences between the control and humor groups in demographics or clinical variables. Baseline serum levels of IL-6, IL-10, tumor necrosis factor-alpha, and B-cell activating factor were also similar in both groups. There was no evidence of a humor effect in terms of decreasing cytokine levels, although there was some suggestion of lowered cortisol secretion in the humor group based the 24-h urinary cortisol levels in a subgroup. CONCLUSION: In contrast to what has been published for RA, we saw no clear effects of humor in altering cytokine levels in SLE, although interesting trends were seen for lower cortisol levels after humor intervention compared with the control group.

Coronary artery disease in the developing world.

BACKGROUND: Coronary artery disease (CAD) is the leading cause of cardiovascular mortality worldwide, with >4.5 million deaths occurring in the developing world. Despite a recent decline in developed countries, both CAD mortality and the prevalence of CAD risk factors continue to rise rapidly in developing countries. The objectives of the current article are to review (1) the literature regarding CAD mortality and the prevalence of CAD risk factors in the developing world, and (2) prevention and control measures. METHODS: We conducted a MEDLINE search of the English language literature for the years 1990 to 2002 to identify articles pertaining to the prevalence of CAD in developing countries. The search was performed using the following key terms: coronary artery disease, developing countries, ischemic heart disease, incidence, prevalence, prevention and risk factors. We also obtained relevant statistical information from The World Health Organization's Internet database. RESULTS: There is a paucity of data regarding CAD and its prevalence in the developing world. However, it is projected that CAD mortality rates will double from 1990 to 2020, with approximately 82% of the increase attributable to the developing world. Existing data suggest that rapid socioeconomic growth in developing countries is increasing exposure to risk factors for CAD, such as diabetes, genetic factors, hypercholesterolemia, hypertension, and smoking. There is a relative lack of prevention and control measures to decrease exposure to these risk factors in developing countries. CONCLUSION: Documented information on the prevalence of CAD in developing countries is sparse, but there is sufficient data to suggest an impending epidemic. Prevention and targeted control of risk factors for CAD could potentially reduce the impact of CAD in the developing world as it has in industrialized nations.

Enhanced T-cell responses to glioma cells coated with the anti-EGF receptor antibody and targeted to activating FcgammaRs on human dendritic cells.

The induction of effective immune responses to tumor vaccines requires the preferential activation of effector T cells relative to regulatory or suppressive T cells. Glial tumors commonly overexpress the epidermal growth factor receptor (EGFR), which can be targeted by monoclonal antibodies. Here we show that the coating of glial tumor cells with a clinical grade anti-EGFR antibody, cetuximab, leads to enhanced tumor-specific, interferon-gamma producing CD8+ T cells by dendritic cells (DCs). The selective targeting of monoclonal antibody coated glioma cells to activating Fcgamma receptors (FcgammaRs) on DCs, which is achieved with a blocking antibody to the inhibitory form of FcgammaR, leads to the induction of antitumor immunity without the need for an exogenous maturation stimulus. Importantly, this approach reduces the concurrent induction of regulatory T cells, which can also be depleted to further enhance immunity. These data suggest that immunity to EGFR expressing tumors, including glioma, can be enhanced through the concerted function of antitumor monoclonal antibodies, activating FcgammaR, and DCs.

Peanut-free guidelines reduce school lunch peanut contents.

BACKGROUND: Some schools implement peanut-free guidelines (PFG) requesting omission of peanut from lunches. Our study assessed parental awareness of, and adherence to, PFG by comparing the percentage of lunches containing peanut between primary school classes with and without PFG in Montreal, Québec. METHODS: Parents, school principals and teachers were queried concerning the school's PFG and children's lunches were inspected by a dietician for peanut-containing foods. RESULTS: When lunch peanut contents were compared in randomly selected classrooms, peanut was found in 5/861 lunches in classes with PFG (0.6%, 95% CI 0.2% to 1.4%) and in 84/845 lunches in classes without PFG (9.9%, 95% CI 8.0% to 12.2%), a 9.4% (95% CI 7.3% to 11.4%) difference. CONCLUSIONS: Our findings demonstrate that PFG are effective in reducing peanut in classrooms providing a basis for future research that should address whether or not the reduction in peanut achieved by restrictive lunch policies decreases the morbidity associated with peanut allergy in the school setting.

Expansion of FOXP3high regulatory T cells by human dendritic cells (DCs) in vitro and after injection of cytokine-matured DCs in myeloma patients.

CD4(+)CD25(+)FOXP3(+) regulatory T cells (Treg's) play an important role in the maintenance of immune tolerance. The mechanisms controlling the induction and maintenance of Treg's in humans need to be defined. We find that human myeloid dendritic cells (DCs) are superior to other antigen presenting cells for the maintenance of FOXP3(+) Treg's in culture. Coculture of DCs with autologous T cells leads to an increase in both the number of Treg's, as well as the expression of FOXP3 protein per cell both in healthy donors and myeloma patients. DC-mediated expansion of FOXP3(high) Treg's is enhanced by endogenous but not exogenous interleukin-2 (IL-2), and DC-T-cell contact, including the CD80/CD86 membrane costimulatory molecules. DCs also stimulate the formation of Treg's from CD25(-) T cells. The efficacy of induction of Treg's by DCs depends on the nature of the DC maturation stimulus, with inflammatory cytokine-treated DCs (Cyt-DCs) being the most effective Treg inducers. DC-induced Treg's from both healthy donors and patients with myeloma are functional and effectively suppress T-cell responses. A single injection of cytokine-matured DCs led to rapid enhancement of FOXP3(+) Treg's in vivo in 3 of 3 myeloma patients. These data reveal a role for DCs in increasing the number of functional FOXP3(high) Treg's in humans.

Selective blockade of inhibitory Fcgamma receptor enables human dendritic cell maturation with IL-12p70 production and immunity to antibody-coated tumor cells.

The final differentiation or maturation of dendritic cells (DCs) in response to environmental stimuli influences their ability to both initiate immunity and determine the quality of the response to antigens. Circulating immune complexes and cell-bound immunoglobulins present in normal human sera represent a potential stimulus for inadvertent DC activation in the steady state and during autoimmunity. Here, we show that selective blockade of the inhibitory Fcgamma receptor (FcgammaR) FcgammaRIIb with recently developed monoclonal antibodies leads to maturation of human monocyte-derived DCs, which depends on the presence of IgG in normal human plasma. Plasma, in the presence of an FcgammaRIIb blockade, caused the DCs to up-regulate the expression of costimulatory molecules and to produce the inflammatory mediator IL-12p70. FcgammaRIIb blockade of DCs loaded with tumor cells led to increased tumor-specific T cell immunity without the need for exogenous stimuli other than human plasma. Therefore, the activation status of DCs in the presence of normal human serum depends on the balance between activating and inhibitory FcgammaRs and can be enhanced by new antibodies that react selectively with FcgammaRIIb. These data suggest an approach for modifying this balance to enhance immunity to immune complexes and antibody-coated tumor cells and to silence DC activation by immune complexes in autoimmune states.