京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第18849号 / 医博第3960号 / 新制||医||1007(附属図書館) / 31800 / 京都大学大学院医学研究科医学専攻 / (主査)教授 三森 経世, 教授 坂井 義治, 教授 長澤 丘司 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

O líquen plano oral (LPO) é uma doença inflamatória crônica que afeta em torno de 1 a 2% da população mundial adulta, entre 30 e 60 anos, principalmente mulheres. As lesões podem estar presentes em diversos sítios, porém tem predileção pela mucosa jugal, gengiva e bordas laterais da língua, todas bilateralmente. As manifestações de LPO são frequentes, e podem se caracterizar clinicamente em seis tipos: reticular, em placas, papular, atrófico, erosivo-ulcerativo e bolhoso, porém o mais comum é o reticular. O presente estudo teve como objetivo avaliar a expressão de genes relacionados à resposta inflamatória e autoimunidade no líquen plano oral (LPO) em pacientes com a variante exclusivamente reticular comparado a controle saudável. Foram incluídos consecutivamente 10 pacientes com LPO que preencheram os critérios de inclusão adotados, sendo 9 mulheres e um homem, e 6 indivíduos controle, sendo 4 mulheres e 2 homens pareados por sexo, idade e uso de medicações sistêmicas. Amostras de mucosa bucal foram coletadas por meio de biópsia incisional em ambos os grupos de pacientes e submetidas à extração de RNA para posterior análise da expressão gênica por PCR-array selecionada para este estudo. Os resultados obtidos foram o aumento da expressão de 8 genes, CXCL 9 e CXCL 10 vão de acordo com a literatura, corroborando com nosso estudo e de certa forma reafirmar mais necessidade de estudos bem desenhados . / The oral lichen planus (OLP) is a chronic inflammatory disease that affects around 1-2% of the adult population between 30 and 60 years, mainly women. The lesions may be present in several sites, but has a predilection for the buccal mucosa, gums and lateral borders of the tongue, all bilaterally. The manifestations of OLP are frequent, and may be characterized clinically in six types: reticular, plaque-like, papular, atrophic, erosive-ulcerative and bullous, but the most common is the reticular . The present study aimed to evaluate the expression of genes related to inflammatory response and autoimmunity in oral lichen planus (OLP) in patients with exclusively reticular variant compared to healthy control. 10 consecutive patients with OLP who met the inclusion criteria, 9 women and one man, and six control subjects were included were 4 women and 2 being proportionally matched by sex, age and use of systemic medications men. Samples of oral mucosa were collected by incisional biopsy in both groups of patients and subjected to RNA extraction for analysis of gene expression by selected for this study-PCR array. The results were the overexpression of genes 8, where only two of them go according to the literature, corroborating our study and somehow reaffirm need for more well-designed studies.

O líquen plano oral (LPO) é uma doença inflamatória crônica que afeta em torno de 1 a 2% da população mundial adulta, entre 30 e 60 anos, principalmente mulheres. As lesões podem estar presentes em diversos sítios, porém tem predileção pela mucosa jugal, gengiva e bordas laterais da língua, todas bilateralmente. As manifestações de LPO são frequentes, e podem se caracterizar clinicamente em seis tipos: reticular, em placas, papular, atrófico, erosivo-ulcerativo e bolhoso, porém o mais comum é o reticular. O presente estudo teve como objetivo avaliar a expressão de genes relacionados à resposta inflamatória e autoimunidade no líquen plano oral (LPO) em pacientes com a variante exclusivamente reticular comparado a controle saudável. Foram incluídos consecutivamente 10 pacientes com LPO que preencheram os critérios de inclusão adotados, sendo 9 mulheres e um homem, e 6 indivíduos controle, sendo 4 mulheres e 2 homens pareados por sexo, idade e uso de medicações sistêmicas. Amostras de mucosa bucal foram coletadas por meio de biópsia incisional em ambos os grupos de pacientes e submetidas à extração de RNA para posterior análise da expressão gênica por PCR-array selecionada para este estudo. Os resultados obtidos foram o aumento da expressão de 8 genes, CXCL 9 e CXCL 10 vão de acordo com a literatura, corroborando com nosso estudo e de certa forma reafirmar mais necessidade de estudos bem desenhados . / The oral lichen planus (OLP) is a chronic inflammatory disease that affects around 1-2% of the adult population between 30 and 60 years, mainly women. The lesions may be present in several sites, but has a predilection for the buccal mucosa, gums and lateral borders of the tongue, all bilaterally. The manifestations of OLP are frequent, and may be characterized clinically in six types: reticular, plaque-like, papular, atrophic, erosive-ulcerative and bullous, but the most common is the reticular . The present study aimed to evaluate the expression of genes related to inflammatory response and autoimmunity in oral lichen planus (OLP) in patients with exclusively reticular variant compared to healthy control. 10 consecutive patients with OLP who met the inclusion criteria, 9 women and one man, and six control subjects were included were 4 women and 2 being proportionally matched by sex, age and use of systemic medications men. Samples of oral mucosa were collected by incisional biopsy in both groups of patients and subjected to RNA extraction for analysis of gene expression by selected for this study-PCR array. The results were the overexpression of genes 8, where only two of them go according to the literature, corroborating our study and somehow reaffirm need for more well-designed studies.

After kidney transplantation the recipient's immune system responds to the donor's antigens and the graft rejection occurs. Borderline changes are a frequent diagnosis after kidney transplantation, representing only mild rejection signs. Some patients with borderline changes undergo progression to rejection. The identification of these at- risk patients by biomarkers will allow enhanced treatment and help to prevent the development of rejection. The aim of my work was to verify biomarkers of rejection in patients with borderline changes. Chemokines CXCL9, CXCL10 and CCL17 in urine/serum of 40 patients with subclinical borderline changes at 3 months and in 25 patients with early borderline changes were determined by ELISA. At 3 months, the higher CXCL10 level predicted rejection with AUC=0.749, p=0.024. High levels of CXL10 had also been found in patients with BKV infection. We did not confirm the relationship between rejection and the CXCL9 and CCL17. In the early posttransplant period the levels of CXCL10 and CXCL9 were elevated in all patients and therefore couldn't be used to predict rejection. The alloreactivity was examined using IFN-γ ELISPOT (n=38). No association between the frequency of IFN-γ producing cells after stimulation with donor cells or CMV peptides and the development of...

Oncolytic viruses (OVs) are promising tumor-selective treatments, and the efficacy of OV therapies has been shown to depend heavily on the successful delivery and spread of these agents within the tumor mass to generate profound immunostimulatory effects. We have previously reported the potential of vanadium-based compounds such as vanadyl sulfate (VS) as immune-stimulatory enhancers of OV immunotherapy. These compounds, in conjunction with RNA-based OVs such as oncolytic VSVΔ51, improve viral spread and oncolysis, leading to long-term antitumor immunity and prolonged survival in resistant tumor models as previously reported. This effect is associated with a virus-induced antiviral type I IFN response shifting towards a type II IFN response. Here, the systemic impact and the relevant immunological changes following VS/VSVΔ51 combination therapy were investigated to understand the immunological mechanism of action leading to improved antitumor responses. We screened for the secretion of chemokines and cytokines in vivo to understand the mechanism of action regulating the recruitment of immune cells to the tumor in the CT26WT tumor model following treatment. Additionally, the antigen-specific immune response was investigated to further identify the relevant immunological changes following treatment with the VS+VSVΔ51 combination. Our data revealed that VS+VSVΔ51 combination therapy significantly increased the levels of IFN-γ and IL-6, and other key important pro-inflammatory cytokines and chemokines. Improved tumor antigen-specific T-cell responses were observed following the combined therapy. Supported by relevant immunological changes and as a proof of concept for the design of more effective therapeutic regimens, we found that local delivery of VSVΔ51 encoded with IL-12 or with other transgenes in combination with VS further improved therapeutic outcomes in a syngeneic CT26WT colon cancer model. We found that CD8+ T cells and Natural Killer (NK) cells play significant roles in establishing the therapeutic efficacy that we observed; Furthermore, engineering new and targeted therapeutic platforms to impact the antitumor immune response further improves the therapeutic benefits of the combined therapy.

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