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Tetsuo Shiohara

Publications and source records attributed to Tetsuo Shiohara.

At least 19 recordsLinked to original sources
PubMed2006

NK cells and gamma delta+ T cells are phenotypically and functionally defective due to preferential apoptosis in patients with atopic dermatitis.

Innate immune cells mediate a first line of defense against pathogens and determine the nature of subsequent acquired immune responses, mainly by producing profound amounts of cytokines. Given these diverse tasks, it is predictable that defective NK and gammadelta(+) T cell responses could be the underlying mechanism for the immunological alterations observed in atopic dermatitis (AD). Indeed, the frequencies of circulating NK cells and gammadelta(+) T cells were profoundly reduced in AD patients. They also displayed a defective ability to sustain TNF-alpha and IFN-gamma, but not IL-4, production after in vitro stimulation, and the defect was restricted to innate immune cells. Surprisingly, on the depletion of CD14(+) monocytes, this selective impairment of TNF-alpha and IFN-gamma production was restored to levels comparable to that observed in controls. Release of IL-10 from monocytes was not a major mechanism of the NK and gammadelta(+) T cell dysfunction. Apoptosis as revealed by annexin V binding, was preferentially observed in NK and gammadelta(+) T cells from AD patients when stimulated in the presence of monocytes, and depletion of monocytes significantly protected these cells from apoptotic cell death. Preferential apoptosis of NK cells by activated monocytes in AD patients was cell-contact-dependent. These results indicate that, once NK and gammadelta(+) T cells in AD patients are in immediate contact with activated monocytes, these cells are specifically targeted for apoptosis, leading to the reduced type 1 cytokine production, thereby directing subsequent acquired immune responses toward a type-2 pattern and increasing susceptibility to infection.

Adult↗
PubMed2006

Non-steroidal anti-inflammatory drugs selectively inhibit cytokine production by NK cells and gamma delta T cells.

Non-steroidal anti-inflammatory drugs (NSAIDs) are known to be risk factors for a systemic inflammatory syndrome in viral infections. Innate immune cells are likely to represent the preferential targets for the deleterious effects of NSAIDs in patients with viral infections. We therefore examined whether various classes of NSAIDs could selectively inhibit cytokine production by innate immune cells. NSAIDs selectively inhibited interferon (IFN)-gamma and tumor necrosis factor (TNF)-alpha production by natural killer (NK) and gammadelta T cells with each NSAID displaying its own unique pattern of inhibition, while sparing that by acquired immune cells. These inhibitions were independent on cyclooxygenase inhibition. These NSAIDs directly inhibited the cytokine production by the purified gammadelta T-cell population without involving other cell populations. The selective inhibition of the early generation of IFN-gamma and TNF-alpha from NK and gammadelta T cells by NSAIDs may serve to drive the subsequent acquired immune responses towards a Th2 phenotype, leading to the aggravation of allergic symptoms. Our results provide a mechanism to explain the deleterious effects of NSAIDs on clinical symptoms of viral infections and allergic diseases and suggest more targeted use depending on the type of disease.

Adult↗
PubMed2006

Expansion of IL-10-producing CD4+ and CD8+ T cells in fixed drug eruption.

BACKGROUND: A severe form of fixed drug eruption (FDE) clinically and histologically mimics toxic epidermal necrolysis (TEN) but, unlike TEN, resolves spontaneously upon withdrawal of the causative drug. OBJECTIVE AND METHODS: We reported a case of a severe FDE caused by mefenamic acid that spontaneously resolved without use of systemic corticosteroids. To clarify the phenotype of the T cells responsible for clinical resolution of FDE, we kinetically examined gamma-interferon (IFN-gamma), interleukin (IL)-2, IL-4 and IL-10 production by peripheral blood T cells of the patient before and after oral challenge with the causative drug using flow cytometry. RESULTS: We found that the proportions of CD4+ and CD8+ T cells capable of producing IFN-gamma and IL-4 remained unchanged after challenge, while those of CD4+ and CD8+ T cells capable of producing IL-10 dramatically increased after challenge. The frequency of CD8+ T cells capable of producing IL-2 decreased after challenge. CONCLUSION: These results suggest that expansion of IL-10-producing CD4+ and CD8+ T cells may be responsible for spontaneous resolution of a severe form of FDE.

Aged↗
PubMed2006

Drug-induced hypersensitivity syndrome due to mexiletine hydrochloride associated with reactivation of human herpesvirus 7.

It has been suggested that reactivation of human herpesvirus 6 (HHV-6) infection may be involved in the pathogenesis of drug-induced hypersensitivity syndrome. We report a 45-year-old Japanese man who developed a generalized papuloerythematous rash, fever, hepatitis, lymphadenopathy and lymphocytosis with an increased number of atypical lymphocytes. He was diagnosed with DIHS due to mexiletine hydrochloride based on laboratory data, results of a patch test and the clinical course of his complaint, and was treated with systemic steroids. In order to determine whether HHV-6 or -7 was associated with the patient's disease, serological assays and PCR were carried out. Significant increases in antibody titers against HHV-6 and -7 were observed from day 12 to 24. From PCR analysis, none of the peripheral blood mononuclear cells or skin tissue samples contained HHV-6 DNA. All samples, however, were found to contain HHV-7 DNA. Reactivation of HHV-7 could be responsible for drug-induced hypersensitivity syndrome.

Anti-Arrhythmia Agents↗
PubMed2006

Drug-induced hypersensitivity syndrome (DIHS): a reaction induced by a complex interplay among herpesviruses and antiviral and antidrug immune responses.

A relationship between viral infections and the simultaneous or subsequent development of allergic inflammation has often been observed in various clinical situations. Recent studies suggest an intimate relationship between reactivations of herpesviruses including human herpesvirus 6 (HHV-6) and the development of a severe systemic hypersensitivity reaction referred to as drug-induced hypersensitivity syndrome (DIHS). This syndrome has several important clinical features that cannot be solely explained by drug antigen-driven oligoclonal expansion of T cells: they include paradoxical worsening of clinical symptoms after discontinuation of the causative drug. In view of the similarity to GVHD or immune reconstitution syndrome (IRS) in clinical manifestations and emergence of viral infections, the clinical symptoms observed during the course of DIHS and GVHD are likely to be mediated by antiviral T cells that can cross-react with the drug and alloantigens, respectively. In considering common intrinsic properties of the causative drugs to potentially induce immunosuppression, reconstitution of a valid immune response to these viruses, which is typically observed in IRS, may be the most crucial process that takes place after withdrawal of the causative drug in patients with DIHS. Thus, this syndrome should be regarded as a reaction induced by a complex interplay among several herpesviruses (EB virus, HHV-6, HHV-7, and cytomegalovirus), antiviral immune responses, and drug-specific immune responses. This review includes discussion of the pathomechanism, the clinical symptoms, laboratory findings, pathological findings and therapy.

Drug Eruptions↗
PubMed2005

Virus reactivation and intravenous immunoglobulin (IVIG) therapy of drug-induced hypersensitivity syndrome.

Drug-induced hypersensitivity syndrome (DIHS) is a severe multi-organ system reaction caused by specific drugs. Many reports have revealed that human herpesvirus 6 (HHV-6) reactivation contributes to the development of DIHS. In addition, recent articles have shown that reactivation of other herpesviruses such as human herpesvirus 7 (HHV-7), Epstein-Barr virus (EBV), cytomegalovirus (CMV) might be also implicated in the development of DIHS. These observations suggest that not only HHV-6 but also other herpesvirses might reactivate from the latency and play an important role in the appearance of clinical manifestations of DIHS. Several patients with DIHS were treated with intravenous immunoglobulin (IVIG) in addition to systemic corticosteroids. The results have been encouraging although virus reactivation could not be suppressed. Although the pathomechanism of IVIG treatment in patients with DIHS remains unknown, the therapeutic effects of IVIG could be dependent, in part, on functional capabilities of anti-virus IgG contained in IVIG.

Drug Hypersensitivity↗
PubMed2005

[Limbic encephalitis associated with drug-induced hypersensitivity syndrome due to phenobarbital--a case report].

A 68-year-old man was diagnosed as drug-induced hypersensitivity syndrome (DIHS) with erythema and liver dysfunction three weeks after an administration of phenobarbital. Three weeks after the appearance of skin eruptions, the patient developed disturbed consciousness and status epilepticus. MRI findings revealed bilateral symmetrical abnormalities localized in the amygdala, hippocampi, parahippocampal gyri, and insula regions, which showed high intensities on diffusion weighted images and decreased apparent diffusion coefficient (ADC) values on an ADC map. We considered that the MRI abnormalities were indicative of cytotoxic edema. Increased serum anti-human herpesvirus 6 (HHV-6) IgG antibody titer and presence of HHV-6 DNA in peripheral blood, revealed by polymerase chain reaction (PCR) analysis, suggested reactivation of HHV-6. However, PCR analysis performed with DNA extracted from the CSF was negative for HHV-6. We concluded that limbic encephalitis in the present case might have been caused by an autoimmune inflammatory mechanism associated with drug-induced hypersensitivity syndrome, as well as a direct infection of HHV-6 to the central nervous system.

Aged↗
PubMed2004

The immunological basis of lichenoid tissue reaction.

An autoimmune attack by T cells on the epidermis is the primary pathological event in the lichenoid tissue reaction (LTR). The severity of epidermal damage in the LTR is dependent on the relative balance between the intensity and perpetuation of T cell activation and the capacity of epidermal cells to protect from the attack. In natural disease processes, T cells activated by some exogenous agents migrate from the blood to the skin sites and invade the epidermis. Although this epidermotropic migration of T cells resulting in epidermal destruction is a complicated multistep process, this can be bypassed in fixed drug eruption (FDE). Thus, FDE is the most simplified disease model for investigating the pathogenesis of the LTR, in that large numbers of effector CD8+ T cells persist as a stable population in the resting lesions without causing epidermal damage and activation of these T cells resulting in localized epidermal injury can only be induced after administration of the causative drugs. Based on the findings observed with these CD8+ skin-resident T cells, we hypothesize that CD8+ T cells primed during viral infections could evolve into long-lived effector memory phenotype T cells; they would be subsequently trapped either specifically or nonspecifically in the inflamed skin sites and eventually persist as a stable population. Once cross-reacted with exogenous stimuli, such as drug or self-antigens, however, they would become effectors of epidermal damage as seen in various lichenoid skin diseases.

Animals↗
PubMed2004

Association between anticonvulsant hypersensitivity syndrome and human herpesvirus 6 reactivation and hypogammaglobulinemia.

BACKGROUND: Anticonvulsant hypersensitivity syndrome (AHS) is a life-threatening, drug-induced, multiorgan system reaction. The identification of predisposing factors is clearly needed to predict the incidence and outcome of AHS; attention has recently been focused on reactivation of human herpesvirus 6 (HHV-6). OBJECTIVE: To determine whether immunosuppressive conditions that can allow HHV-6 reactivation could be specifically detected in association with the onset of AHS. DESIGN: We analyzed patients with AHS who were treated during 1997-2002. Two groups of patients receiving anticonvulsants served as controls. SETTING: Department of Dermatology, Kyorin University School of Medicine, Tokyo, Japan. Patients Ten patients with AHS. MAIN OUTCOME MEASURES: The results of serologic tests for antibody titers for various viruses, including HHV-6, HHV-6 DNA detection by real-time polymerase chain reaction, immunoglobulin levels by turbidimetric immunoassay, IgG subclass levels by nephelometry, and CD19(+) B-cell counts by flow cytometric analysis, were sequentially assessed. RESULTS: Serum IgG levels (mean, 745 mg/dL) and circulating B-cell counts (mean, 88/ micro L) in patients with AHS were significantly decreased at onset compared with control groups (P<.001 and P =.007, respectively). These alterations returned to normal on full recovery. Reactivation of HHV-6 as judged by a greater than 4-fold increase in HHV-6 IgG titers was exclusively detected in most patients with AHS associated with decreased IgG levels and B-cell counts. CONCLUSIONS: A decrease in immunoglobulin levels and B-cell counts can be associated with HHV-6 reactivation and the subsequent onset of AHS. These immunological alterations might be a useful predictor of the development of AHS.

Adult↗
PubMed2004

Animal models for atopic dermatitis: are they relevant to human disease?

Over the last decade, animal models of atopic dermatitis (AD) have received increasing attention. They include NC/Nga mice, a hapten-induced mouse model, and transgenic and knockout mouse models. Although the pathogenesis of skin inflammation elicited in these models and that in AD are not quite the same, it is pertinent to ask what these animal models really tell us about the pathogenesis and possible therapies for the disease. NC/Nga mice may yield information relevant to the dissection of the crucial components of the pathophysiology of AD rather than the assessment of potentially therapeutic agents for its treatment. A hapten-induced mouse model created by repeated application of 2,4,6-trinitrochlorobenzene (TNCB) is a simple and reproducible one. This model offers several advantages over others: by changing hapten and the mouse strain used, various types of chronic inflammation, probably reflecting heterogeneity in clinical presentation of AD, can be induced; this model is also of enormous value in its high reproducibility as well as the ease of quantitative assessment by measuring ear thickness. Among various transgenic and knockout mouse models, the IL-18-transgenic mouse is one of the closest available mouse models of human AD, although the onset of the AD-like lesions in the IL-18-transgenic mice is such a late event. Although these mice all have significant disadvantages, it is important to review the current literature on the models in the hope that one may identify useful areas for investigation.

Animals↗
PubMed2004

Successful desensitization to fixed drug eruption: the presence of CD25+CD4+ T cells in the epidermis of fixed drug eruption lesions may be involved in the induction of desensitization.

BACKGROUND: Fixed drug eruption (FDE) is a distinct type of drug-induced eruption, in which intraepidermal CD8+ T cells in the lesional skin are the final effector cells in the epidermal injury of FDE. Desensitization is a unique approach for the management of drug eruption, which has been reported to be effective in treating FDE. However, the mechanisms underlying desensitization to FDE are quite unknown. OBJECTIVE AND METHODS: We reported a case of successful desensitization to allopurinol-induced FDE. To clarify the mechanisms underlying desensitization to FDE, we examined the phenotype of T cells in the epidermis of FDE lesions before and after desensitization using flow cytometry. RESULTS: The overwhelming majority of intraepidermal T cells in the FDE lesion before desensitization consisted of CD8+ T cells, whereas a significant number of CD25+CD4+ T cells were present in the epidermis of FDE lesions after desensitization. CONCLUSION: The presence of CD25+CD4+ T cells in the epidermis of FDE lesions may be involved in the induction of desensitization to FDE.

Adult↗
PubMed2003

In vitro differentiation from naive to mature E-selectin binding CD4 T cells: acquisition of skin-homing properties occurs independently of cutaneous lymphocyte antigen expression.

We previously showed that skin-homing CD4 T cells in peripheral blood can be subdivided into three populations on the basis of the expression pattern of the cutaneous lymphocyte Ag (CLA) and fucosyltransferase VII (FucT-VII): FucT-VII(+)CLA(-), FucT-VII(+)CLA(+), and FucT-VII(-)CLA(+). In view of the known late appearance of CLA during T cell differentiation, T cells programmed to attain skin-homing properties may start to generate E-selectin-binding epitopes at early stages of differentiation before induction of CLA expression. To this end, the in vitro differentiation from naive to CLA(+) memory T cells was followed after activation with anti-CD3 mAb. Here we demonstrate that naive skin-homing CD4 T cell precursors undergo a linear differentiation process from the FucT-VII(+)CLA(-) phenotype to the FucT-VII(+)CLA(+) phenotype and eventually to the FucT-VII(-)CLA(+) phenotype. The appearance of the FucT-VII(+)CLA(-) subset coincided with or could be immediately followed by the generation of E-selectin binding epitopes, and even after E-selectin-binding epitopes were no longer detectable, CLA remained expressed for prolonged periods of time, suggesting that induction of functional E-selectin ligands depends primarily on the expression of FucT-VII, but not CLA. Immunofluorescence and confocal microscopy studies of these T cells confirm that most E-selectin ligands were found independently of CLA expression.

Adult↗