RESUMO
Atopic dermatitis is a chronic form of allergic contact dermatitis that is closely associated with a compromised epidermal barrier. Immunogenicity of a given electrophilic hapten after penetration of this barrier depends directly on biochemical reactions in the thiol-rich layer in the stratum granulosum. In response to electrophilic hapten, NF-erythroid 2-related factor 2 (NRF2) in keratinocytes efficiently induces the production of antioxidants. In this study, we show that the immunogenicity of a given hapten depends directly on the extent to which it induces antioxidant host defenses within the epidermal tissue. We found that allergic contact dermatitis did not develop in NRF2-deficient mice because of compromise of the epidermal innate immune responses that upregulate IL-1α. We also analyzed epidermal NRF2 in association with congenital disorders with features similar to atopic dermatitis in humans. Epidermal samples from patients with Netherton syndrome and peeling skin syndrome exhibited elevated levels of NRF2 and also elevated levels of its downstream target, small proline-rich protein 2. Taken together, these results suggest that the thiol-mediated biochemical responses in the stratum granulosum provide a critical link between defective epidermal barrier function and the development of atopy. Likewise, our results suggested that NRF2 may have a profound impact on the generation of cutaneous immunological memory.
Assuntos
Antioxidantes/metabolismo , Dermatite Atópica/metabolismo , Epiderme/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Pele/metabolismo , Animais , Células Cultivadas , Dermatite Atópica/imunologia , Dermatite Esfoliativa/imunologia , Dermatite Esfoliativa/metabolismo , Epiderme/imunologia , Humanos , Imunidade Inata/imunologia , Interleucina-1alfa/imunologia , Interleucina-1alfa/metabolismo , Queratinócitos/imunologia , Queratinócitos/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Fator 2 Relacionado a NF-E2/imunologia , Síndrome de Netherton/imunologia , Síndrome de Netherton/metabolismo , Pele/imunologia , Dermatopatias Genéticas/imunologia , Dermatopatias Genéticas/metabolismo , Regulação para Cima/imunologiaRESUMO
OBJECTIVES: To investigate whether autoimmunity to transcriptional intermediary factor 1 (TIF1)γ, a ubiquitous nuclear autoantigen for myositis-specific autoantibodies detected in patients with dermatomyositis (DM) is pathogenetic for inflammatory myopathy. METHODS: Wild-type, ß2-microglobulin-null, perforin-null, Igµ-null and interferon α/ß receptor (IFNAR)-null mice were immunised with recombinant human TIF1γ whole protein. A thymidine incorporation assay was performed using lymph node T cells from TIF1γ-immunised mice. Plasma was analysed using immunoprecipitation followed by western blot analysis and enzyme-linked immunosorbent assays. Femoral muscles were histologically and immunohistochemically evaluated. CD8+ or CD4+ T cells isolated from lymph node T cells or IgG purified from plasma were adoptively transferred to naïve mice. TIF1γ-immunised mice were treated with anti-CD8 depleting antibody and a Janus kinase inhibitor, tofacitinib. RESULTS: Immunisation with TIF1γ-induced experimental myositis presenting with necrosis/atrophy of muscle fibres accompanied by CD8+ T cell infiltration successfully in wild-type mice, in which TIF1γ-specific T cells and antihuman and murine TIF1γ IgG antibodies were detected. The incidence and severity of myositis were significantly lower in ß2-microglobulin-null, perforin-null, CD8-depleted or IFNAR-null mice, while Igµ-null mice developed myositis normally. Adoptive transfer of CD8+ T cells induced myositis in recipients, while transfer of CD4+ T cells or IgG did not. Treatment with tofacitinib inhibited TIF1γ-induced myositis. CONCLUSIONS: Here we show that TIF1γ is immunogenic enough to cause experimental myositis, in which CD8+ T cells and type I interferons, but not CD4+ T cells, B cells or antibodies, are required. This murine model would be a tool for understanding the pathologies of DM.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Dermatomiosite/imunologia , Modelos Animais de Doenças , Camundongos , Doença Autoimune do Sistema Nervoso Experimental/imunologia , Fatores de Transcrição/imunologia , Transferência Adotiva , Animais , Linfócitos T CD4-Positivos/transplante , Linfócitos T CD8-Positivos/transplante , Humanos , Imunização , Imunoglobulina G/imunologia , Cadeias mu de Imunoglobulina/genética , Inibidores de Janus Quinases/farmacologia , Camundongos Knockout , Perforina/genética , Piperidinas/farmacologia , Pirimidinas/farmacologia , Receptor de Interferon alfa e beta/genética , Linfócitos T/imunologia , Microglobulina beta-2/genéticaRESUMO
Psoriasis is an autoinflammatory/autoimmune skin disease and the epitome of an exaggerated primary inflammatory response in the surface barrier tissue. Despite the efficacy of dimethyl fumarate, an electrophilic drug for psoriasis management, there is a paucity of mechanistic evidence in vivo. In response to electrophiles, the Kelch-like erythroid cell-derived protein with cap-n-collar homology-associated protein 1/nuclear factor erythroid 2-related factor 2 (NRF2) system mediates a myriad of cytoprotective mechanisms, including the regulation of excessive inflammatory response and epidermal differentiation. Because the psoriasiform tissue reaction comprises neutrophil infiltration and parakeratotic scaling, it is hypothesized that Nrf2 not only regulates inflammatory responses but also maintains epidermal differentiation, a hallmark of epidermal homeostasis. By using the imiquimod-induced cutaneous inflammation model, an exaggerated inflammatory response and impaired epidermal differentiation in Nrf2-/- mice was detected. Dimethyl fumarate treatment in Nrf2+/+ mice attenuated a psoriasiform tissue reaction and rescued epidermal differentiation, which was not observed in Nrf2-/- mice. In accordance with the fact that psoriasis plaques form well-demarcated parakeratotic lesions in association with the psoriasiform tissue reaction, the lesional skin showed reduced expression levels of NRF2 and its downstream target genes compared with nonlesional skin. In conclusion, Nrf2 attenuates the psoriasiform tissue reaction and underscores the mechanistic legitimacy of the electrophile-based approach for the management of psoriasis.
Assuntos
Imiquimode/efeitos adversos , Inflamação/patologia , Fator 2 Relacionado a NF-E2/metabolismo , Paraceratose/patologia , Psoríase/patologia , Animais , Diferenciação Celular , Células Cultivadas , Quimera , Epiderme/efeitos dos fármacos , Epiderme/patologia , Feminino , Homeostase/efeitos dos fármacos , Humanos , Imuno-Histoquímica , Inflamação/induzido quimicamente , Queratinócitos/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator 2 Relacionado a NF-E2/genética , Paraceratose/induzido quimicamente , Psoríase/induzido quimicamente , Pele/efeitos dos fármacos , Pele/patologiaRESUMO
Some bone lesions are reported to mimic bone metastasis on imaging tests. Herein, we report a case of a 55-year-old Japanese man who presented with a skin tumor on the left lower extremity. He also had a history of recurrent generalized cutaneous blister and erosion formation since childhood. His skin lesions were diagnosed as cutaneous squamous cell carcinoma complicated by recessive dystrophic epidermolysis bullosa. Magnetic resonance imaging of the left lower extremity detected multiple focal bone lesions mimicking bone metastases in the left femur and tibia. However, bone biopsy revealed that the bone lesions were osteonecrosis without tumor cells. We suggest that cancer-induced osteonecrosis should be included in the differential diagnosis of bone lesions suspected of being metastases on magnetic resonance imaging.
Assuntos
Neoplasias Ósseas/diagnóstico por imagem , Carcinoma de Células Escamosas/diagnóstico por imagem , Epidermólise Bolhosa Distrófica/diagnóstico por imagem , Neoplasias Femorais/diagnóstico por imagem , Imageamento por Ressonância Magnética , Osteonecrose/diagnóstico por imagem , Neoplasias Cutâneas/diagnóstico por imagem , Tíbia/diagnóstico por imagem , Biópsia , Neoplasias Ósseas/secundário , Carcinoma de Células Escamosas/secundário , Diagnóstico Diferencial , Epidermólise Bolhosa Distrófica/patologia , Neoplasias Femorais/secundário , Humanos , Masculino , Pessoa de Meia-Idade , Osteonecrose/patologia , Valor Preditivo dos Testes , Neoplasias Cutâneas/patologia , Tíbia/patologiaAssuntos
Antineoplásicos Imunológicos/farmacologia , Microambiente Celular/efeitos dos fármacos , Microambiente Celular/imunologia , Imunomodulação/efeitos dos fármacos , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Pele/imunologia , Pele/metabolismo , Animais , Antineoplásicos Imunológicos/uso terapêutico , Dermatite de Contato/imunologia , Dermatite de Contato/metabolismo , Dermatite de Contato/patologia , Modelos Animais de Doenças , Camundongos , Transdução de Sinais/efeitos dos fármacos , Pele/efeitos dos fármacos , Pele/patologia , Subpopulações de Linfócitos T/efeitos dos fármacos , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismoAssuntos
Antineoplásicos Fitogênicos/administração & dosagem , Neoplasias da Medula Óssea/tratamento farmacológico , Etoposídeo/administração & dosagem , Neoplasias Pulmonares/tratamento farmacológico , Linfoma de Células T/tratamento farmacológico , Paniculite/tratamento farmacológico , Administração Oral , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/análise , Biópsia , Neoplasias da Medula Óssea/química , Neoplasias da Medula Óssea/patologia , Humanos , Imuno-Histoquímica , Neoplasias Pulmonares/química , Neoplasias Pulmonares/patologia , Linfoma de Células T/química , Linfoma de Células T/patologia , Masculino , Paniculite/patologia , Resultado do TratamentoRESUMO
PD-1 is an immunoregulatory receptor that can bind PD-L1 or PD-L2 expressed on stimulated antigen-presenting cells. In this study, isolated antigen-presenting cells (macrophages and dendritic cells) were cultured with IFN-γ, IL-4, or IL-17A, and the expression of PD-L1 and PD-L2 was compared by flow cytometry. Strong upregulation of PD-L1 expression was observed on IFN-γ stimulation of both antigen-presenting cells as well as in response to IL-17A stimulation of macrophages compared with the expression in unstimulated controls. In contrast, only stimulation with IL-4 could upregulate PD-L2 expression on both antigen-presenting cells. Therefore, experiments were performed in murine models, including DNFB-induced contact hypersensitivity, calcipotriol-induced atopic dermatitis-like skin inflammation, and imiquimod-induced psoriasis-like dermatitis models, to trigger IFN-γâmediated T helper type (Th)1-, IL-4âmediated Th2-, and IL-17Aâmediated Th17-type responses, respectively. In both Th1- and Th17-type immunity models, changes in ear thickness were more severe in Pd-l1âdeficient mice than in wild-type or Pd-l2âdeficient mice. In the Th2-type immunity model, changes in thickness in Pd-l2âdeficient mice were more severe than that in wild-type or Pd-l1âdeficient mice. Collectively, PD-L1 has predominant roles in Th1 and Th17 type immunity, whereas PD-L2 is involved in Th2-type immunity.
Assuntos
Antígeno B7-H1/metabolismo , Células Dendríticas/imunologia , Dermatite Atópica/imunologia , Dermatite de Contato/imunologia , Inflamação/imunologia , Macrófagos/imunologia , Proteína 2 Ligante de Morte Celular Programada 1/metabolismo , Psoríase/imunologia , Pele/patologia , Células Th1/imunologia , Células Th17/imunologia , Células Th2/imunologia , Animais , Apresentação de Antígeno , Antígeno B7-H1/genética , Calcitriol/análogos & derivados , Células Cultivadas , Citocinas/metabolismo , Dinitrofluorbenzeno , Modelos Animais de Doenças , Humanos , Imiquimode , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína 2 Ligante de Morte Celular Programada 1/genética , Pele/imunologiaRESUMO
Acute graft-versus-host disease (aGVHD) induced by allogenic hematopoietic stem cell transplantation is an immunological disorder in which donor lymphocytes attack recipient organs. It has been proven that recipient nonhematopoietic tissue cells, such as keratinocytes, are sufficient as immunological targets for allogenic donor T cells, whereas Langerhans cells (LCs) are potent professional hematopoietic antigen-presenting cells existing in the target epidermis and eliminated during the early phase of mucocutaneous aGVHD. Moreover, LCs have been reported to negatively regulate various types of immune responses. Here, we present data showing that initial depletion of recipient LCs exacerbates mucocutaneous lesions in a murine model of allogenic bone marrow transplantation-induced aGVHD. Furthermore, another murine model of mucocutaneous aGVHD induced in mice with keratinocytes genetically expressing chicken ovalbumin by transfer of ovalbumin-specific CD8+ OT-I cells also showed that LC-depleted recipient mice develop aggravated mucocutaneous disease owing to decreased apoptosis of skin-infiltrating OT-I cells. Moreover, coexisting LCs directly induce apoptosis and inhibit the proliferation of OT-I cells in vitro partially via B7 family proteins. Collectively, our results indicate that LCs negatively regulate mucocutaneous aGVHD-like lesions in situ by inhibiting the number of infiltrating CD8+ T cells.
Assuntos
Transplante de Medula Óssea/efeitos adversos , Linfócitos T CD8-Positivos/imunologia , Doença Enxerto-Hospedeiro/imunologia , Células de Langerhans/fisiologia , Dermatopatias/imunologia , Doença Aguda , Animais , Apoptose , Antígenos B7/fisiologia , Células Cultivadas , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Inibidor 1 da Ativação de Células T com Domínio V-Set/fisiologiaRESUMO
Patients with graft-versus-host disease (GVHD) develop characteristic mucocutaneous phenomena consisting of erosive erythema with histopathological findings including interface dermatitis and keratinocyte (KC) death, resulting in widespread sclerodermatous changes. We found that KCs exhibit marked production of TGFß1 in skin lesions of chronic GVHD but not in those of acute GVHD. To further investigate the roles of KCs, the main targets of donor T cells, in sclerodermatous changes followed by interface dermatitis, we established a murine model of chronic GVHD-like sclerodermatous changes followed by acute GVHD-like mucocutaneous injury in genetically modified mice transferred with KC-specific CD8 T cells. Although transfer of granzyme B-deficient CD8 T cells did not result in either mucocutaneous injury or sclerodermatous changes in recipients, IFN-γ-deficient CD8 T-cell recipients developed severe acute mucocutaneous injury but milder sclerodermatous changes than wild-type CD8 T-cell recipients. Moreover, IFN-γ-deficient CD8 T-cell recipients had a lower expression of TGFß1 in the epidermis than the control. Murine primary KCs undergoing FasL-induced apoptosis and incubated with IFN-γ produced TGFß1, the production of which was inhibited by a pan-caspase inhibitor. Our results indicate that IFN-γ promotes TGFß1 production by apoptotic KCs, which mediates the development of widespread sclerodermatous changes in KC-targeting GVHD.
Assuntos
Doença Enxerto-Hospedeiro/imunologia , Interferon gama/metabolismo , Esclerodermia Localizada/imunologia , Pele/patologia , Doença Aguda , Adolescente , Adulto , Idoso , Animais , Apoptose/imunologia , Biópsia , Linfócitos T CD8-Positivos/imunologia , Doença Crônica , Modelos Animais de Doenças , Proteína Ligante Fas/metabolismo , Feminino , Doença Enxerto-Hospedeiro/patologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Interferon gama/genética , Queratinócitos/imunologia , Queratinócitos/metabolismo , Queratinócitos/patologia , Masculino , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Cultura Primária de Células , Esclerodermia Localizada/patologia , Pele/citologia , Pele/imunologia , Fator de Crescimento Transformador beta1/metabolismo , Transplante Homólogo/efeitos adversos , Adulto JovemRESUMO
The exact mechanisms of the imiquimod (IMQ)-induced antitumor effect have not been fully understood. Although both topical IMQ treatment and anti-PD-1 antibody may be used for primary skin lesions or skin metastases of various cancers, the efficacy of each monotherapy for these lesions is insufficient. Using a murine tumor model and human samples, we aimed to elucidate the detailed mechanisms of the IMQ-induced antitumor effect and analyzed the antitumor effect of combination therapy of topical IMQ plus anti-PD-1 antibody. Topical IMQ significantly suppressed the tumor growth of MC38 in wildtype mice. IMQ upregulated interferon γ (IFN-γ) expression in CD8+ T cells in both the lymph nodes and the tumor, and the antitumor effect was abolished in both Rag1-deficient mice and IFN-γ-deficient mice, indicating that IFN-γ produced by CD8+ T cells play a crucial role in the IMQ-induced antitumor effect. IMQ also upregulated PD-1 expression in T cells as well as PD-L1/PD-L2 expression in myeloid cells, suggesting that IMQ induces not only T-cell activation but also T-cell exhaustion by enhanced PD-1 inhibitory signaling. Combination therapy of topical IMQ plus anti-PD-1 antibody exerted a significantly potent antitumor effect when compared with each single therapy, indicating that the combination therapy is a promising therapy for the skin lesions of various cancers.
RESUMO
Angiomatoid Spitz nevus (ASN) is a rare histological variant of Spitz nevus (SN) that is characterized by prominent blood vessel proliferation around the intradermal melanocytes of SN. In contrast, SN may have pagetoid components, which are characterized by epidermal proliferation of single melanocytes. However, cases of ASN with predominant pagetoid melanocytic proliferation in the epidermis have not been reported. Here, we report a case of ASN with surrounding pagetoid melanocytic proliferation without formation of tumor nests in the epidermis in the plantar region. A 12-year-old girl presented with a bright red nodule surrounded by a brown macule on the sole of her right foot. Histologically, the nodule showed tumor nests in the dermis, composed of spindle or epithelioid melanocytes containing abundant cytoplasm and large nuclei. Around the nests, numerous blood vessels were seen. In the overlying epidermis of the nodule, numerous eosinophilic Kamino bodies were found along the dermal-epidermal interface. In the macule, proliferation of oval melanocytes was present as single-cell units in the epidermis. Theses melanocytes had abundant cytoplasm with large nuclei, which were larger than those of the surrounding keratinocytes. From these findings, a diagnosis of ASN with surrounding pagetoid melanocytic proliferation was made. Vascular endothelial growth factor and fibroblast growth factor 2 were strongly expressed in the melanocytes as well as in the endothelial cells in our case. Therefore, angiogenic factors produced by the melanocytes of SN might have played important roles in the surrounding angiogenesis of this case.
Assuntos
Melanócitos/patologia , Neovascularização Patológica/patologia , Nevo de Células Epitelioides e Fusiformes/diagnóstico , Neoplasias Cutâneas/diagnóstico , Pele/patologia , Proliferação de Células , Criança , Dermoscopia , Células Endoteliais/patologia , Endotélio Vascular/citologia , Endotélio Vascular/patologia , Feminino , Fator 2 de Crescimento de Fibroblastos/análise , Fator 2 de Crescimento de Fibroblastos/metabolismo , Pé , Humanos , Imuno-Histoquímica , Nevo de Células Epitelioides e Fusiformes/patologia , Nevo de Células Epitelioides e Fusiformes/cirurgia , Pele/irrigação sanguínea , Pele/citologia , Pele/diagnóstico por imagem , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/cirurgia , Fator A de Crescimento do Endotélio Vascular/análise , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
Recent clinical trials revealed that both immune checkpoint inhibitors (ICI) and BRAF/MEK inhibitors significantly prolonged survival in melanoma patients when used for both advanced stage disease and postoperative adjuvant therapy. Although BRAF/MEK inhibitors are associated with a higher objective response rate than ICI, most patients relapse during treatment. However, progression patterns during treatment with BRAF/MEK inhibitors have not been extensively investigated. Here, we retrospectively collected the data of melanoma patients initially treated with BRAF/MEK inhibitors or anti-programmed death 1 (PD-1) antibody monotherapy at the University of Tsukuba Hospital and compared their results. The χ2 -test revealed that frequency of brain metastasis (BM) development was significantly higher in cases treated with BRAF/MEK inhibitors compared with those with anti-PD-1 antibody monotherapy. In addition, BM-free survival in cases treated with BRAF/MEK inhibitors was significantly shorter than those treated with anti-PD-1 antibody monotherapy. Our results indicate that BM development during treatment with BRAF/MEK inhibitors may be more frequent than anti-PD-1 antibody monotherapy, even though the extracranial metastases are well controlled. Therefore, we recommend frequent brain examinations during treatment with BRAF/MEK inhibitors to detect BM at an early stage and to promptly administrate ICI with local radiation therapy.
Assuntos
Neoplasias Encefálicas , Proteínas Proto-Oncogênicas B-raf , Humanos , Quinases de Proteína Quinase Ativadas por Mitógeno , Recidiva Local de Neoplasia , Receptor de Morte Celular Programada 1 , Inibidores de Proteínas Quinases/efeitos adversos , Proteínas Proto-Oncogênicas B-raf/genética , Estudos RetrospectivosRESUMO
Use of immune checkpoint inhibitors that target programmed cell death-1 (PD-1) can lead to various autoimmune-related adverse events (irAEs) including psoriasis-like dermatitis. Our observations on human samples indicated enhanced epidermal infiltration of CD8 T cells, and the pathogenesis of which appears to be dependent on IL-6 in the PD-1 signal blockade-induced psoriasis-like dermatitis. By using a murine model of imiquimod-induced psoriasis-like dermatitis, we further demonstrated that PD-1 deficiency accelerates skin inflammation with activated cytotoxic CD8 T cells into the epidermis, which engage in pathogenic cross-talk with keratinocytes resulting in production of IL-6. Moreover, genetically modified mice lacking PD-1 expression only on CD8 T cells developed accelerated dermatitis, moreover, blockade of IL-6 signaling by anti-IL-6 receptor antibody could ameliorate the dermatitis. Collectively, PD-1 signal blockade-induced psoriasis-like dermatitis is mediated by PD-1 signaling on CD8 T cells, and furthermore, IL-6 is likely to be a therapeutic target for the dermatitis.
Assuntos
Antineoplásicos Imunológicos/efeitos adversos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Interleucina-6/metabolismo , Ativação Linfocitária/imunologia , Psoríase/etiologia , Psoríase/metabolismo , Animais , Antineoplásicos Imunológicos/farmacologia , Biomarcadores , Relação CD4-CD8 , Linfócitos T CD8-Positivos/efeitos dos fármacos , Citocinas/metabolismo , Modelos Animais de Doenças , Suscetibilidade a Doenças , Epiderme/imunologia , Epiderme/metabolismo , Epiderme/patologia , Humanos , Imuno-Histoquímica , Interleucina-6/sangue , Queratinócitos/imunologia , Queratinócitos/metabolismo , Ativação Linfocitária/efeitos dos fármacos , Camundongos , Camundongos Knockout , Fenótipo , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Psoríase/diagnósticoRESUMO
Morphea profunda refers to inflammatory and sclerotic lesions that start primarily from the deep dermis, subcutaneous fat and fascia. Its pediatric case published work is limited. Here, we report the case of an 8-year-old girl with a 5-year history of multiple subcutaneous nodules on her extremities and a right wrist joint contracture who had been previously diagnosed with juvenile idiopathic arthritis and treated with salazosulfapyridine, low-dose prednisolone (PSL) and methotrexate. We performed biopsies of two subcutaneous nodules, which revealed the typical morphology of morphea profunda. She was administrated a tapered course of oral PSL then cyclosporin A (CyA) for 20 weeks which completely resolved her joint contracture and subcutaneous nodules. We reviewed 11 previously reported cases of morphea profunda and found that some include circumscribed/linear morphea that develop into subcutaneous tissues, indicating that "classical" morphea profunda arising within the deep tissues has rarely been reported. Our report is the first to demonstrate the efficacy of CyA for treatment of morphea profunda, and the possibility of CyA as a treatment option to reduce oral steroid doses in juvenile cases.