<p>Osobe kojima su transplantirani organi imaju povećan rizik pojave malignih oboljenja, među kojima dominiraju maligni tumori kože. Smatra se da je osnovni razlog primena imunosupresivne terapije, ali jo&scaron; nije sasvim jasan mehanizam i nivo dejstva različitih imunosupresiva. Važan uticaj na nastanak većine malignih tumora kože ima ultraljubičasto (UV) zračenje koje izaziva pojačano starenje kože u vidu histolo&scaron;ki prepoznatljivog fotoo&scaron;tećenja, sa odlikama razvoja elastoze i limfocitne infiltracije. U na&scaron;oj zemlji do sada nisu sprovođena istraživanja rizika pojave maligniteta kože kod transplantiranih pacijenata, ne postoje podaci o njihovoj incidenci, uticaju imunosupresivne terapije i drugim potencijalnim faktorima rizika. U dostupnoj literaturi nema objavljenih radova iz oblasti analize histolo&scaron;kog fotoo&scaron;tećenja kože kod osoba na imunosupresivnoj terapiji. Ciljevi ove studije preseka bili su utvrđivanje učestalosti, vrste i lokalizacije premalignih i malignih lezija kože kod pacijenata nakon transplantacije bubrega, povezanosti njihove pojave sa dužinom, vrstom i režimom primene imunosupresivne terapije i sa histolo&scaron;ki verifikovanim fotoo&scaron;tećenjem perilezionalne kože. U studiju je uključeno 66 pacijenata kojima je transplantiran bubreg (primaoci organskog transplantata &ndash; POT). Relevantni podaci su prikupljeni putem upitnika i iz medicinske dokumentacije, kliničko-dermoskopskim pregledom kože uočene suspektne lezije su bioptirane u cilju postavljanja dijagnoze i utvrđivanja histolo&scaron;kih parametara fotoo&scaron;tećenja, a u studiju su uključeni i maligni tumori kože POT ispitanika uklonjeni u periodu od prethodnih 5 godina ali nakon transplantacije. Radi komparacije prisutnih faktora rizika i stepena fotoo&scaron;tećenja kože sa op&scaron;tom populacijom formirana je kontrolna grupa (KG) ispitanika kojima je prethodno bioptirana koža, bez oboljenja bubrega i bez imunosupresije, slična po polu i životnoj dobi sa onim POT ispitanicima kojima je urađena biopsija. Za svaku leziju iz POT grupe obezbeđene su po 2 lezije iz KG, tako da je pojedinim ispitanicima POT grupe analizirano vi&scaron;e lezija, dok je u KG 1 ispitanik &ndash; 1 lezija. Osnovno oboljenje bubrega do započinjanja dijalize kod ispitanika POT grupe prosečno je trajalo 7,67 godina, u strukturi oboljenja bubrega dominirao je hronični glomerulonefritis sa 31,8%, a ispitanici su na dijalizi bili prosečno 4,54 godine. Prosečna životna dob ispitanika u momentu transplantacije iznosila je 42,5 godina, 60,6% imalo je isključivo kadaveričnu transplantaciju, a prosečno trajanje jatrogene imunosupresije iznosilo je 4,89 god. U POT grupi bioptirane su 33 lezije, među kojima su od značaja za studiju bile 2 (6,1%) aktinične keratoze (AK), 3 (9,1%) displastična nevusa (DN), 1 (3,0%) melanom (MM), 3 (9,1%) skvamocelularna karcinoma (SCK) i 6 (18,2%) bazocelularnih karcinoma (BCK). U POT grupi učestalost MM bila je 1,5%, učestalost SCK 4,5%, učestalost BCK 9,1%, dok je utvrđeni relativan rizik pojave MM u POT populaciji 227 puta veći, BCK 316 puta veći, a SCK 805 puta veći nego u op&scaron;toj populaciji. Relativan rizik nastanka AK i DN nije određen zbog izostanka zvanične registracije u op&scaron;toj populaciji. POT grupa i KG nisu se statistički značajno razlikovale po Ficpatrikovom fototipu kože, profesionalnoj izloženosti UV zračenju, upotrebi solarijuma, broju solarnih opekotina, ličnoj anamnezi malignih tumora kože i konzumiranju cigareta. Pripadnici KG su se značajno vi&scaron;e rekreativno izlagali UV zračenju, če&scaron;će koristili sredstva za za&scaron;titu od sunčevog zračenja, če&scaron;će imali bliske srodnike sa malignim tumorima kože, če&scaron;će konzumirali alkohol, značajno veći broj ispitanika KG imao je pregled kompletne kože i informaciju o merama prevencije od strane lekara, dok 50% ispitanika POT grupe nije znalo da su pod povećanim rizikom pojave maligniteta kože. U stepenu elastoze među grupama nije postojala statistički značajna razlika, dok je limfocitna infiltracija bila marginalno izrazitija u POT grupi bez obzira na vrstu lezije. U POT grupi utvrđena je statistički značajna povezanost prisustva malignog tumora sa većim stepenom perilezionalne limfocitne infiltracije i elastoze. U KG utvrđena je statistički značajna povezanost prisustva malignog tumora sa većim stepenom limfocitne infiltracije, dok nije bilo statistički značajne razlike u stepenu perilezionalne elastoze. U studiji je utvrđeno da osobe nakon transplantacije bubrega imaju statistički značajno veći rizik nastanka BCK, SCK i MM kože u odnosu na op&scaron;tu populaciju, sa najče&scaron;ćom lokalizacijom ovih tumora u predelu glave. Dužina primene imunosupresivne terapije uop&scaron;teno nije statistički značajno uticala na pojavu premalignih i malignih tumora kože, ali je kumulativna doza pojedinih imunosupresiva poput ciklosporina i azatioprina imala statistički značajan uticaj na pojavu premalignih i malignih lezija kože. Dužina imunosupresije je statistički značajno uticala na stepen elastoze, ali je imala marginalan uticaj na stepen perilezionalne limfocitne infiltracije.</p> / <p>Organ transplant recipients are at an increased risk of developing malignancies, with the predominance of malignant skin tumors. The main cause is considered to be the administration of immunosuppressive therapy, but the mechanism and effect levels of different immunosuppressive agents are still not completely clear. Ultraviolet (UV) rays also influence the development of malignant skin tumors, causing increased skin aging with histologically recognisable photo damage, with its hallmark being development of elastosis and lymphocytic infiltration. No research on the topic of risks of malignant skin tumors in transplant patients has been done in our country, there is no data on their incidence, or on the effects of immunosuppressive agents and other potential risk factors. There are also no published studies in the field of hystological photo damage analysis in patients on immunosuppressive therapy. The aims of this study were to establish the rates of occurance, types and localisation of premalignant and malignant skin lesions in kidney transplant recipients (KTR) and to associate their advent with the length, type and regimen of immunosuppressive therapy. A total of 66 KTR patients were enrolled in the study. Relevant information was gathered through a specially constructed questionnaire and from the medical records, followed by combined clinical and dermoscopic skin examination to detect suspicious lesions which were biopsied in order to determine the histopathologic diagnosis of the lesion and perilesional degree of photo damage. The study also encompassed malignant skin tumors of KTR patients that have been removed in the last 5 years, but after the transplantation. For the sake of comparison of the risk factors and the levels of photo damage with the general population, an age and sex - matched control group (CG) of patients with previous skin biopsy but without kidney disease and immunosuppression was formed. For each lesion from KTR group, 2 lesions from CG were provided, meaning that some KTR patients had several lesions analysed, whereas in the CG only 1 lesion per patient was analyzed. The average duration of underlying kidney diseases in KTR was 7,67 years, the most frequent being chronic glomerulonephritis (31,8%), and an average duration of dialysis was 4,54 years. The mean age at transplantation was 42,5 years, with 60,6% of the KTR having exclusively cadaveric graft. The mean duration of the iatrogenic immunosuppression was 4,89 years. In the KTR group a total of 33 lesions were biopsied, 2 of which were actinic keratoses (AK) (6,1%), 3 were dysplastic nevi (DN) (9,1%), 1 melanoma (MM) (3,0%), 3 squamous cell carcinomas (SCC) (9,1%) and 6 basal cell carcinomas (BCC) (18,2%). The estimated frequency of MM was 1,5%, SCC 4,5%, BCC 9,1%, and the estimated relative risk of MM in KTR being 227, BCC 316, and SCC 805 times higher compared to the general population. The relative risk of AK and DN development could not have been estimated as there are no official records in the general population. The KTR and CG were not significantly different judging by the Fitzpatrick skin phototype, occupational UV exposure, sunbed usage, personal history of skin cancers, or smoking. The controls were recreationally more exposed to UV rays, used sun protective measures more frequently, had more relatives with skin cancers and consumed alcohol more frequently. A significantly greater number of controls had had complete skin examination and protective measures counceling by the doctor, while 50% of KTR patients did not even know that they were at an increased risk of malignant skin tumor development. There was no significant difference in elastosis levels among the groups, whereas the lymphocitic infiltration was only marginally greater in the KTR group. A significant association between the level of perilesional photodamage and developement of malignant tumors was estimated for the KTR group, whereas in the CG only the perilesional lymphocitic infiltration was strongly associated to malignant lesions. The study results suggest that KTR patients have a significantly higher risk of BCC, SCC and MM development in comparison with the general population, the most common localisation being in the head region. The duration of the immunosuppressive therapy had no significant effect on the premalignant and malignant tumors development, whereas the cummulative dose of certain immunosuppressives (such as cyclosporine and azathioprine) affected the development notably. The duration of immunosuppression statistically influenced the elastosis levels, but had only a marginal influence on the perilesional lymphocitic infiltration levels.</p>

Objetivo: Uma série de casos sugerindo uma possível associação de pancreatite aguda (PA) e síndrome de ativação macrofágica (SAM) em lúpus eritematoso sistêmico pediátrico (LESP) foi reportada em dez crianças no nosso serviço, no entanto, não existem dados relativos à comparação entre PA e SAM em grandes populações de LESP e LES adulto (LESA). Métodos: Este estudo incluiu 362 pacientes LESP e 1.830 pacientes LESA. SAM foi diagnosticada de acordo com os critérios diagnósticos preliminares e PA de acordo com a presença de dor abdominal e/ou vômitos associados a um aumento de enzimas pancreáticas e/ou alterações radiológicas pancreáticas nos exames de ultrassonografia e/ou tomografia abdominal. Dados demográficos, características clínicas, SLEDAI-2K, SLICC/ACR-DI e tratamento foram avaliados. Resultados: A frequência de PA foi significantemente aumentada no LESP em comparação ao LESA [12/362 (3,3%) vs. 20/1830 (1,1%), p=0,003], com similar duração da PA nos dois grupos [22 (6-60) vs. 15 (4-90), dias, p=0,534]. As frequências de SAM (85% vs 30%, p=0,003) e óbito (31% vs. 0%; p=0,017) foram significantemente elevadas em crianças com PA comparadas com adultos com PA. Na análise dos pacientes com PA e SAM em comparação com os com somente PA sem SAM demonstrou que a idade dos pacientes com PA e SAM foi significantemente menor em comparação com aqueles sem SAM [15 (8,8- 55) vs. 33,5 (10,2-45,7) anos, p=0,007]. As frequências de febre (94% vs. 37%, p=0,001), leucopenia (82% vs. 19%, p=0,0001), trombocitopenia (65% vs. 19%, p=0,013), hipertrigliceridemia (87% vs. 42%, p=0,037) e hiperferritinemia (93% vs. 37%, p=0,011) foram significantemente aumentadas nos pacientes com PA e SAM comparados aos pacientes com somente PA. A concomitância de febre e hiperferritinemia foi significantemente mais freqüente no primeiro grupo (86% vs. 12%, p=0,0015). Conclusões: Este estudo forneceu novos dados que evidenciaram que SAM ocorreu na maioria dos LESP com PA com uma maior mortalidade em comparação com LESA. Além disso, foram identificados em pacientes com PA e SAM, um conjunto de parâmetros clínicos e laboratoriais associado com as duas complicações / Objective: We previously reported a case series of acute pancreatitis (AP) and macrophage activation syndrome (MAS) in childhood (cSLE) patients, however there are no data regarding the comparison of AP and MAS in large populations of cSLE and adult SLE (aSLE). Methods: This study included 362 cSLE and 1,830 aSLE patients. MAS was diagnosed according to preliminary diagnostic guidelines and AP according to the presence of abdominal pain or vomiting associated to an increase of pancreatic enzymes and/or pancreatic radiological abnormalities. Demographic data, clinical features, SLEDAI-2K, SLICC/ACR-DI and treatment were assessed. Results: Higher and significant frequency of AP in cSLE compared to aSLE patients [12/362(3.3%) vs. 20/1830(1.1%), p=0.003], with similar AP duration [22(6- 60) vs. 15(4-90) days, p=0.534]. MAS (85% vs. 30%, p=0.003) and death by MAS complication (31% vs. 0%, p=0.017) were significantly higher in children with AP compared with aSLE with AP. Further analysis of patients with AP and MAS compared with AP without MAS demonstrated that age in MAS patients was significantly lower compared with those without this complication [15(8.8-55) vs. 33.5(10.2-45.7) years, p=0.007]. The frequencies of fever (94% vs. 37%,p=0.001), leucopenia (82% vs. 19%,p=0.0001), thrombocytopenia (65% vs. 19%,p=0.013), hypertriglyceridemia (87% vs. 42%,p=0.037) and hyperferritinemia (93% vs. 37%,p=0.011) were also more frequently observed in AP patients with MAS compared in AP patients without MAS. Fever and hyperferritinemia concomitantly were more frequent in the former group (86% vs. 12%, p=0.0015). Conclusions: This study provides novel data demonstrating that MAS occur in the majority of cSLE with AP with a higher mortality compared to aSLE. In addition, we identified in AP patients, a cluster of MAS clinical and laboratorial parameters more associated with this complication

Cytomegalovirus (CMV) is a ubiquitous pathogen affecting over 95% of the world’s population. While infection is typically asymptomatic in healthy individuals, the virus persists life-long in its host and can be reactivated following withdrawal of immune control. As such, it remains a serious clinical concern in individuals who are immunocompromised, such as newborns and neonates, transplant and/or chemotherapy recipients, and HIV/AIDS patients. CMV also has the ability to cause immunosuppression, the mechanisms of which include defective antigen presentation to T cells and interference with haematopoiesis in the bone marrow (BM). Due to strict species specificity, murine CMV (MCMV) provides a relevant model for the study of CMV modulation of the immune system in vivo in its natural host. The type I interferons (IFNs) represent a major family of cytokines involved in the early response to MCMV infection. Their anti-viral activity and regulation of NK cell activation and cytotoxicity are of significant interest in the context of MCMV infection, as genetic resistance to MCMV is mediated by the ability of Ly49H+ NK cells to directly recognise and lyse infected cells. Chapter 2 comprises an analysis of acute MCMV infection in the absence of type I IFN activity. These studies were conducted in IFNAR1 and IFNAR2 deficient mice, which lack components of the type I IFN receptor. Data obtained from these studies confirmed the essential requirement for type I IFN in controlling viral titres, promoting expansion of splenic Ly49H+ NK cells, and inducing early activation of NK cell cytotoxicity. In addition, our data depicted an accumulation of infected myeloid cells in the absence of effective NK cell-mediated control. This was paralleled by a significant increase in the level of serum TNF-a and IFN-¿, an effect which in some cases has been linked to serious pathological disease. Thus, the data described in this chapter provide an insight into the consequences arising from delayed NK cell responses to MCMV infection in the absence of type I IFN. vii Type I IFN can also potentially affect BM haematopoiesis. BM atrophy and impairment of myelopoiesis are serious consequences of CMV infection. During acute MCMV infection we consistently observed a profound loss of splenic dendritic cells (DCs) in BALB/c mice. Since all DC subsets are derived from BM haematopoietic progenitor cells, the possibility that MCMV might interfere with BM haematopoiesis and DC differentiation was explored. Chapters 3 and 4 describe the impact of acute MCMV infection on BM progenitors, with particular emphasis on the differentiation capabilities of these cells in ex vivo culture systems. Chapter 3 focuses on the effect of MCMV infection on BM cellularity and frequency of specific BM progenitor populations. A thorough analysis of contributing factors, such as viral infection of BM cells, involvement of type I and II IFNs, progenitor cell trafficking and NK cell activity in the BM compartment, was conducted. Our results showed that a severe loss of BM cellularity occurs in MCMV-infected mice. Furthermore, when BM cells from MCMV-infected mice were cultured ex vivo in granulocyte macrophage-colony stimulating factor (GM-CSF), there was an impairment in their ability to differentiate into DCs.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2006. / Härtill 4 uppsatser.

Objetivo: Uma série de casos sugerindo uma possível associação de pancreatite aguda (PA) e síndrome de ativação macrofágica (SAM) em lúpus eritematoso sistêmico pediátrico (LESP) foi reportada em dez crianças no nosso serviço, no entanto, não existem dados relativos à comparação entre PA e SAM em grandes populações de LESP e LES adulto (LESA). Métodos: Este estudo incluiu 362 pacientes LESP e 1.830 pacientes LESA. SAM foi diagnosticada de acordo com os critérios diagnósticos preliminares e PA de acordo com a presença de dor abdominal e/ou vômitos associados a um aumento de enzimas pancreáticas e/ou alterações radiológicas pancreáticas nos exames de ultrassonografia e/ou tomografia abdominal. Dados demográficos, características clínicas, SLEDAI-2K, SLICC/ACR-DI e tratamento foram avaliados. Resultados: A frequência de PA foi significantemente aumentada no LESP em comparação ao LESA [12/362 (3,3%) vs. 20/1830 (1,1%), p=0,003], com similar duração da PA nos dois grupos [22 (6-60) vs. 15 (4-90), dias, p=0,534]. As frequências de SAM (85% vs 30%, p=0,003) e óbito (31% vs. 0%; p=0,017) foram significantemente elevadas em crianças com PA comparadas com adultos com PA. Na análise dos pacientes com PA e SAM em comparação com os com somente PA sem SAM demonstrou que a idade dos pacientes com PA e SAM foi significantemente menor em comparação com aqueles sem SAM [15 (8,8- 55) vs. 33,5 (10,2-45,7) anos, p=0,007]. As frequências de febre (94% vs. 37%, p=0,001), leucopenia (82% vs. 19%, p=0,0001), trombocitopenia (65% vs. 19%, p=0,013), hipertrigliceridemia (87% vs. 42%, p=0,037) e hiperferritinemia (93% vs. 37%, p=0,011) foram significantemente aumentadas nos pacientes com PA e SAM comparados aos pacientes com somente PA. A concomitância de febre e hiperferritinemia foi significantemente mais freqüente no primeiro grupo (86% vs. 12%, p=0,0015). Conclusões: Este estudo forneceu novos dados que evidenciaram que SAM ocorreu na maioria dos LESP com PA com uma maior mortalidade em comparação com LESA. Além disso, foram identificados em pacientes com PA e SAM, um conjunto de parâmetros clínicos e laboratoriais associado com as duas complicações / Objective: We previously reported a case series of acute pancreatitis (AP) and macrophage activation syndrome (MAS) in childhood (cSLE) patients, however there are no data regarding the comparison of AP and MAS in large populations of cSLE and adult SLE (aSLE). Methods: This study included 362 cSLE and 1,830 aSLE patients. MAS was diagnosed according to preliminary diagnostic guidelines and AP according to the presence of abdominal pain or vomiting associated to an increase of pancreatic enzymes and/or pancreatic radiological abnormalities. Demographic data, clinical features, SLEDAI-2K, SLICC/ACR-DI and treatment were assessed. Results: Higher and significant frequency of AP in cSLE compared to aSLE patients [12/362(3.3%) vs. 20/1830(1.1%), p=0.003], with similar AP duration [22(6- 60) vs. 15(4-90) days, p=0.534]. MAS (85% vs. 30%, p=0.003) and death by MAS complication (31% vs. 0%, p=0.017) were significantly higher in children with AP compared with aSLE with AP. Further analysis of patients with AP and MAS compared with AP without MAS demonstrated that age in MAS patients was significantly lower compared with those without this complication [15(8.8-55) vs. 33.5(10.2-45.7) years, p=0.007]. The frequencies of fever (94% vs. 37%,p=0.001), leucopenia (82% vs. 19%,p=0.0001), thrombocytopenia (65% vs. 19%,p=0.013), hypertriglyceridemia (87% vs. 42%,p=0.037) and hyperferritinemia (93% vs. 37%,p=0.011) were also more frequently observed in AP patients with MAS compared in AP patients without MAS. Fever and hyperferritinemia concomitantly were more frequent in the former group (86% vs. 12%, p=0.0015). Conclusions: This study provides novel data demonstrating that MAS occur in the majority of cSLE with AP with a higher mortality compared to aSLE. In addition, we identified in AP patients, a cluster of MAS clinical and laboratorial parameters more associated with this complication

As infecções são a causa mais freqüente de morbidade e mortalidade observadas tanto aguda como tardiamente nos pacientes receptores de transplante pulmonar, o que pode estar diretamente relacionado a uma deficiência no transporte mucociliar do sistema respiratório. Nosso objetivo foi avaliar a influência de dois fatores envolvidos com o transplante pulmonar sobre o transporte mucociliar de ratos: a secção e anastomose brônquica e a imunossupressão pela ciclosporina A. Setenta e dois ratos foram distribuídos aleatoriamente em cinco grupos de acordo com: i) procedimento operatório e ii) terapia a que seriam submetidos. Os resultados mostram que houve uma diminuição significativa da Freqüência de Batimento Ciliar in situ, da Transportabilidade do Muco in vitro e da Velocidade de Transporte Mucociliar in situ medidos a partir do brônquio principal esquerdo dos ratos tratados com ciclosporina A (p<0,001). A Freqüência de Batimento Ciliar in situ dos brônquios operados mostrou-se diminuída também no grupo tratado com solução salina e sacrificado no 30º dia após a operação (p=0,001). Já a Velocidade de Transporte Mucociliar in situ mostrou uma diminuição significativa em todos os grupos submetidos à secção brônquica (p<0,001). Houve um efeito sinérgico entre a terapia com ciclosporina A e a secção brônquica, causando um prejuízo ao transporte mucociliar ainda maior do que quando analisados isoladamente. Concluímos que a Velocidade de Transporte Mucociliar in situ foi agudamente prejudicada após a secção brônquica e terapia imunossupressora pela ciclosporina A, havendo diminuição da freqüência de batimento dos cílios e alteração das propriedades viscoelásticas do muco respiratório. / Infections are the most common cause of early and late morbidity and mortality in lung transplant recipient, and can be directly related to impaired mucociliary transport. Our aim was to assess the influence of bronchial section and imunossupression on mucociliary transport in rats. Seventy two rats were randomly distributed in five groups according to i) surgical procedure and ii) drug therapy. There was a significant impairment on Ciliary Beating Frequency in situ, Mucus Transportability Rate in vitro and Mucociliary Transport Speed in situ from operated bronchus of cyclosporine A-treated rats (p<0.001). Ciliary Beating Frequency from operated bronchus was also impaired in saline-treated rats that were killed on 30th postoperative day (p=0.001). Mucociliary Transport Speed was impaired in all bronchi underwent to section (p<0.001). We conclude that bronchial section and cyclosporine therapy impaired all factors analyzed. Also there was a synergic effect between cyclosporine therapy and bronchial section on ciliary beating frequency.

Indiana University-Purdue University Indianapolis (IUPUI) / Platelet-activating Factor (PAF) stimulates various cell types by the activation of the G-protein coupled PAF-receptor (PAFR). Systemic PAFR activation induces an acute pro-inflammatory response, as well as delayed systemic immunosuppressive effects in vivo. De novo enzymatic PAF synthesis and degradation are closely regulated, but oxidative stressors, such as UVB, and cigarette smoke, can generate PAF-like species via the oxidation of membrane lipids in an unregulated process. Mast cells (MCs) and the PAFR have been shown to be necessary to mediate the resulting systemic immune suppression from oxidative stressors. The work herein implicates pro-oxidative chemotherapeutics, such as melphalan and etoposide, in mediating augmentation in tumor growth by inducing the generation of PAFR agonists via the oxidation of membrane lipids. This work also demonstrates the role of MCs and MC-released mediators in PAFR systemic immunosuppression. Through a contact hypersensitivity (CHS) model, the MC PAFR was found to be necessary and sufficient for PAF to mediate systemic immunosuppression. Additionally, activation of the MC PAFR seems to induce MC histamine and prostaglandin E2 release. Furthermore, by transplanting histamine- or COX-2-deficient MCs into MC-deficient mice, MC-derived histamine and prostaglandin release were found to be necessary for PAF to induce systemic immunosuppression. Lastly, we have evidence to suggest that prostaglandin release modulates MC migration to draining lymph nodes, a process necessary to promote immunosuppression. These studies fit with the hypothesis that MC PAFR activation mediates PAFR systemic immunosuppression in part by histamine and prostaglandin release.

Introdução: Uma imunossupressão eficaz é fundamental para a sobrevivência do paciente após o transplante de pulmão. Estudos prévios demonstraram que drogas imunossupressoras como ciclosporina A, tacrolimo, micofenolato de sódio e prednisona prejudicaram a depuração das vias aéreas de ratos. Para prevenir a rejeição aguda, o basiliximab tem sido utilizado como terapia de indução previamente ao transplante de pulmão em muitos centros ao redor do mundo. Entretanto, existem poucos trabalhos reportando seus efeitos adversos. Objetivo: Avaliar se o basiliximab isolado e em conjunto com a terapia tríplice (tacrolimo, micofenolato de sódio e prednisona) causa efeitos adversos no aparelho mucociliar traqueobrônquico, alterando a depuração mucociliar das vias aéreas de ratos. Método: Oitenta ratos foram distribuídos em quatro grupos conforme o tratamento: Controle, Basiliximab, Tríplice e Basiliximab+Tríplice; e dois subgrupos de acordo com o tempo de tratamento: 7 e 15 dias. Após o período de tratamento, os animais foram eutanasiados e as seguintes análises foram realizadas: análise do lavado broncoalveolar, frequência de batimento ciliar (FBC), velocidade de transporte mucociliar (VTMC), transportabilidade do muco in vitro, histologia, expressão do gene Muc5ac, concentração da proteína mucina do gene Muc5ac e avaliação de apoptose celular no epitélio das vias aéreas. Resultados: Não houve alteração do número de leucócitos no lavado broncoalveolar e da FBC entre os grupos. Já a VTMC foi menor nos grupos Basiliximab e Basiliximab+Tríplice tratados por 7 dias, enquanto nos animais tratados por 15 dias a velocidade foi menor nos grupos Trípice e Basiliximab+Tríplice. O transporte do muco in vitro foi menor no grupo Basiliximab+Tríplice tratado por 15 dias. A porcentagem dos mucos ácido e neutro não foi diferente entre os grupos tratados por 7 e 15 dias, o mesmo ocorreu para a expressão e concentração da proteína mucina do gene Muc5ac. Os grupos Tríplice e Basiliximab+Tríplice tratados por 7 e 15 dias, respectivamente, apresentaram número maior de células apoptóticas no epitélio da via aérea. Conclusão: A droga basiliximab, isolada e em conjunto com a terapia tríplice, prejudicou o aparelho mucociliar traqueobrônquico de ratos, especificamente a depuração mucociliar / Introduction: Optimal immunosuppression is critical to the survival of the patient after lung transplantation. Previous studies showed that immunosuppressive drugs such as cyclosporine, tacrolimus, sodium mycophenolate and prednisone impaired mucociliary clearance of rats. To prevent acute rejection, basiliximab has been used as induction therapy before lung transplantation in many centers around the world. However, there are few studies reporting its side effects. Objective: Evaluate if basiliximab alone and in combination with triple therapy (tacrolimus, sodium mycophenolate and prednisone) causes adverse effects on the tracheobronchial mucociliary apparatus by impairing airways mucociliary clearance of rats. Method: Eighty rats were divided into four groups according to treatment: Control, Basiliximab, Triple and Basiliximab+Triple; and according to the treatment time: 7 and 15 days. After the treatment period, the animals were euthanized and the following analyzes were performed: bronchoalveolar lavage, ciliary beating frequency (CBF), mucociliary transport velocity (MCTV), mucus transportability rate in vitro, hystology, Muc5ac gene expression, concentration of the mucin protein of the Muc5ac gene and evaluation of cellular apoptosis in the airway epithelium. Results: There was no alteration in the number of leukocytes in the bronchoalveolar lavage fluid and the CBF between groups. The MCTV was lower in the Basiliximab and Basiliximab+Triple groups treated for 7 days, while the velocity was lower in the Triple and Basiliximab+Triple groups treated for 15 days. The mucus transportability rate in vitro was lower in the Basiliximab+Triple group treated for 15 days. There was no difference in percentage of both acidic mucus and neutral mucus between groups treated for 7 and 15 days. Also, there was no difference in the expression and concentration of the mucin of the Muc5ac gene. The Triple and Basiliximab+Triple groups treated for 7 and 15 days, respectively, had a higher number of apoptotic cells in the airway epithelium. Conclusion: The basiliximab, alone and in conjunction with triple therapy, impaired the tracheobronchial mucociliary apparatus of rats, specifically the mucociliary clearance

Introdução: Uma imunossupressão eficaz é fundamental para a sobrevivência do paciente após o transplante de pulmão. Estudos prévios demonstraram que drogas imunossupressoras como ciclosporina A, tacrolimo, micofenolato de sódio e prednisona prejudicaram a depuração das vias aéreas de ratos. Para prevenir a rejeição aguda, o basiliximab tem sido utilizado como terapia de indução previamente ao transplante de pulmão em muitos centros ao redor do mundo. Entretanto, existem poucos trabalhos reportando seus efeitos adversos. Objetivo: Avaliar se o basiliximab isolado e em conjunto com a terapia tríplice (tacrolimo, micofenolato de sódio e prednisona) causa efeitos adversos no aparelho mucociliar traqueobrônquico, alterando a depuração mucociliar das vias aéreas de ratos. Método: Oitenta ratos foram distribuídos em quatro grupos conforme o tratamento: Controle, Basiliximab, Tríplice e Basiliximab+Tríplice; e dois subgrupos de acordo com o tempo de tratamento: 7 e 15 dias. Após o período de tratamento, os animais foram eutanasiados e as seguintes análises foram realizadas: análise do lavado broncoalveolar, frequência de batimento ciliar (FBC), velocidade de transporte mucociliar (VTMC), transportabilidade do muco in vitro, histologia, expressão do gene Muc5ac, concentração da proteína mucina do gene Muc5ac e avaliação de apoptose celular no epitélio das vias aéreas. Resultados: Não houve alteração do número de leucócitos no lavado broncoalveolar e da FBC entre os grupos. Já a VTMC foi menor nos grupos Basiliximab e Basiliximab+Tríplice tratados por 7 dias, enquanto nos animais tratados por 15 dias a velocidade foi menor nos grupos Trípice e Basiliximab+Tríplice. O transporte do muco in vitro foi menor no grupo Basiliximab+Tríplice tratado por 15 dias. A porcentagem dos mucos ácido e neutro não foi diferente entre os grupos tratados por 7 e 15 dias, o mesmo ocorreu para a expressão e concentração da proteína mucina do gene Muc5ac. Os grupos Tríplice e Basiliximab+Tríplice tratados por 7 e 15 dias, respectivamente, apresentaram número maior de células apoptóticas no epitélio da via aérea. Conclusão: A droga basiliximab, isolada e em conjunto com a terapia tríplice, prejudicou o aparelho mucociliar traqueobrônquico de ratos, especificamente a depuração mucociliar / Introduction: Optimal immunosuppression is critical to the survival of the patient after lung transplantation. Previous studies showed that immunosuppressive drugs such as cyclosporine, tacrolimus, sodium mycophenolate and prednisone impaired mucociliary clearance of rats. To prevent acute rejection, basiliximab has been used as induction therapy before lung transplantation in many centers around the world. However, there are few studies reporting its side effects. Objective: Evaluate if basiliximab alone and in combination with triple therapy (tacrolimus, sodium mycophenolate and prednisone) causes adverse effects on the tracheobronchial mucociliary apparatus by impairing airways mucociliary clearance of rats. Method: Eighty rats were divided into four groups according to treatment: Control, Basiliximab, Triple and Basiliximab+Triple; and according to the treatment time: 7 and 15 days. After the treatment period, the animals were euthanized and the following analyzes were performed: bronchoalveolar lavage, ciliary beating frequency (CBF), mucociliary transport velocity (MCTV), mucus transportability rate in vitro, hystology, Muc5ac gene expression, concentration of the mucin protein of the Muc5ac gene and evaluation of cellular apoptosis in the airway epithelium. Results: There was no alteration in the number of leukocytes in the bronchoalveolar lavage fluid and the CBF between groups. The MCTV was lower in the Basiliximab and Basiliximab+Triple groups treated for 7 days, while the velocity was lower in the Triple and Basiliximab+Triple groups treated for 15 days. The mucus transportability rate in vitro was lower in the Basiliximab+Triple group treated for 15 days. There was no difference in percentage of both acidic mucus and neutral mucus between groups treated for 7 and 15 days. Also, there was no difference in the expression and concentration of the mucin of the Muc5ac gene. The Triple and Basiliximab+Triple groups treated for 7 and 15 days, respectively, had a higher number of apoptotic cells in the airway epithelium. Conclusion: The basiliximab, alone and in conjunction with triple therapy, impaired the tracheobronchial mucociliary apparatus of rats, specifically the mucociliary clearance

Indiana University-Purdue University Indianapolis (IUPUI) / Graft-versus-host disease (GVHD) remains the major complication after allogeneic hematopoietic stem cell transplantation (HSCT), resulting from immunological attack on target organs such as gastrointestinal (GI) tract, liver and skin from donor allogeneic T cells. The most common treatment for GVHD is immunosuppressive drugs such as corticosteroids, which may result in many side effects including the loss of the beneficial graft-versus-leukemia (GVL) effect and increased infection rates. However, GVHD-specific drugs have yet to be implemented. Here we show that by targeting on a novel pathogenic CD4+ T cell subpopulation that our lab previously found in patients with GI GVHD, we can develop new avenues to treat GVHD. This novel population is characterized as CD146+CCR5+ T cells, co-expressing IL-17A and IFN-γ. We found that the inducible T-cell costimulator (ICOS), which has been reported to be important for human Th17 differentiation in vitro, is critical for the development of this nonconventional T Helper 1 (Th1*)-polarized CD146+CCR5+ conventional T cells (Tconvs) population. Furthermore, we found that ICOS can induce the generation of Th1*-polarized CD146+CCR5+ regulatory T cells (Tregs) population, lowering the frequencies of phenotypic markers of functional Tregs. Our data also showed that inhibiting the major transcriptional factor of Th17, RAR-related orphan receptor gamma t (RORγt), could prevent the development of CD146+CCR5+ Tconvs in vitro. Our results demonstrate how pathogenic CD146+CCR5+ T cells are induced through ICOS or RORγt, suggesting new targets for GVHD treatment. We anticipate our assay to be a starting point for the development of novel GVHD-specific drugs. For example, the treatments that focus on inhibiting RORγ would have fewer side effects than general immunosuppressive drugs that GVHD patients use today and inhibit GVHD while sparing the GVL effect. Furthermore, we expect the CD146+CCR5+ Tconvs and/or Tregs can be used as GVHD biomarkers. These biomarkers may guide preemptive treatments such as RORγt inhibitor.