Differential regulation of dendritic cell - T cell cross talk in the gut associated lymphoid tissue

Dendritic cells (DC) play a central role in the regulation of immune responses by processing and presenting antigens to naïve T cells. It has been proposed that after the initial interaction between DC and T cells, T cell-induced DC apoptosis serves as a down-regulatory mechanism that prevents the otherwise continuous activation of T cells by antigen-bearing DC. Our aim was to investigate and compare the susceptibility of Peyer's patch (PP)-derived and systemic (splenic) DC to antigen-specific T cell-mediated apoptosis in mice of different genetic background. Freshly isolated CD11c(+/hi)B220(-) DC from intestinal Peyer's patch and spleen from Balb/c and C3H/HeJ mice were co-cultured with syngeneic antigen-specific T cells in the presence or absence of the relevant antigen. In both mouse strains PP-DC showed higher susceptibility to T cell-mediated apoptosis compared to splenic ones, but levels of DC apoptosis were overall higher in C3H/HeJ mice compared to Balb/c. DC apoptosis was induced by both Th1 and Th2 antigen-specific clones and was strictly MHC class II-dependent in both strains, and interestingly we observed that although CD95-CD95L ligation played an overall minor part in T cell-induced DC apoptosis its role varied according to the mouse strain. Here, we demonstrated that PP-DC and splenic DC significantly differed in regard to their susceptibility to T cell-mediated killing. We interpreted these data as showing that the reciprocal regulation between DC and T cells in the gastrointestinal immune system is under stricter control compared to the systemic immune system and we hypothesized that these events are likely to contribute to the generation of fine balanced responses to intestinal antigen

Production of IL-12 by Peyer patch-dendritic cells is critical for the resistance to food allergy

BACKGROUND: Dendritic cells (DCs) play a pivotal role in antigen presentation and regulation of immune responses; however, their involvement in food allergy remains to be fully understood. OBJECTIVE: Our aim was to investigate T(H)1-T(H)2 reciprocal regulation of DCs' function in the gut and systemic immune system and its effect on food allergy in mice with different susceptibility to food allergy. METHODS: Freshly isolated CD11c(+)B220(-)DCs from peanut-sensitized allergy-susceptible C3H/HeJ and allergy-resistant Balb/c mice were cultured to determine levels of IL-12p70 produced in the presence of cytokines, including IL-4. Systemic levels of IL-12 were assessed in vivo after antigen challenge with or without IL-4. Targeted oral delivery of microencapsulated neutralizing anti-IL-12 antibody to Peyer patches (PPs) was performed in Balb/c before administration of each sensitizing dose. RESULTS: Peyer patch-DCs but not splenic DCs from sensitized C3H/HeJ but not Balb/c mice produced less IL-4-dependent IL-12p70. In vivo data confirmed this was restricted to the gut immune system, and it was not linked to reduced expression of IL-4 receptor or the lack of functional Toll-like receptor 4; instead, IL-4 failed to inhibit IL-10 production by PP-DCs, a pathway critically involved in IL-4-dependent production of IL-12p70. Finally, neutralization of IL-12 within PPs by specific antibody during antigen presentation significantly increased Balb/c susceptibility to food allergy. CONCLUSION: Reciprocal T(H)1-T(H)2 control of DCs' function within the inductive site of the gut immune system is altered in food allergy. CLINICAL IMPLICATIONS: Production of IL-12p70 by PP-DCs during antigen presentation is critical for the development of food allergy

Enhanced infection prophylaxis reduces mortality in severely immunosuppressed HIV-infected adults and older children initiating antiretroviral therapy in Kenya, Malawi, Uganda and Zimbabwe: the REALITY trial

Meeting abstract FRAB0101LB from 21st International AIDS Conference 18–22 July 2016, Durban, South Africa. Introduction: Mortality from infections is high in the first 6 months of antiretroviral therapy (ART) among HIV‐infected adults and children with advanced disease in sub‐Saharan Africa. Whether an enhanced package of infection prophylaxis at ART initiation would reduce mortality is unknown. Methods: The REALITY 2×2×2 factorial open‐label trial (ISRCTN43622374) randomized ART‐naïve HIV‐infected adults and children >5 years with CD4 <100 cells/mm3. This randomization compared initiating ART with enhanced prophylaxis (continuous cotrimoxazole plus 12 weeks isoniazid/pyridoxine (anti‐tuberculosis) and fluconazole (anti‐cryptococcal/candida), 5 days azithromycin (anti‐bacterial/protozoal) and single‐dose albendazole (anti‐helminth)), versus standard‐of‐care cotrimoxazole. Isoniazid/pyridoxine/cotrimoxazole was formulated as a scored fixed‐dose combination. Two other randomizations investigated 12‐week adjunctive raltegravir or supplementary food. The primary endpoint was 24‐week mortality. Results: 1805 eligible adults (n = 1733; 96.0%) and children/adolescents (n = 72; 4.0%) (median 36 years; 53.2% male) were randomized to enhanced (n = 906) or standard prophylaxis (n = 899) and followed for 48 weeks (3.8% loss‐to‐follow‐up). Median baseline CD4 was 36 cells/mm3 (IQR: 16–62) but 47.3% were WHO Stage 1/2. 80 (8.9%) enhanced versus 108(12.2%) standard prophylaxis died before 24 weeks (adjusted hazard ratio (aHR) = 0.73 (95% CI: 0.54–0.97) p = 0.03; Figure 1) and 98(11.0%) versus 127(14.4%) respectively died before 48 weeks (aHR = 0.75 (0.58–0.98) p = 0.04), with no evidence of interaction with the two other randomizations (p > 0.8). Enhanced prophylaxis significantly reduced incidence of tuberculosis (p = 0.02), cryptococcal disease (p = 0.01), oral/oesophageal candidiasis (p = 0.02), deaths of unknown cause (p = 0.02) and (marginally) hospitalisations (p = 0.06) but not presumed severe bacterial infections (p = 0.38). Serious and grade 4 adverse events were marginally less common with enhanced prophylaxis (p = 0.06). CD4 increases and VL suppression were similar between groups (p > 0.2). Conclusions: Enhanced infection prophylaxis at ART initiation reduces early mortality by 25% among HIV‐infected adults and children with advanced disease. The pill burden did not adversely affect VL suppression. Policy makers should consider adopting and implementing this low‐cost broad infection prevention package which could save 3.3 lives for every 100 individuals treated