Induction of regulatory dendritic cells by topical application of NF-kappaB decoy oligodeoxynucleotides.

Dendritic cells (DC) have a key role in inducing an immune response, but DC in different maturation states are responsible for inducing tolerance. Topical application of nuclear factor (NF)-kappaB decoy oligodeoxynucleotides (ODN) induces antigen-specific peripheral tolerance in delayed-type hypersensitivity (DTH) to ovalbumin (OVA) by expanding CD4(+)CD25(+) regulatory T cells and by inhibiting DC migration. Herein we describe how topical NF-kappaB decoy ODN modulate DC maturation with respect to their migration, phenotype, and cytokine profiles. Topical application of NF-kappaB decoy ODN after OVA sensitization delayed the migration of Langerhans cells (LC) into draining lymph nodes, and morphologically mature LC remained in the peripheral tissue 2 days longer than in OVA-sensitized mice without application of NF-kappaB decoy ODN. During migration, NF-kappaB decoy-treated DC preferentially expressed inhibitory B7 molecules (i.e., B7-H1, B7-DC, and B7-H3) compared to OVA-sensitized DC without NF-kappaB decoy ODN, whereas co-stimulatory molecules (MHC class II, B7-1 and B7-2) were upregulated. Adoptive transfer of NF-kappaB decoy-treated DC inhibited DTH induction in prophylactic and therapeutic experiments. Inhibition of DTH by DC transfer was antigen-specific in vivo. This decoy ODN strategy might be useful for regulating immunity through DC.

Case of unilateral focal dermal hypoplasia (Goltz syndrome).

Focal dermal hypoplasia (FDH) is a rare multisystem condition in which developmental defects of the skin are associated with ocular, dental and skeletal abnormalities. Herein, we report an 8-year-old girl with FDH. Her body halves were asymmetric and she had linear cutaneous atrophy with yellow nodules on her extremities. Syndactylies of the third and fourth fingers of the right hand and second and third toes of the right foot were also observed. Histological examination revealed dermal hypoplasia and upward extension of the adipose tissue. Based on these observations, she was diagnosed with unilateral FDH.

Antigen-specific peripheral tolerance induced by topical application of NF-kappaB decoy oligodeoxynucleotide.

Activation and maturation of dendritic cells (DC) are crucial for the establishment of delayed-type hypersensitivity (DTH). However, antigen presentation by immature DC (iDC) might lead to antigen-specific peripheral tolerance. NF-kappaB plays significant roles in upregulation of co-stimulatory molecules and cytokines in DC and therefore we investigated whether NF-kappaB decoy oligodeoxynucleotide (ODN) might induce tolerance to DTH. NF-kappaB decoy ODN suppressed ovalbumin (OVA)-induced DTH responses not only in naïve but also in presensitized mice. The suppressive effect was found to be antigen-specific. NF-kappaB decoy ODN-induced tolerance involved CD4(+)CD25(+) regulatory T cells (Treg), because in vivo depletion of CD25(+) T cells abrogated the tolerance, whereas adoptive transfer of such T cell population from tolerant mice induced tolerance. Furthermore, the induction of Treg was related to insufficient migration and/or maturation of DC, because a sizable DC population still remained in peripheral tissue even after exposure to exogenous antigen in NF-kappaB decoy ODN-treated mice. Even if they migrated into lymph nodes, they showed insufficient upregulation of co-stimulatory molecules and impaired antigen-specific activation of T cells. Topical application of NF-kappaB decoy ODN might thus be a new approach to induce antigen-specific peripheral tolerance.

Successful treatment with topical tacrolimus in four cases of discoid lupus erythematosus.

Discoid lupus erythematosus (DLE), a cutaneous form of lupus erythematosus, is characterized as atrophic and scaly erythema and the lesions are often refractory to a wide range of topical or systemic therapies. Herein, we present four cases of DLE that were successfully treated with topical tacrolimus. Tacrolimus ointment (0.1%) was applied to DLE lesions twice daily and the erythematous plaques readily diminished after 4-8 weeks. Adverse effects, such as burning sensation or irritations, were not observed. These results indicate that topical tacrolimus might be an effective and alternative treatment to control DLE.

Pyoderma gangrenosum associated with nasal septal perforation, oropharyngeal ulcers and IgA paraproteinemia.

We report a case of pyoderma gangrenosum (PG) associated with nasal septal perforation, pharyngeal ulcers and IgA paraproteinemia. A 28-year-old woman first developed painful undermined ulcers on her perianal, inguinal and axillary areas when she was 22 years old. Histological findings from the cutaneous ulcers showed dermal and epidermal infiltrate of neutrophils, which was compatible with PG. Laboratory examinations did not detect any associations of systemic diseases other than polyclonal IgA paraproteinemia. Nasal fiberscopy revealed septal perforation and multiple ulcers on her pharynx. The biopsy specimen from the pharyngeal ulcers showed a polymorphous cellular infiltrate without necrotizing vasculitis or granuloma. However, there were no atypical lymphocytes that are typically seen in nasal NK/T lymphoma. By immunohistochemical analysis, the infiltrated lymphocytes were proved to be T cells and Epstein-Barr virus encoded RNA (EBER) was not detected. No pulmonary or renal lesions resembling Wegener's granulomatosis were found. Taken together, the nasal septal perforation was considered as nasal involvement of PG.

Topical tacrolimus therapy for pyoderma gangrenosum.

Pyoderma gangrenosum (PG) is a type of neutrophilic disorder with a chronic clinical course. Immunosuppressive agents have been used for its management. Among them, corticosteroid is known as the most effective. However, other immunosuppressants including cyclosporine A have been selected for patients with PG who were refractory to systemic steroids. Herein we report a case of PG resistant to systemic steroids, who was successfully treated with topical tacrolimus. A fifty-four year-old male had a 14-year history of PG. In 2002, necrotic ulcers appeared on his right leg that were refractory to oral prednisolone (30 mg/day). The application of topical tacrolimus to the border of the ulcers hastened epithelization of the ulcers and allowed for reduction of the oral prednisolone. Topical tacrolimus therapy may be an effective alternative for PG when the lesion is poorly controlled by corticosteroid.

A case of tufted hair folliculitis.

A 35-year-old man developed red papules and plaques with alopecia and hair tufts on the parietal and occipital areas of his scalp. Each tuft was comprised of 5 to 25 hairs arising from individual hair follicules. Histopathological findings showed a dense infiltration of plasma cells in the dermis. Based on these findings, he was diagnosed as tufted hair folliculitis. Oral minocycline and topical gentamicin were not effective, but the patient responded well to four weeks of oral refampicin.

A case of bullous Sézary syndrome.

Sézary syndrome is an aggressive variant of cutaneous T cell lymphoma with poor prognosis and clinically characterized by erythroderma and Sézary cells in the blood. Here we report a case of bullous Sézary syndrome. A seventy-year-old male presented with erythroderma and inguinal lymph node swelling. Histopathological examination showed dermal and epidermal infiltration of atypical lymphocytes and Sézary cells could be detected in peripheral blood samples. He was therefore diagnosed as Sézary syndrome. Four months after the onset, he developed bullae on axillary and inguinal areas, featuring subepidermal blistering with basal cell degeneration and dense infiltration of atypical lymphocytes. Autoimmune bullous diseases were excluded by negative immunofluorescence. Bullous forms of Sézary syndrome are extremely rare although several cases of a bullous variant of mycosis fungoides have been reported.

c-Rel is required for the development of thymic Foxp3+ CD4 regulatory T cells.

During thymopoiesis, a unique program of gene expression promotes the development of CD4 regulatory T (T reg) cells. Although Foxp3 maintains a pattern of gene expression necessary for T reg cell function, other transcription factors are emerging as important determinants of T reg cell development. We show that the NF-kappaB transcription factor c-Rel is highly expressed in thymic T reg cells and that in c-rel(-/-) mice, thymic T reg cell numbers are markedly reduced as a result of a T cell-intrinsic defect that is manifest during thymocyte development. Although c-Rel is not essential for TGF-beta conversion of peripheral CD4(+)CD25(-) T cells into CD4(+)Foxp3(+) cells, it is required for optimal homeostatic expansion of peripheral T reg cells. Despite a lower number of peripheral T reg cells in c-rel(-/-) mice, the residual peripheral c-rel(-/-) T reg cells express normal levels of Foxp3, display a pattern of cell surface markers and gene expression similar to those of wild-type T reg cells, and effectively suppress effector T cell function in culture and in vivo. Collectively, our results indicate that c-Rel is important for both the thymic development and peripheral homeostatic proliferation of T reg cells.

Regulation of NF-kappaB signaling by decoy oligodeoxynucleotides.

The nuclear factor-kappa B (NF-kappaB) plays a critical role in regulating expression of genes responsible for a wide range of cellular processes, including innate and adoptive immune responses, and pathways related to cell survival and proliferation. Based on its property as a transcription factor, NF-kappaB has been considered as a good target for the treatment of inflammatory immune diseases. To regulate gene expression, "decoy" oligodeoxynucleotides (ODNs) are ideal tools to interfere with binding of transcription factors to promoter regions in genes. Herein we review the application of NF-kappaB decoy ODNs to control inflammatory disorders and transplantation tolerance. In addition, we provide information about induction of antigen-specific peripheral tolerance by their topical application. Regulation of NF-kappaB signaling by NF-kappaB decoy ODNs might be an effective tool to control a variety of disorders caused by inflammatory immune responses.

Recombinant cholera toxin B subunit activates dendritic cells and enhances antitumor immunity.

Activation of dendritic cells (DC) is crucial for priming of cytotoxic T lymphocytes (CTL), which have a critical role in tumor immunity, and it is considered that adjuvants are necessary for activation of DC and for enhancement of cellular immunity. In this study, we examined an adjuvant capacity of recombinant cholera toxin B subunit (rCTB), which is non-toxic subunit of cholera toxin, on maturation of murine splenic DC. After the in vitro incubation of DC with rCTB, the expression of MHC class II and B7-2 on DC was upregulated and the secretion of IL-12 from DC was enhanced. In addition, larger DC with longer dendrites were observed. These data suggest that rCTB induced DC maturation. Subsequently, we examined the induction of tumor immunity by rCTB-treated DC by employing Meth A tumor cells in mice. Pretreatment with subcutaneous injection of rCTB-treated DC pulsed with Meth A tumor lysate inhibited the growth of the tumor cells depending on the number of DC. Moreover, intratumoral injection of rCTB-treated DC pulsed with tumor lysate had therapeutic effect against established Meth A tumor. Immunization with DC activated by rCTB and the tumor lysate increased number of CTL precursor recognizing Meth A tumor. The antitumor immune response was significantly inhibited in CD8+ T cell-depleted mice, although substantial antitumor effect was observed in CD4+ T cell-depleted mice. These results indicated that rCTB acts as an adjuvant to enhance antitumor immunity through DC maturation and that CD8+ T cells play a dominant role in the tumor immunity. Being considered to be safe, rCTB may be useful as an effective adjuvant to raise immunity for a tumor in clinical application.