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Taisuke Ito

Publications and source records attributed to Taisuke Ito.

13 recordsLinked to original sources
PubMed2006

Induction of therapeutically relevant cytotoxic T lymphocytes in humans by percutaneous peptide immunization.

Percutaneous peptide immunization (PPI) is a simple and noninvasive immunization approach to induce potent CTL responses by peptide delivery via skin with the stratum corneum removed. After such a barrier disruption in human skin, epidermal Langerhans cells, although functionally matured through the up-regulation of HLA expression and costimulatory molecules, were found to emigrate with a reduced number of dendrites. CD8(+) populations binding to MHC-peptide tetramers/pentamers and producing IFN-gamma appeared in the blood after PPI with HLA class I-restricted antigenic peptides. PPI with melanoma-associated peptides reduced the lesion size and suppressed further development of tumors in four of seven patients with advanced melanoma. These beneficial effects were accompanied by the generation of circulating CTLs with in vitro cytolytic activity and extensive infiltration of tetramer/pentamer-binding cells into regressing lesions. PPI elicited neither local nor systemic toxicity or autoimmunity, except for vitiligo, in patients with melanoma. Therefore, PPI represents a novel therapeutic intervention for cancer in the clinical setting.

Administration, Cutaneous↗
PubMed2005

Human hair follicles display a functional equivalent of the hypothalamic-pituitary-adrenal axis and synthesize cortisol.

The skin and its major appendages are prominent target organs and potent sources of key players along the classical hypothalamic-pituitary axis, such as corticotropin releasing hormone (CRH), adrenocorticotropic hormone (ACTH), and alpha melanocyte stimulating hormone (alpha-MSH), and even express key steroidogenic enzymes. Therefore, it may have established local stress response systems that resemble the hypothalamic-pituitary-adrenal (HPA) axis. However, functional evidence that this is indeed the case in normal human skin in situ has still been missing. We show that microdissected, organ-cultured human scalp hair follicles respond to CRH stimulation by up-regulating proopiomelanocortin (POMC) transcription and immunoreactivity (IR) for ACTH and alpha-MSH, which must have been processed from POMC. CRH, alpha-MSH, and ACTH also modulate expression of their cognate receptors (CRH-R1, MC1-R, MC2-R). In addition, the strongest stimulus for adrenal cortisol production, ACTH, also up-regulates cortisol-IR in the hair follicles. Isolated human hair follicles secrete substantial levels of cortisol into the culture medium, and this activity is further up-regulated by CRH. CRH also modulates important functional hair growth parameters in vitro (hair shaft elongation, catagen induction, hair keratinocyte proliferation, melanin production). Finally, human hair follicles display HPA axis-like regulatory feedback systems, since the glucocorticoid receptor agonist hydrocortisone down-regulates follicular CRH expression. Thus, even in the absence of endocrine, neural, or vascular systemic connections, normal human scalp hair follicles directly respond to CRH stimulation in a strikingly similar manner to what is seen in the classical HPA axis, including synthesis and secretion of cortisol and activation of prototypic neuroendocrine feedback loops.

Adrenocorticotropic Hormone↗
PubMed2005

A 'hairy' privilege.

Understanding how selected tissue sites establish immune privilege (IP) is of interest to both basic immunology and clinical medicine: it provides novel insights into autoimmunity, fetal and allotransplant rejection and tumor escape from immunosurveillance. Here, we review why the hair follicle can serve as a uniquely accessible, widely available and instructive model for studying the establishment, maintenance, collapse and restoration of IP. The hair follicle epithelium rhythmically generates, maintains and deconstructs an area of relative IP, characterized by very low expression of MHC Ia and suppressed MHC II-dependent antigen presentation, accompanied by the local production of potent immunosuppressants capable of downregulating MHC I (e.g. transforming growth factor-beta1, alpha-melanocyte-stimulating hormone). We discuss the physiological functions of hair follicle IP, illustrate its clinical and therapeutic relevance by focusing on alopecia areata, an autoimmune hair loss disorder, and outline important unanswered questions for future research into one of nature's most intriguing and abundant, yet commonly ignored, sites of IP.

Animals↗
PubMed2005

A hot new twist to hair biology: involvement of vanilloid receptor-1 (VR1/TRPV1) signaling in human hair growth control.

The vanilloid receptor-1 (VR1, or transient receptor potential vanilloid-1 receptor, TRPV1) is activated by capsaicin, the key ingredient of hot peppers. TRPV1 was originally described on sensory neurons as a central integrator of various nociceptive stimuli. However, several human skin cell populations are also now recognized to express TRPV1, but with unknown function. Exploiting the human hair follicle (HF) as a prototypic epithelial-mesenchymal interaction system, we have characterized the HF expression of TRPV1 in situ and have examined TRPV1 signaling in organ-cultured human scalp HF and outer root sheath (ORS) keratinocytes in vitro. TRPV1 immunoreactivity was confined to distinct epithelial compartments of the human HF, mainly to the ORS and hair matrix. In organ culture, TRPV1 activation by capsaicin resulted in a dose-dependent and TRPV1-specific inhibition of hair shaft elongation, suppression of proliferation, induction of apoptosis, premature HF regression (catagen), and up-regulation of intrafollicular transforming growth factor-beta(2). Cultured human ORS keratinocytes also expressed functional TRPV1, whose stimulation inhibited proliferation, induced apoptosis, elevated intracellular calcium concentration, up-regulated known endogenous hair growth inhibitors (interleukin-1beta, transforming growth factor-beta(2)), and down-regulated known hair growth promoters (hepatocyte growth factor, insulin-like growth factor-I, stem cell factor). These findings strongly support TRPV1 as a significant novel player in human hair growth control, underscore the physiological importance of TRPV1 in human skin beyond nociception, and identify TRPV1 as a promising, novel target for pharmacological manipulations of epithelial growth disorders.

Apoptosis↗
PubMed2005

Immunology of the human nail apparatus: the nail matrix is a site of relative immune privilege.

The nail apparatus is constantly exposed to environmental damage. It requires effective immune responses to combat infection, while avoiding the loss of nail production and regeneration by autoaggressive immunity. By immunohistology, we define here previously unknown characteristics of the normal human nail immune system (NIS). Compared with other regions of nail epithelium, human leukocyte antigen (HLA)-A/B/C expression is prominently down regulated on both keratinocytes and melanocytes of the proximal nail matrix (PNM), whereas HLA-G(+) is upregulated here. Together with the expression of macrophage migration inhibitory factor in PNM, this may serve to inhibit an natural killer (NK) cell attack on major histocompatibility complex (MHC) class Ia-negative PNM. PNM also displays strong immunoreactivity for potent, locally generated immunosuppressants such as transforming growth factor-beta1, alpha-melanocyte stimulating hormone, insulin-like growth factor-1, and adrenocorticotropic hormone, exhibits unusually few CD1a(+), CD4(+), or CD8(+), NK, and mast cells. Finally, MHC class II and CD 209 expression on CD1a(+) cells in and around the PNM is reduced, indicating diminished antigen-presenting capacity. Thus, the NIS strikingly differs from the skin immune system, but shows intriguing similarities to the hair follicle immune system, including the establishment of an area of relative immune privilege in the PNM. This nail immune privilege may offer a relative safeguard against autoimmunity. But, the localized intraepithelial defect of innate and adaptive immunity in the PNM revealed here also may impede effective anti-infection defense.

Antigens, CD↗
PubMed2004

Collapse and restoration of MHC class-I-dependent immune privilege: exploiting the human hair follicle as a model.

The collapse of major histocompatibility complex (MHC) class-I-dependent immune privilege can lead to autoimmune disease or fetal rejection. Pragmatic and instructive models are needed to clarify the as yet obscure controls of MHC class I down-regulation in situ, to dissect the principles of immune privilege generation, maintenance, and collapse as well as to develop more effective strategies for immune privilege restoration. Here, we propose that human scalp hair follicles, which are abundantly available and easily studied, are ideally suited for this purpose: interferon-gamma induces ectopic MHC class I expression in the constitutively MHC class-I-negative hair matrix epithelium of organ-cultured anagen hair bulbs, likely via interferon regulatory factor-1, along with up-regulation of the MHC class I pathway molecules beta(2)microglobulin and transporter associated with antigen processing (TAP-2). In the first report to identify natural immunomodulators capable of down-regulating MHC class I expression in situ in a normal, neuroectoderm-derived human tissue, we show that ectopic MHC class I expression in human anagen hair bulbs can be normalized by treatment with alpha-MSH, IGF-1, or TGF-beta1, all of which are locally generated, as well as by FK506. These agents are promising candidates for immune privilege restoration and for suppressing MHC class I expression where this is clinically desired (eg, in alopecia areata, multiple sclerosis, autoimmune uveitis, mumps orchitis, and fetal or allograft rejection).

Down-Regulation↗
PubMed2003

Anti-allergic drug olopatadine suppresses murine contact hypersensitivity and downmodulates antigen-presenting ability of epidermal Langerhans cells.

Olopatadine hydrochloride is an H1-receptor-blocker but has other anti-allergic pharmacological potencies. We investigated whether olopatadine inhibits murine contact hypersensitivity, focussing on its modulatory action on epidermal Langerhans cells serving as antigen-presenting cells. While BALB/c mice were sensitized and challenged epicutaneously with hapten, they were administered intraperitoneally with olopatadine. Olopatadine at 1 or 0.2 mg/kg of weight significantly suppressed the sensitivity when injected at least once before sensitization or challenge. In olopatadine-injected mice, the ability of Langerhans cells to present hapten to primed T cells was reduced with decreased expression of MHC class II and co-stimulatory molecules. Langerhans cells exposed in vitro to 10(-5) or 10(-6) M olopatadine had less antigen-presenting activity than control, whereas neither T cell proliferation nor keratinocyte production of IL-1alpha and IP-10 was affected at these doses. These findings suggest that olopatadine downmodulates contact hypersensitivity at least partly by interfering with the antigen-presenting ability of Langerhans cells.

Animals↗
PubMed2003

Alterations of immune functions in barrier disrupted skin by UVB irradiation.

BACKGROUND: While immunologic events elicited by acute barrier disruption or UVB irradiation have been studied in detail, the biological sequel of multiple insults to the skin is not well understood. OBJECTIVE: Since the skin would receive a variety of simultaneous stimuli in daily life, we tested the effects of sequential treatments with barrier disruption and UVB exposure on skin immunity. METHODS: Earlobes of BALB/c mice received tape-stripping and subsequently low-dose UVB exposure. Control mice were treated with either tape-stripping or UVB. The expression of surface markers and cytokine production in Langerhans cells and keratinocytes and the elicitation response of contact hypersensitivity were compared. RESULTS: By flow cytometry, tape-stripping augmented the expression of MHC class II, CD54, CD80, CD86 and CD40 on Langerhans cells, whereas UVB decreased the expression of some of these molecules. Combination of tape-stripping and UVB induced largely intermediate levels between these two. Upon stimulation with L cells expressing CD40L, Langerhans cells from tape-stripped and UVB-irradiated earlobes strongly transcribed mRNA for interleukin-1beta compared to each treatment. In keratinocytes, tape-stripping or UVB slightly upregulated tumor necrosis factor-alpha and interleukin-1alpha production at both mRNA and protein levels, whereas these two treatments synergistically increased the production of these cytokines. The in vitro hapten-presenting ability of Langerhans cells to trinitrophenyl-immune lymph node T cells ranked first in tape-stripping, second in tape-stripping plus UVB and third in UVB, and so did the intensity of elicitation responses in contact hypersensitivity to a hapten, picryl chloride. CONCLUSION: It is suggested that barrier disruption and UVB antagonize with each other in contact hypersensitivity as a reflection of their effects on Langerhans cell antigen-presenting function, but they synergize in cytokine production by both Langerhans cells and keratinocytes.

Animals↗
PubMed2003

The hair follicle and immune privilege.

This essay reviews the available evidence that the proximal hair follicle epithelium generates and maintains an area of relative immune privilege during a defined segment of the hair cycle (i.e., during anagen). This immune privilege is chiefly characterized by a very low level of expression of MHC class Ia antigens and by the local production of potent immunosuppressive agents, such as alpha-MSH and TGF-beta1. We discuss the putative functions of immune privilige of the anagen hair bulb, favoring the view that immune privilege serves mainly to sequester anagen- and/or melanogenesis-associated autoantigens from immune recognition by autoreactive CD8+ T cells. On this basis, we develop how the "immune privilege collapse model" of alopecia areata pathogenesis was conceived. In our discussion of the clinical implications of immune privilege, we outline the currently available evidence in support of this still hypothetical scenario to explain the initiation, progression, and termination of alopecia areata lesions. We review the most recent evidence from our laboratory that alpha-MSH, IGF-1, and TGF-beta1 can downregulate IFN-gamma-induced ectopic MHC class I expression in human anagen hair bulbs in vitro. Finally, we suggest that hair follicle-derived alpha-MSH, IGF-gamma, and TGF-beta1 form part of a constitutively active "IP restoration machinery" of the anagen hair bulb, which we propose to be recruited whenever the hair follicle suffers immune injury. Finally, we sketch some particularly promising avenues for future investigation into the far too long ignored hair follicle immune privilege.

Animals↗
PubMed2002

Unique therapeutic effects of the Japanese-Chinese herbal medicine, Sairei-to, on Th1/Th2 cytokines balance of the autoimmunity of MRL/lpr mice.

Sairei-to, one of the Japanese-Chinese herbal medicines has been used for the treatment of various diseases, especially collagen disease and edema in nephrotic syndrome. However, the mechanism of the therapeutic effects remains uncertain. Therefore, we investigated the immunological changes of skin, kidney, spleen cells and serum in autoimmune-prone MRL/lpr, MRL/n and C57BL/6J mice treated with Sairei-to. In MRL/lpr mice treated with Sairei-to, the improvement of proteinuria, reduction in the number of hematoxylin bodies in kidney, and reduced serum levels of blood urea nitrogen were observed. These results indicate that Sairei-to can improve or inhibit the progression of lupus nephritis. The proportion of CD19 and the serum levels of IgG1, which is one of the pathogenesis of lupus dermatoses and lupus nephritis, were significantly reduced in Sairei-to-treated MRL/lpr mice. Therefore, it is suspected that the B cell function was suppressed by Sairei-to. In addition, CD4/8 ratio in spleen cells and the degree of lymphoproliferation in MRL/lpr mice also decreased. Interestingly, IL-4 producing spleen cells were increased significantly by ELISPOT assay, and IFN-gamma mRNA expressions were reduced in Sairei-to-treated MRL/lpr mice. Regarding the Th balance, an imbalance towards Th1 predominance may play a significant role in MRL/lpr mice, and the Th1 axis was suppressed and the Th2 axis became predominant in Sairei-to-treated MRL/lpr mice. On the other hand, Th2 cell type immunoglobulins (IgG1) were suppressed. These results suggested that Sairei-to is potential for impairing shifted Th1/Th2 balance and hypergammaglobulinemia resulting in therapeutic effects.

Animals↗
PubMed2002

Dominant expression of CXCR3 is associated with induced expression of IP-10 at hapten-challenged sites of murine contact hypersensitivity: a possible role for interferon-gamma-producing CD8(+) T cells in IP-10 expression.

Murine contact hypersensitivity is elicited as a consequence of immunologic reactions triggered by skin-applied antigen, interactions among Langerhans cells, T cells, keratinocytes and mast cells, and a variety of chemokines generated by cellular interactions. In this study, we sensitized and challenged BALB/c mice with hapten, dinitrofluorobenzene or picryl chloride, and examined the expressions of mRNA for chemokines and their receptors by reverse transcription-polymerase chain reaction in the skin of elicited earlobes. CXC chemokines, IP-10 and Mig, were transcribed 24-48 h after challenge. This was associated with the expression of their agonistic receptor CXCR3, while mRNA for TARC and MDC, and their receptor CCR4 were not detected. Since CXCR3 and CCR4 are expressed preferentially on types 1 (Th1/Tc1) and 2 (Th2) T cells, respectively, the results suggested that the former type of T cells predominantly infiltrate at the elicited sites. Immune lymph node cells of the sensitized mice also expressed mRNA for CXCR3 but not CCR4 with concomitant transcription of interferon-gamma (IFN-gamma) but not interleukin-4 subsequent to challenge. The percentage of lymph node CD8(+) T cells was increased from 16% in naive mice to 30-50% in hapten-challenged mice, and in the immune lymph nodes, CD8(+) cells were the major source of IFN-gamma compared to CD4(+) cells. Since IFN-gamma is known to stimulate keratinocytes to produce IP-10 and Mig, it is suggested that these IFN-gamma-producing CD8(+) T cells enhance the production of these chemokines, thereby functioning as not only the effector cells but also the cytokine source to sustain the challenge reaction.

Animals↗
PubMedDate not supplied

Anti-allergic Psidium guajava extracts exert an antitumor effect by inhibition of T regulatory cells and resultant augmentation of Th1 cells.

Th1 polarization is one of the mechanisms underlying the therapeutic effects of herbal medicine. The action of anti-allergic agents from Psidium guajava (P. guajava) on T cell immunity in mice was investigated. The addition of P. guajava extracts blocked IL-10-mediated, in vitro induction of T regulatory (Tr) cells from CD4+ splenocytes of C57BL/6 mice, whereas the extracts exerted only a weak or no effect on the development of Th1 and Th2 cells. Accordingly, Tr cells were not induced from splenocytes of mice administered orally with the extracts. Furthermore, P. guajava extracts shifted the Th1/Th2 balance to a Th1 dominant status by directly attenuating Tr cell activity. In a study of tumor immunity, mice pretreated with the extracts exhibited retarded growth of s.c. inoculated B16 melanoma cells. These findings suggest that P. guajava extracts are efficacious for the prevention of tumor development by depressing Tr cells and subsequently shifting to Th1 cells.

Animals↗