Critical role of intestinal interleukin-4 modulating regulatory T cells for desensitization, tolerance, and inflammation of food allergy.

BACKGROUND AND OBJECTIVE: The mechanism inducing either inflammation or tolerance to orally administered food allergens remains unclear. To investigate this we analyzed mouse models of food allergy (OVA23-3) and tolerance (DO11.10 [D10]), both of which express ovalbumin (OVA)-specific T-cell receptors. METHODS: OVA23-3, recombination activating gene (RAG)-2-deficient OVA23-3 (R23-3), D10, and RAG-2-deficient D10 (RD10) mice consumed a diet containing egg white (EW diet) for 2-28 days. Interleukin (IL)-4 production by CD4+ T cells was measured as a causative factor of enteropathy, and anti-IL-4 antibody was used to reveal the role of Foxp3+ OVA-specific Tregs (aiTreg) in this process. RESULTS: Unlike OVA23-3 and R23-3 mice, D10 and RD10 mice did not develop enteropathy and weight loss on the EW diet. On days 7-10, in EW-fed D10 and RD10 mice, splenic CD4+ T cells produced significantly more IL-4 than did those in the mesenteric lymph nodes (MLNs); this is in contrast to the excessive IL-4 response in the MLNs of EW-fed OVA23-3 and R23-3 mice. EW-fed R23-3 mice had few aiTregs, whereas EW-fed RD10 mice had them in both tissues. Intravenous injections of anti-IL-4 antibody recovered the percentage of aiTregs in the MLNs of R23-3 mice. On day 28, in EW-fed OVA23-3 and R23-3 mice, expression of Foxp3 on CD4+ T cells corresponded with recovery from inflammation, but recurrence of weight loss was observed on restarting the EW diet after receiving the control-diet for 1 month. No recurrence developed in D10 mice. CONCLUSIONS: Excessive IL-4 levels in the MLNs directly inhibited the induction of aiTregs and caused enteropathy. The aiTregs generated in the attenuation of T cell-dependent food allergic enteropathy may function differently than aiTregs induced in a tolerance model. Comparing the two models enables to investigate their aiTreg functions and to clarify differences between inflammation with subsequent desensitization versus tolerance.

Peyer's patches and mesenteric lymph nodes cooperatively promote enteropathy in a mouse model of food allergy.

BACKGROUND AND OBJECTIVE: To improve the efficacy and safety of tolerance induction for food allergies, identifying the tissues responsible for inducing intestinal inflammation and subsequent oral tolerance is important. We used OVA23-3 mice, which express an ovalbumin-specific T-cell receptor, to elucidate the roles of local and systemic immune tissues in intestinal inflammation. METHODS AND RESULTS: OVA23-3 mice developed marked enteropathy after consuming a diet containing egg white (EW diet) for 10 days but overcame the enteropathy (despite continued moderate inflammation) after receiving EW diet for a total of 28 days. Injecting mice with anti-IL-4 antibody or cyclosporine A confirmed the involvement of Th2 cells in the development of the enteropathy. To assess the individual contributions of Peyer's patches (PPs), mesenteric lymph nodes (MLNs), and the spleen to the generation of effector CD4+ T-cells, we analyzed the IL-4 production, proliferation in response to ovalbumin, and CD4+ T-cell numbers of these tissues. EW feeding for 10 days induced significant IL-4 production in PPs, the infiltration of numerous CD4+ T-cells into MLNs, and a decrease in CD4+ T-cell numbers in spleen. On day 28, CD4+ T-cells from all tissues had attenuated responses to ovalbumin, suggesting tolerance acquisition, although MLN CD4+ T-cells still maintained IL-4 production with proliferation. In addition, removal of MLNs but not the spleen decreased the severity of enteropathy and PP-disrupted mice showed delayed onset of EW-induced inflammatory responses. Disruption of peripheral lymphoid tissues or of both PPs and MLNs almost completely prevented the enteropathy. CONCLUSIONS: PPs and MLNs coordinately promote enteropathy by generating effector T-cells during the initial and exacerbated phases, respectively; the spleen is dispensable for enteropathy and shows tolerogenic responses throughout EW-feeding. The regulation of PPs may suppress the initiation of intestinal inflammation, subsequently restricting MLNs and inhibiting the progression of food-allergic enteropathy.

[Investigation of radioactivity measurement of medical radioactive waste].

To explore the possibility of which medical radioactive wastes could be disposed as general wastes after keeping them a certain period of time and confirming that their radioactivity reach a background level (BGL), we made a survey of these wastes in several nuclear medicine facilities. The radioactive wastes were collected for one week, packed in a box according to its half-life, and measured its radioactivity by scintillation survey meter with time. Some wastes could reach a BGL within 10 times of half-life, but 19% of the short half-life group (group 1) including 99mTc and 123I, and 8% of the middle half-life group (group 2) including 67Ga, (111)In, and 201Tl did not reach a BGL within 20 times of half-life. A reason for delaying the time of reaching a BGL might be partially attributed to high initial radiation dose rate or heavy package weight. However, mixing with the nuclides of longer half-life was estimated to be the biggest factor affecting this result. When disposing medical radioactive wastes as general wastes, it is necessary to avoid mixing with radionuclide of longer half-life and confirm that it reaches a BGL by actual measurement.