ABSTRACT Introduction: Systemic Mastocytosis comprises a group of neoplastic diseases characterized by clonal expansion and infiltration of mast cells into several organs. The diagnosis and treatment of this disease may be challenging for non-specialists. Objective: Make suggestions or recommendations in Systemic Mastocytosis based in a panel of Brazilian specialists. Method and results: An online expert panel with 18 multidisciplinary specialists was convened to propose recommendations on the diagnosis and treatment of Systemic Mastocytosis in Brazil. Recommendations were based on discussions of topics and multiple-choice questions and were graded using the Oxford Centre for Evidence-Based Medicine 2011 Levels of Evidence Chart. Conclusion: Twenty-two recommendations or suggestions were proposed based on a literature review and graded according to the findings.

Abstract Objectives The study describes a case series of hereditary angioedema with C1 Inhibitor Deficiency (C1INH-HAE) in order to corroborate six clinical warning signs “HAAAAE (H4AE)” to enable early identification of this disease. Methods The authors analyzed the C1INH-HAE cohort to analyze the clinical aspects of the present study's patients and corroborate the six clinical warning signs of the Hereditary Angioedema Brazilian Guidelines. Data regarding demographics, the onset of disease, time to diagnosis, frequency of attacks per year, organs involved, triggers, crisis duration and their outcomes, and disease treatment were collected. Then the authors developed an acronym, H4AE, to help healthcare professionals remember the warning signs. Results The authors included 98 patients in the study, with a mean age of 38.1 years, 67.3% being female, and 75.3% with a family history of HAE. HAE diagnosis was delayed, on average, 13.7 years after its initial manifestation. Exploratory laparotomy was reported by 26.9%, and orotracheal intubation by 21.3% of the present study's patients; 61.3% and 30.3% of them were admitted at least once in the hospital and in the intensive care unit, respectively. The authors constructed an acronym “H4AE” with the six warning signs of HAE: Hereditary, recurrent Angioedema, Abdominal pain, Absence of urticaria, Absence of response to antihistamines, Estrogen association. Conclusion C1INH-HAE is still underdiagnosed and associated with high morbidity. The study showed clinical features of this disease, corroborating the warning signs, which may be useful in raising awareness and improving the diagnosis of C1INH-HAE. The authors suggest the acronym “H4AE” to remind the warning signs.

RESUMO Relatamos os casos de dois irmãos adolescentes com dermatite atópica grave e que, apesar de pesarem cerca de 40kg, apresentaram boa resposta ao dupilumabe com a dose off-label para indivíduos com 12 anos e peso de 60kg. Ambos já tinham usado ciclosporina, azatioprina, metotrexato e corticoide oral por longos períodos, acrescidos de tratamentos tópicos sem controle adequado da doença. As lesões cutâneas eram constantes e disseminadas, e os irmãos apresentavam infeções de pele frequentes e qualidade de vida muito ruim, com inúmeras consequências físicas e psicossociais, como o abandono da atividade escolar pelo prurido intenso, pela aparência e pelo bullying sofrido. Apresentavam também retardo de crescimento e de desenvolvimento. Em 2018, o dupilumabe, um agente imunobiológico, foi aprovado para o tratamento de dermatite atópica moderada a severa para adultos e, em 2019, ampliado para faixa etária de 12 a 17 anos. Embora já tivesse a aprovação da Agência Nacional de Vigilância Sanitária no Brasil, a apresentação de 200mg (indicada para o peso dos pacientes) não estava disponível, sem previsão de chegada. Assim, pesando os riscos e benefícios da situação de ambos, optamos por tratá-los com dose de adulto (ataque de 600mg por via subcutânea e 300mg por via subcutânea a cada 2 semanas) apesar do baixo peso. Até o momento, eles realizaram oito aplicações, apresentando importante melhora da doença e da qualidade de vida. Não houve efeitos adversos importantes – apenas a piora da conjuntivite alérgica em um deles. Os pacientes e sua família estão muito satisfeitos, e nós avaliamos que a terapia está sendo bem-sucedida.

ABSTRACT We report the cases of two adolescent siblings with severe atopic dermatitis, who, despite weighing approximately 40kg, presented a good response to dupilumab with the off-label dose for individuals aged 12 years and weighing 60kg. Both had already used cyclosporine, azathioprine, methotrexate and oral corticosteroids for long periods, plus topical treatments with no adequate disease control. Skin lesions were constant and widespread, with frequent skin infections and very poor quality of life, with numerous physical and psychosocial consequences, such as dropping out of school activities due to severe itching, appearance and bullying. They also showed delayed growth and development. In 2018, dupilumab, an immunobiological agent, was approved for treatment of moderate to severe atopic dermatitis in adults and, in 2019, extended to the 12-17-year age group. Although it had already been approved by the Brazilian Health Surveillance Agency, the 200mg presentation (indicated for the weight of patients) was not available, with no expected arrival date. Therefore, weighing the risks and benefits of the situation of both, we chose to treat them with an adult dose (loading dose of 600mg subcutaneously, and 300mg subcutaneously every 2 weeks) despite the low weight. So far, they have received eight injections, showing significant improvement of disease and quality of life. There were no major adverse effects, only worsening of allergic conjunctivitis in one of them. The patients and their family are very satisfied, and we believe that the therapy has been successful.

RESUMO As crises de angioedema são causas comuns de atendimentos nas emergências, e devido ao potencial de gravidade, é importante que os profissionais que atuam nesses serviços conheçam suas causas e abordagem. Os mecanismos envolvidos no angioedema sem urticas podem ser histaminérgicos ou mediados por bradicinina. As causas mais comuns de angioedema mediado por histamina são alimentos, medicamentos, ferroada de insetos e idiopática. Quando o mediador é a bradicinina, os desencadeantes são os inibidores da enzima conversora de angiotensina e fatores relacionados ao angioedema adquirido com deficiência do inibidor de C1 ou angioedema hereditário que são menos comuns, mas muito importantes pela possibilidade de desfecho fatal. O angioedema hereditário é uma doença rara, caracterizada por crises de edema que acometem o tecido subcutâneo e mucosas de vários órgãos, manifestando-se principalmente por crises de angioedema e dor abdominal. Esse tipo de angioedema não responde ao tratamento usual com adrenalina, anti-histamínicos e corticosteroides. Assim, se não identificados e tratados adequadamente, esses pacientes têm risco de morte por edema de laringe estimado em 25% a 40%. O tratamento do angioedema hereditário mudou drasticamente nos últimos anos, com o desenvolvimento de novos e eficientes fármacos para as crises: inibidor de C1 derivado de plasma, inibidor de C1 recombinante humano, antagonista do receptor B2 da bradicinina (icatibanto) e o inibidor da calicreína (ecalantide). No Brasil, até o momento, estão liberados para uso o inibidor de C1 derivado de plasma e o icatibanto. O manejo correto desses pacientes na emergência evita cirurgias desnecessárias e, principalmente, desfechos fatais.

ABSTRACT Angioedema attacks are common causes of emergency care, and due to the potential for severity, it is important that professionals who work in these services know their causes and management. The mechanisms involved in angioedema without urticaria may be histamine- or bradykinin-mediated. The most common causes of histamine-mediated angioedema are foods, medications, insect sting and idiopathic. When the mediator is bradykinin, the triggers are angiotensin-converting enzyme inhibitors and factors related to acquired angioedema with deficiency of C1-inhibitor or hereditary angioedema, which are less common, but very important because of the possibility of fatal outcome. Hereditary angioedema is a rare disease characterized by attacks of edema that affect the subcutaneous tissue and mucous membranes of various organs, manifesting mainly by angioedema and abdominal pain. This type of angioedema does not respond to the usual treatment with epinephrine, antihistamines and corticosteroids. Thus, if not identified and treated appropriately, these patients have an estimated risk of mortality from laryngeal edema of 25% to 40%. Hereditary angioedema treatment has changed dramatically in recent years with the development of new and efficient drugs for attack management: plasma-derived C1 inhibitor, recombinant human C1-inhibitor, bradykinin B2 receptor antagonist (icatibant), and the kallikrein inhibitor (ecallantide). In Brazil, plasma-derived C1 inhibitor and icatibant have already been approved for use. Proper management of these patients in the emergency department avoids unnecessary surgery and, especially, fatal outcomes.

ABSTRACT COVID-19 (coronavirus disease, described in 2019) is an infectious disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Most confirmed cases are mild or asymptomatic, but the most severe cases can progress to severe pneumonia with respiratory failure and death. In Brazil, there is a scenario of an exponential increase in cases, making it challenging to identify the source of contagion. We cannot yet specify when the peak of the COVID-19 outbreak will occur in our country or when the numbers of new contaminants and deaths will begin to decrease. So, the most important thing is protection against a virus for which all the details about contagion, transmission, and treatment are not known. The pandemic impacted and modified medical care, especially for surgical specialties, where face-to-face care is essential and cannot be replaced entirely by telemedicine. Thus, this review aimed to compile theoretical and practical aspects regarding the pandemic COVID-19 and its impact on plastic surgery activity routine. Protocols are proposed for resuming our routines, analyzing countries’ experience at an advanced stage of the pandemic. COVID19 COVID 19 COVID-1 2019 SARSCoV2. SARSCoV2 SARSCoV SARS CoV . (SARS-CoV-2) asymptomatic death Brazil contagion decrease So transmission known specialties facetoface face telemedicine Thus routine routines countries COVID1 1 COVID- 201 (SARS-CoV-2 20 (SARS-CoV- (SARS-CoV

RESUMO COVID-19 (coronavirus disease, descrito em 2019) é uma doença infecciosa causada pelo coronavírus da síndrome respiratória aguda grave 2 (SARS-CoV-2). A maioria dos casos confirmados é leve ou assintomático, mas os casos mais graves podem evoluir para pneumonia grave com insuficiência respiratória e morte. Atualmente ocorre, no Brasil, um cenário de aumento exponencial de casos, dificultando a identificação da fonte de contágio. Ainda não podemos precisar quando ocorrerá o pico do surto de COVID-19 em nosso país ou quando os números de novos contaminados e óbitos começarão a diminuir. Nesse momento, o mais importante é a proteção contra um vírus do qual não se conhece todos os detalhes sobre contágio, transmissão e tratamento. A pandemia impactou e modificou a assistência médica, principalmente das especialidades cirúrgicas, onde o atendimento presencial é fundamental e não pode ser substituído integralmente pela telemedicina. Assim, o objetivo desta revisão foi compilar aspectos teóricos e práticos referentes à pandemia COVID-19 e seu impacto na rotina da atividade da cirurgia plástica. São propostos protocolos para retomada de nossas rotinas, analisando a experiência de países em fase mais adiantada da pandemia. COVID19 COVID 19 COVID-1 coronavirus disease 2019 SARSCoV2. SARSCoV2 SARSCoV SARS CoV . (SARS-CoV-2) assintomático morte ocorre Brasil contágio diminuir momento tratamento médica cirúrgicas telemedicina Assim plástica rotinas COVID1 1 COVID- 201 (SARS-CoV-2 20 (SARS-CoV- (SARS-CoV

RESUMO A erupção fixa por drogas é uma reação de hipersensibilidade a medicamento não imediata, caracterizada por placas eritematosas ou violáceas, arredondadas, recorrentes, de bordas bem definidas e que aparecem sempre na mesma localização cada vez que o medicamento culpado é administrado. A prática habitual é evitar a droga envolvida e utilizar um medicamento estruturalmente diferente. Contudo, há situações em que não há terapêutica segura e eficaz. Em tais situações, a dessensibilização é a única opção. Descrevemos o caso de um paciente que apresentou erupção fixa por drogas por sulfametoxazol-trimetoprim, tendo sido submetido à dessensibilização com sucesso, mas necessitou repetição do procedimento duas vezes, por recidiva da reação após reintrodução inadvertida em dose plena. Em reação de hipersensibilidade a medicamento não imediata, a indicação é controversa e não há padronização técnica. Além disso, não se conhece o tempo durante o qual essa tolerância é perdida após a suspensão da droga envolvida. Nas reações não imediatas graves e dos tipos II e III, a dessensibilização está contraindicada. O paciente foi submetido a dessensibilização ao sulfametoxazol-trimetoprim por três vezes − a primeira com recorrência de lesões, e a segunda e terceira sem manifestações, sendo todas concluídas com sucesso e sem uso de pré-medicação.

ABSTRACT The fixed drug eruption is a non-immediate hypersensitivity reaction to drug, characterized by recurrent erythematous or violaceous, rounded, well-defined border plaques, which always appear in the same location every time the culprit drug is administered. The usual practice is to avoid the drug involved and to use a structurally different drug. However, there are situations in which there is no safe and effective therapy. In such situations, desensitization is the only option. We describe the case of a patient who presented fixed eruption due to sulfamethoxazole-trimethoprim, who underwent successful desensitization, but required a repeat procedure twice due to relapse after inadvertent full-dose reintroduction. In non-immediate hypersensitivity reaction to drug, the indication is controversial and there is no technical standardization. Furthermore, the time at which such tolerance is lost after discontinuing the drug involved is unknown. In severe non-immediate reactions of types II and III, desensitization is contraindicated. The patient underwent desensitisation to sulfamethoxazole-trimethoprim three times − the first with recurrence of lesions and the second and third without manifestations, all concluded successfully and with no premedication.

RESUMO Relatamos o caso de uma paciente com dermatite atópica grave, que mostrou boa resposta ao dupilumabe. Ela já tinha usado dois agentes imunossupressores, a ciclosporina A e o micofenolato de mofetila, para o tratamento da dermatite atópica, sem obter o controle adequado da doença. Ela também vinha fazendo uso de todas as medidas de controle para casos graves da doença: cuidados com o banho, controle ambiental, corticosteroides potentes tópicos e emolientes. Apresentava prurido e lesões cutâneas constantes, infeções de pele frequentes e qualidade de vida ruim. Passou a apresentar depressão devido à sua doença. Recentemente, o dupilumabe, um agente biológico novo, foi aprovado para o tratamento de dermatite atópica moderada a severa em muitos países, incluindo o Brasil. Dupilumabe é um anticorpo monoclonal cujo alvo é a cadeia alfa comum aos receptores da interleucina (IL) 4 e IL-13, duas citocinas envolvidas no perfil de resposta imune Th2, que promove inflamação atópica. De modo pioneiro no Brasil, a paciente iniciou o tratamento, com dose de ataque de 600mg por via subcutânea de dupilumabe e 300mg também por via subcutânea a cada 2 semanas. Até o momento deste relato, ela realizou quatro aplicações, apresentando grande melhora da doença e da qualidade de vida. Não houve efeitos adversos, nem no local da injeção e nem de outro tipo. A paciente e sua família estão muito satisfeitas, e os médicos que a tratam avaliam que a terapia está sendo bem-sucedida. Este relato de caso subsidia o uso de dupilumabe no tratamento da dermatite atópica grave refratária ao uso de imunossupressores.

ABSTRACT Case report of a patient with severe atopic dermatitis who showed a good response to dupilumab. She had already used two immunosuppressive agents, cyclosporine A and mycophenolate mofetil, for the treatment of atopic dermatitis with no proper control of the disease. She had also been taking all measures to control severe cases of the disease: bath and environmental controls, topical potent corticosteroids and emollients. She presented constant pruritus and skin lesions, frequent skin infections e poor quality of life. She also developed depression due to her disease. Recently, dupilumab, a new biological agent, was approved for the treatment of moderate/severe atopic dermatitis in many countries, including Brazil. Dupilumab is a monoclonal antibody with a common alpha chain of interleukin (IL) 4 and IL-13 receptors, two cytokines involved in the Th2 profile immune response that promote atopic inflammation. In a pioneer way in Brazil, the patient initiated the treatment with an attack dose of 600mg subcutaneous of dupilumab and 300mg subcutaneous every other week. Up to now, she has taken four applications, presenting a great improvement of the disease and her quality of life. There were no adverse effects, nor in the injection site nor of other kind. Patient and her family are very satisfied, and the medical team evaluates that the treatment is being well succeed. The case report described here subsidizes the use of dupilumab in the treatment of severe atopic dermatitis refractory to use of immunosuppressive agents.

OBJECTIVE: To assess the incidence of intra-operative immediate hypersensitivity reactions and anaphylaxis. METHODS: A cross-sectional observational study was conducted at the Department of Anesthesiology, University of São Paulo School of Medicine, Hospital das Clínicas, São Paulo, Brazil, from January to December 2010. We developed a specific questionnaire to be completed by anesthesiologists. This tool included questions about hypersensitivity reactions during anesthesia and provided treatments. We included patients with clinical signs compatible with immediate hypersensitivity reactions. Hhypersensitivity reactions were categorized according to severity (grades I-V). American Society of Anesthesiologists physical status classification (ASA 1-6) was analyzed and associated with the severity of hypersensitivity reactions. RESULTS: In 2010, 21,464 surgeries were performed under general anesthesia. Anesthesiologists answered questionnaires on 5,414 procedures (25.2%). Sixty cases of intra-operative hypersensitivity reactions were reported. The majority patients (45, 75%) had hypersensitivity reactions grade I reactions (incidence of 27.9:10,000). Fifteen patients (25%) had grade II, III or IV reactions (intra-operative anaphylaxis) (incidence of 7:10,000). No patients had grade V reactions. Thirty patients (50%) were classified as ASA 1. The frequency of cardiovascular shock was higher in patients classified as ASA 3 than in patients classified as ASA 1 or ASA 2. Epinephrine was administered in 20% of patients with grade III hypersensitivity reactions and in 50% of patients with grade II hypersensitivity reactions. CONCLUSIONS: The majority of patients had hypersensitivity reactions grade I reactions; however, the incidence of intra-operative anaphylaxis was higher than that previously reported in the literature. Patients with ASA 3 had more severe anaphylaxis; however, the use of epinephrine was not prescribed in all of these cases. Allergists and anesthesiologists should implement preventive measures to reduce the occurrence of anaphylaxis.

OBJECTIVE: To assess the risk factors, incidence and severity of adverse drug reactions in in-patients. METHODS: This prospective study evaluated 472 patients treated at a teaching hospital in Brazil between 2010 and 2013 by five medical specialties: Internal Medicine, General Surgery, Geriatrics, Neurology, and Clinical Immunology and Allergy. The following variables were assessed: patient age, gender, comorbidities, family history of hypersensitivity, personal and family history of atopy, number of prescribed drugs before and during hospitalization, hospital diagnoses, days of hospitalization. The patients were visited every other day, and medical records were reviewed by the investigators to detect adverse drug reactions. RESULTS: There were a total of 94 adverse drug reactions in 75 patients. Most reactions were predictable and of moderate severity. The incidence of adverse drug reactions was 16.2%, and the incidence varied, according to the medical specialty; it was higher in Internal Medicine (30%). Antibiotics were the most commonly involved medication. Chronic renal failure, longer hospital stay, greater number of diagnoses and greater number of medications upon admission were risk factors. For each medication introduced during hospitalization, there was a 10% increase in the rate of adverse drug reaction. In the present study, the probability of observing an adverse drug reaction was 1 in 104 patients per day. CONCLUSIONS: Adverse drug reactions are frequent and potentially serious and should be better monitored in patients with chronic renal failure or prolonged hospitalization and especially in those on ‘polypharmacy’ regimens. The rational use of medications plays an important role in preventing adverse drug reactions.

Hereditary angioedema is an autosomal dominant disease characterized by recurrent angioedema attacks with the involvement of multiple organs. The disease is unknown to many health professionals and is therefore underdiagnosed. Patients who are not adequately diagnosed and treated have an estimated mortality rate ranging from 25% to 40% due to asphyxiation by laryngeal angioedema. Intestinal angioedema is another important and incapacitating presentation that may be the main or only manifestation during an attack. In this article, a group of experts from the “Associação Brasileira de Alergia e Imunologia (ASBAI)” and the “Grupo de Estudos Brasileiro em Angioedema Hereditário (GEBRAEH)” has updated the Brazilian guidelines for the diagnosis and treatment of hereditary angioedema.

Resumo A morfologia das aves é pouco relatada, o que dificulta a prática veterinária nestes animais. O seu sistema respiratório é diferenciado pela presença dos sacos aéreos, estrutura de fundamental importância para as aves, porém muito susceptível a doenças. Dessa forma, objetivou-se descrever a anatomia dos sacos aéreos (SA) em codornas em relação às suas relações topográficas. Para tanto, foram dissecadas quinze codornas que tiveram seu trato respiratório injetado com Neoprene látex corado e fixadas em solução de formol a 10%. O SA cervical é ímpar e possui uma porção mediana localizada entre as artérias braquiocefálicas. O SA clavicular também é ímpar e inicia-se próximo às primeiras vértebras torácicas. Os SA torácicos cranial e caudal estão lateralmente ao pulmão e medialmente às costelas. O SA torácico cranial dispõe-se da margem dorso-látero-cranial até a margem ventral do fígado e o SA torácico caudal, do quarto látero-caudal do fígado até o terço cranial do SA abdominal. O SA abdominal vai da base caudal do fígado até a região cloacal. Contudo, os sacos aéreos das codornas estudadas nesta pesquisa seguem um padrão topográfico, formando divertículos entre os órgãos adjacentes.

Abstract The morphology of birds is rarely reported, hindering veterinary practice in these animals. The respiratory system is distinguished by the presence of air bags, a structure of fundamental importance to the birds, but very susceptible to diseases. Thus, the objective of this study was to describe the anatomy of the air sacs (AS) in quails regarding their topographical relationships. To this, fifteen quails that had their respiratory tract injected with Neoprene, stained and fixed in formalin 10% latex were dissected. Cervical AS is unique and has a middle portion located between the brachiocephalic arteries. The clavicular AS is also odd and starts near the first thoracic vertebrae. The cranial and caudal thoracic AS are lateral to the lung and medially to the ribs. The cranial thoracic AS goes from the dorsal lateral-cranial margin to the ventral margin of the liver, and the caudal thoracic AS goes from the fourth lateral-caudal margin of the liver to the cranial third of the abdominal AS. Abdominal AS goes from the liver to the base of the vent area. However, the air sacs in quails studied in this research follow a topographic pattern, forming diverticula between adjacent organs.

Resumo A gestação é um estado fisiológico que exige adaptações imunológicas para que transcorra normalmente. Nesse período a mãe e o feto apresentam uma relação imunológica, ou seja, a interface materno fetal. A enzima indoleamina 2,3 dioxigenase (IDO) desempenha um papel importante na tolerância materno fetal, por ser responsável pela metabolização do triptofano, impedindo por diversas vias a proliferação principalmente de linfócitos TCD8. Diversos tipos celulares estão presentes na interface materno fetal e vários deles podem expressar a IDO. Os leucócitos com perfil Th1 produzem uma citocina conhecida: o interferon γ que estimula a expressão da IDO em vários tipos celulares. Os linfócitos são divididos em subpopulações de acordo com sua função e fenótipo. Seus tipos incluem linfócitos T, linfócitos B e as células natural killer (NK). Hormônios também atuam nesse processo a progesterona que exerce função determinante sobre a resposta imunológica materna podendo alterar o prognóstico gestacional e o estrógeno essencial para a tolerância materno fetal e manutenção da prenhez. Dessa maneira este trabalho tem por objetivo principal identificar os linfócitos presentes na placenta bovina em cultivo que expressam IDO (linfócitos T, linfócitos B e células NK), frente a estimulação por progesterona, estrógeno e interferon γ nas diversas fases gestacionais utilizando a citometria de fluxo. Segundo os resultados no período de 67,5 a 77, 5 dias com a adição de interferon γ a expressão da enzima IDO aumentou discretamente nos linfócitos TCD3, TCD4, e diferente dos linfócitos T CD8 apresentaram uma elevada expressão da enzima (4,48 ± 2,12 - 8,65± 4,91). No período de 92,5 a 172, 5 dias os linfócitos TCD4, TCD8 e TCD25 apresentaram uma diminuição da IDO. No período final de 195 a 222,5 dias, os linfócitos TCD3, TCD4 e os BCD25 aumentaram a expressão da IDO quando submetidos ao interferon γ, no entanto, os linfócitos T CD8 e as células NK não apresentaram alterações significativas. Com base nos resultados apresentados pode-se concluir que todos os tipos celulares foram capazes de expressar a IDO mediante a suplementação com interferon γ, sendo que o linfócito T CD8 apresentou uma diferença bastante significativa quanto ao aumento da IDO, já o estrógeno elevou a expressão da IDO somente nos linfócitos B (CD25) e a progesterona diminuiu a expressão da enzima nos linfócitos T (CD3 e CD4) e nas células NK. Estes resultados sugerem um mecanismo de regulação do sistema imunológico desempenhado pelos hormônios esteroides presentes durante o processo gestacional, particularmente pela modulação da expressão da IDO.

Abstract Pregnancy is a physiological state that requires immune adaptation in order to be successfully carried on. During this period, mother and fetus establish an immune tolerance status at the maternal fetal interface. Indoleamine 2,3-dioxygenase (IDO) plays an important role in maternal-fetal tolerance by metabolizing tryptophan, impairs by several pathways, mainly T CD8 cells proliferation. Several cell types are present in the maternal fetal interface and several of them can express IDO. Leucocytes with Th1 produce a cytokine known as interferon γ that stimulates the expression of IDO in several cell types. Lymphocytes are divided into sub-populations according to their function and phenotype: T lymphocytes, B lymphocytes and natural killer cells (NK). Hormones also involved in this process where progesterone exerts decisive role on maternal immune response that may change gestational outcome and estrogen is essential for fetal maternal tolerance and maintenance of pregnancy. Therefore, the main objective of this study was to identify lymphocytes in the bovine placental cell culture that are sensitive to progesterone, estrogen and interferon γ, IDO expression in various gestational stages using flow cytometry. According to the results in the gestational period from 67.5 to 77.5 days with the addition of interferon γ expression IDO was slightly increased in TCD3 lymphocytes, CD4, and differently from the other T cells CD8 displayed an higher expression of the enzyme (4.48±2.12 to 8.65±4.91). In the period from 92.5 to 172. 5 days the CD4 lymphocytes, CD8 and TCD25 showed a significant decrease of IDO expression (p<0.05). At the final stages between 195 and 222, 5 days TCD3 lymphocytes, CD4 and BCD25 increased expression when subjected to interferon γ supplementation; however, CD8 T cells and NK cells showed no significant changes. Based on the results presented we can conclude that all cell types were able to express IDO by supplementation with interferon γ, and that T CD8 lymphocyte showed an highly significant increase of IDO expression, whereas estrogen increased the expression of IDO only in B lymphocytes (CD25), and progesterone decreased enzyme expression in T lymphocytes (CD3 and CD4) and in NK cells. These results suggest a regulatory mechanism of the immunological system by steroidal hormones during gestation, particularly by modulating IDO expression.

RESUMO Objetivo Desenvolver um novo modelo experimental de doença pulmonar alérgica crônica por ácaro, com proeminente produção de imunoglobulina E (IgE) específica, infiltrado inflamatório eosinofílico nas vias aéreas e remodelamento, comparando duas vias diferentes de sensibilização. Métodos O protocolo teve duração de 30 dias. Camundongos BALB/c foram divididos em seis grupos submetidos à sensibilização por via subcutânea ou intraperitoneal com solução salina (controles negativos),Dermatophagoides pteronyssinus (Der p) 50 ou 500mcg, em três aplicações. Posteriormente, foram submetidos à provocação intranasal com Der p ou salina por 7 dias e sacrificados 24 horas após o último desafio. Avaliamos a titulação de IgE específica anti-Der p, densidade eosinofílica no espaço peribroncovascular e remodelamento das vias aéreas. Resultados Tanto os animais sensibilizados por via subcutânea como intraperitoneal produziram IgE específica anti-Der p. Ocorreu aumento da eosinofilia peribroncovascular apenas nos animais que receberam menor dose de Der p. Porém apenas o grupo sensibilizado com Der p 50mcg subcutânea apresentou remodelamento significativo das vias aéreas. Conclusão Neste modelo murino de asma, as duas vias de sensibilização levaram à produção de IgE específica e eosinofilia nas vias aéreas. No entanto, apenas a via subcutânea foi capaz de induzir ao remodelamento. Além disso, doses menores de Der p utilizadas foram superiores às mais elevadas, sugerindo tolerância. Mais estudos são necessários para avaliar a eficácia deste modelo no desenvolvimento da hiperresponsividade brônquica, mas ele pode ser replicado em experimentos para criação de novas estratégias terapêuticas medicamentosas ou imunoterápicas.

ABSTRACT Objective To develop a new experimental model of chronic allergic pulmonary disease induced by house dust mite, with marked production of specific immunoglobulin E (IgE), eosinophilic inflammatory infiltrate in the airways and remodeling, comparing two different routes of sensitization. Methods The protocol lasted 30 days. BALB/c mice were divided into six groups and were sensitized subcutaneously or intraperitoneally with saline (negative control), Dermatophagoides pteronyssinus (Der p) 50 or 500mcg in three injections. Subsequently they underwent intranasal challenge with Der p or saline for 7 days and were sacrificed 24 hours after the last challenge. We evaluated the titration of specific IgE anti-Der p, eosinophilic density in peribronchovascular space and airway remodeling. Results Both animals sensitized intraperitoneally and subcutaneously produced specific IgE anti-Der p. Peribronchovascular eosinophilia increased only in mice receiving lower doses of Der p. However, only the group sensitized with Der p 50mcg through subcutaneously route showed significant airway remodeling. Conclusion In this murine model of asthma, both pathways of sensitization led to the production of specific IgE and eosinophilia in the airways. However, only the subcutaneously route was able to induce remodeling. Furthermore, lower doses of Der p used in sensitization were better than higher ones, suggesting immune tolerance. Further studies are required to evaluate the efficacy of this model in the development of bronchial hyperresponsiveness, but it can already be replicated in experiments to create new therapeutic drugs or immunotherapeutic strategies.