Motoko Yasutomi

Dysregulation of IL-13 production by cord blood CD4+ T cells is associated with the subsequent development of atopic disease in infants.

Early intervention strategies in allergic diseases will be dependent on identification of newborns at high risk for later development of atopic disease. In this cohort study of 106 neonates, we investigated whether cytokine production property and responsiveness to IL-12 of neonatal CD4+ T cells were associated with the subsequent development of atopic disease and whether a skewed cytokine production property was intrinsic to helper T cells. To exclude the effects of contaminating cells, highly purified cord blood CD4+ T cells were stimulated with anti-CD3 MAb and recombinant B7-2 molecule in the presence or absence of IL-12. Production of IL-13 and interferon-γ was determined by ELISA. The infants were assessed at 12 mo for the development of atopic diseases. CD4+ T cells of neonates who manifested allergic symptoms (atopic group) produced higher levels of IL-13 compared with those of the nonatopic group in both the presence and absence of IL-12. No significant difference was noted between the two groups with respect to interferon-γ production. Moreover, higher IL-13 production was also observed in neonates with chronic eczema than those with short-term eczema. Our data suggest that increased production of IL-13 by neonatal CD4+ T cells is a useful marker of newborns at high risk for subsequent development of atopic diseases and that an intrinsic abnormality of CD4+ T cell is associated with the pathogeneses of atopic disease, especially atopic dermatitis in infants.

Monocyte Chemoattractant Protein-1 Selectively Inhibits the Acquisition of CD40 Ligand-Dependent IL-12-Producing Capacity of Monocyte-Derived Dendritic Cells and Modulates Th1 Immune Response

Accumulating evidence indicates that monocyte chemoattractant protein-1 (MCP-1), a CC chemokine, also displays immunoregulatory functions and may be involved in Th subset differentiation. In this study, we examined the effects of MCP-1 on the cytokine-driven differentiation of monocytes into dendritic cells (DCs), the most potent APCs for naive T cells. We found that DCs generated in the presence of MCP-1 displayed a markedly reduced production of IL-12 in response to CD40 ligand but not in response to Staphylococcus aureus stimulation in the presence or absence of IFN-γ. The production of IL-10, a potent endogenous IL-12 inhibitor, was not affected by MCP-1. Whereas the inhibitory activity of MCP-1 on IL-12 production by monocytes was sensitive to pertussis toxin, its effects on DC differentiation were pertussis toxin resistant. MCP-1 did not affect the surface phenotype and T cell-stimulating activity of DCs, but most interestingly, naive T cells stimulated with MCP-1-primed DCs produced much less IFN-γ but the same levels of IL-13. Taken together, our results indicated that MCP-1 modulates the differentiation of monocytes into DCs and may thereby inhibit Th1 cell development.

Transmaternal exposure to bisphenol a modulates the development of oral tolerance

Bisphenol A (BPA) is a representative endocrine disruptor that may have adverse effects on human health. Since the development of oral tolerance during infancy may play an important role in the prevention of food allergies, we examined whether transmaternal exposure to BPA influences the development of oral tolerance. To measure antigen-specific responses, female wild-type mice mated with male ovalbumin (OVA)-specific T-cell receptor transgenic (TCR-tg) mice were fed with BPA during pregnancy and while nursing. OVA was administered to OVA-TCR-tg offspring during their weaning period. Oral administration of both high and low doses of OVA suppressed OVA-specific cell proliferation and cytokine production in both BPA-exposed and nonexposed control mice, but the OVA-mediated suppression was significantly more diminished by the BPA exposure. The accumulation of CD4+CD25+Foxp3+ T cells was diminished in the BPA-exposed offspring. Moreover, after low dose OVA administration, serum OVA-specific IgG1 and IgG2a levels were higher in the BPA-exposed offspring than in nonexposed ones. Taken together, our results indicate that transmaternal exposure to BPA seems to modulate the mechanisms underlying tolerance induction; therefore, BPA may partially interrupt the development of oral tolerance.

Erythromycin Differentially Inhibits Lipopolysaccharide- or Poly(I:C)-Induced but Not Peptidoglycan-Induced Activation of Human Monocyte-Derived Dendritic Cells

Erythromycin (EM) has attracted attention because of its anti-inflammatory effect. Because dendritic cells (DCs) are the most potent APCs involved in numerous pathologic processes including innate immunity, we examined effects of EM on the activation of human DCs by pathogen-derived stimuli. Monocyte-derived DCs were pretreated with EM and subsequently stimulated with peptidoglycan, polyriboinosinic:polyribocytidylic acid (poly(I:C)), or LPS. The activation of DCs was assessed by surface molecule expression and cytokine production. To reveal the signaling pathways affected by EM, TLR expression, NF-κB, IFN regulatory factor-3, and AP-1 activation were examined. EM inhibited costimulatory molecule expression and cytokine production that was induced by poly(I:C) and LPS but not by peptidoglycan. EM pretreatment down- and up-regulated mRNA levels of TLR3 and TLR2, respectively, but did not affect that of TLR4. EM suppressed IFN regulatory factor-3 activation and IFN-β production but not AP-1 activation induced by poly(I:C) and LPS. The inhibitory effect of EM on NF-κB activation was observed only in poly(I:C)-stimulated DCs. EM selectively suppressed activation of DCs induced by LPS and poly(I:C) in different ways, suggesting that the immuno-modulating effects of EM depend on the nature of pathogens. These results might explain why EM prevents the virus-induced exacerbation in the chronic inflammatory respiratory diseases and give us the clue to design new drugs to treat these diseases.

Steroid-sparing effect of tacrolimus in a patient with juvenile dermatomyositis presenting poor bioavailability of cyclosporine A

Cyclosporine A is known to have a steroid-sparing effect in patients with juvenile dermatomyositis. On the other hand, the clinical usefulness of tacrolimus, another immunosuppressive drug, for the treatment of juvenile dermatomyositis has not yet been reported. Here we present a case of steroid-dependent juvenile dermatomyositis in whom the steroid dosage was successfully tapered by the administration of tacrolimus. A 13-year-old Japanese girl had a 4-year history of dermatomyositis, which was diagnosed by the presence of Gottron papules, a heliotrope rash, and muscular weakness (Fig. 1). The patient was started on prednisolone (2 mg/kg per day) and showed good clinical response. However, she relapsed with elevated CRP levels and muscular pain during tapering off of the steroid use and required high doses of prednisolone (0.5–1mg/kg per day) to control the symptoms for 2.5 years (Fig. 2). Azathioprine was also administered but did not produce any steroid-sparing effects. Methotrexate was introduced and discontinued due to hepatotoxicity; high dose c-globulin treatment was tried and discontinued because of meningismus. Subsequently, the patient received cyclosporine A (7.5 mg/kg per day, b.i.d.); the plasma concentrations remained around 140 ng/ml even 2 h after administration, resulting in a failure to reduce the steroid level. Rather than increasing the dosage of cyclosporine A, we chose to give the patient tacrolimus, with the informed consent of her parents. Two weeks after the commencement of tacrolimus (0.12 mg/kg per day), with trough levels around 6 ng/ml, the patient’s CRP and erythrocyte sedimentation rate levels were normalised and muscle strength gradually returned. Since the last remission, she has never complained about her muscular pain for 2 years. Moreover the prednisolone was successfully tapered to 0.06 mg/kg per day without either any symptoms of relapse or elevation of CRP for 1 year (Fig. 2). The bioavailability of the oral formulation of cyclosporine A is variable even as a microemulsion [4]. Compared with adults, paediatric patients show poorer absorption, accelerated metabolism, and more rapid clearance of cyclosporine A, so they often require higher doses to achieve therapeutic plasma levels [1]. For the treatment of juvenile dermatomyositis, an oral dose of 2.5 to 7.5 mg/kg per day is generally recommended [2]. In this case, even though a sufficient dosage of cyclosporine A was administered, the patient’s plasma concentration failed to achieve therapeutic levels. Although the precise mechanisms for the low plasma concentration were not determined, steroid-induced obesity and hyperlipidaemia might be contributing factors. Fig. 1 Gottron papules (A) and a heliotrope rash (B) on our patient’s hand and face

IL-17A/F Modulates Fibrocyte Functions in Cooperation with CD40-Mediated Signaling

T helper 17 (Th17) cells that produce interleukin (IL)-17A and IL-17F have been found to participate in the development of bronchial asthma and bleomycin-induced pulmonary fibrosis. However, whether they play a causative role in the airway remodeling observed in these respiratory diseases remains unclear. Because fibrocytes are involved in tissue repair and fibrosis and are presumably precursors of lung fibroblasts and myofibroblasts, we examined the effects of IL-17A/F on fibrocyte functions. Both IL-17A and IL-17F enhanced fibrocytes’ α-smooth muscle actin expression. Priming fibrocytes with IL-17A enhanced their CD40-mediated IL-6 production, whereas IL-17F-priming increased the CD40-mediated mRNA expression of collagen I, vascular endothelial growth factor, and angiogenin. CD4+ T cells co-cultured with fibrocytes produced IL-17A, which was inhibited by blocking CD40 and CD40 ligand interactions. These findings suggest that cooperative interactions between fibrocytes and Th17 cells play an important role via CD40- and IL-17A/F-mediated signaling for collagen and proangiogenic factor production, which may lead to the extracellular matrix deposition and neovascularization seen in airway remodeling.

Early (4-7 days of age) dexamethasone therapy for prevention of chronic lung disease in preterm infants.

We conducted a comparative study to evaluate whether early (4–7 days of age) low-dose dexamethasone (DEX) therapy in preterm infants with surfactant-pretreated respiratory distress syndrome (RDS) would facilitate extubation and improve the clinical outcome. Twenty-six preterm infants with surfactant-pretreated RDS who were oxygen- and ventilator-dependent at 4 days of postnatal age were enrolled. Twelve infants were in the historical comparison group, and 14 infants were assigned to receive DEX 0.125 mg/kg i.v., every 12 h, for a total of 6 doses. At study entry, the two groups had a comparable clinical status. DEX therapy significantly facilitated weaning from mechanical ventilation (median interval, 6 vs. 24 days, p < 0.005) and shortened duration of oxygen supplementation (9 vs. 28 days, p < 0.05) as compared with the historical comparison group. At 28 days of age, the occurrence of chronic lung disease (CLD) was significantly lower (1/14 vs. 6/12, p < 0.05) and there was a significant decrease in the incidence of ventilator dependence (0/14 vs. 5/12, p < 0.05) in the DEX group. DEX therapy did not influence the incidence of significant complications such as infection, periventricular leukomalacia or retinopathy of prematurity. We conclude that in a selected high-risk group of preterm infants, early low-dose DEX treatment results in improvement in pulmonary outcome without significant side effects.

Immunotherapy with oligomannose‐coated liposomes ameliorates allergic symptoms in a murine food allergy model

Allergen‐specific immunotherapy has been anticipated to be a disease‐modifying therapy for food allergies. We previously reported that CD8+ regulatory T cells may prevent antigen‐sensitized mice from developing allergic diarrhea. Because oligomannose‐coated liposomes (OML) have been shown to induce MHC class I‐restricted CD8+ T cell responses, we analyzed the adjuvant activities of OML for inducing regulatory CD8+ T cells and mucosal tolerogenic responses in allergen‐sensitized mice.

Marked elevation of interleukin-6 in mild encephalopathy with a reversible splenial lesion (MERS) associated with acute focal bacterial nephritis caused by Enterococcus faecalis

This report describes two cases of mild encephalitis/encephalopathy with reversible splenial lesion (MERS) associated with acute focal bacterial nephritis (AFBN). The patients, who presented with fever and delirious behavior, exhibited hyponatremia and markedly elevated interleukin (IL)-6 in cerebrospinal fluid (CSF) and serum. Enterococcus faecalis was detected in the urine culture. After ampicillin treatment, their consciousness improved without neurological sequelae. Moreover, a diffusion-weighted MRI abnormality, i.e., intensified signals in splenium of the corpus callosum, disappeared. MERS is a possible complication of AFBN. Elevated CSF IL-6 levels suggest that remote activation of intracerebral immune response through the immune-neuroendocrine pathway might play an important role in the pathophysiology of MERS.

Antigen-primed splenic CD8+ T cells impede the development of oral antigen–induced allergic diarrhea

BACKGROUND Although CD4+ T-cell populations are thought to be involved in the pathophysiology of food allergy and oral tolerance, the role of CD8+ T cells remains uncertain. OBJECTIVE We analyzed regulatory effects of adoptively transferred CD8+ T cells on the development of allergic diarrhea in antigen-sensitized mice that had a significantly reduced number of conventional TCRalphabeta+ CD8+ T cells. METHODS Ovalbumin-specific T-cell receptor transgenic mice were systemically sensitized to ovalbumin. Splenic CD8+ T cells purified from ovalbumin-sensitized or nonsensitized wild-type mice or IL-10 knockout mice were adoptively transferred to ovalbumin-sensitized ovalbumin-specific T-cell receptor transgenic mice. Allergic diarrhea induced by oral administration of ovalbumin, ovalbumin-specific immunoglobulin production, and cytokine production in intestines and mesenteric lymph nodes were assessed. RESULTS Adoptive transfer of splenic CD8+ T cells from ovalbumin-primed mice, but not from nonprimed mice, suppressed the development of allergic diarrhea, which was associated with in vivo increased IL-10 mRNA expression and in vitro antigen-specific IL-10 production by mesenteric lymph node cells. Upregulation of serum ovalbumin-specific IgE was not suppressed by ovalbumin-primed CD8+ T-cell transfer. Although administration of IL-10 before ovalbumin challenge failed to alleviate allergic diarrhea, transfer of splenic CD8+ T cells from IL-10 knockout mice showed diminished preventive effects. CONCLUSION Systemic immunization with allergen simultaneously induces regulatory CD8+ T cells that can inhibit the development of allergic diarrhea. IL-10 production by regulatory CD8+ T cells appears to be partially involved in these inhibitory mechanisms.