Zugl.: München, Univ., Diss., 2008

Ulm, Univ., Diss., 2008.

Submitted by Fabio Sobreira Campos da Costa (fabio.sobreira@ufpe.br) on 2017-04-07T12:49:00Z No. of bitstreams: 2 license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) Tese Mayara final [08-09-2016].pdf: 6000027 bytes, checksum: 8aba9ff907d1176a530d19ec2bb6fad1 (MD5) / Made available in DSpace on 2017-04-07T12:49:00Z (GMT). No. of bitstreams: 2 license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) Tese Mayara final [08-09-2016].pdf: 6000027 bytes, checksum: 8aba9ff907d1176a530d19ec2bb6fad1 (MD5) Previous issue date: 2015-09-02 / CAPES / Doença inflamatória intestinal descreve um grupo heterogêneo de doenças inflamatórias crônicas do trato gastrointestinal. Os dois principais tipos de DII são retocolite ulcerativa idiopática e doença de Crohn. A patogênese dessas doenças é caracterizada pela inflamação persistente no intestino, envolvendo uma interação entre fatores genéticos, ambientais e imunológicos. Foram investigados aspectos clínico-epidemiológicos e analisados os polimorfismos dos genes da reposta imune em pacientes brasileiros com doença inflamatória intestinal em diferentes formas anátomo-clínicas. Um total de 101 pacientes foram analisados (43 - retocolite ulcerativa idiopática e 58 - doença de Crohn) para os polimorfismos dos genes do fator de necrose tumoral alfa (TNF-α -308 G/A; rs1800629), interleucina-10 (IL-10 -1082 G/A; rs1800896), domínio do recrutamento e ativação da caspase 15/receptor tipo NOD2 (CARD15/NOD2; rs2066844 e rs2066845), receptor tipo NOD contendo domínio pirina – NLRP1 (rs12150220), NLRP3 (rs35829419) e interleucina -1beta (IL-1β -511T/C; rs16944). A forma anatómica-clínica de DC predominante foi a fistulizante (29,31%), seguida por inflamatória (27,58%) e estenosante (27,58%). O grupo controle foi composto por 91 indivíduos saudáveis. Os genes do receptor tipo NOD contendo domínio pirina 1 e 3 e do domínio do recrutamento e ativação da caspase 15/receptor tipo NOD2 variantes R702W e G908R não foram associados à susceptibilidade a doença inflamatória intestinal. Em relação ao polimorfismo da interleucina 10, nenhuma diferença estatística foi encontrada entre os genótipos e alelos para a doença inflamatória intestinal comparado aos controles. Fator de necrose tumoral alfa mostrou uma associação estatisticamente significativa entre pacientes e controles de retocolite ulcerativa idiopática que sugere que a presença do alelo A predispõe o aparecimento de retocolite ulcerativa idiopática, mas não doença de Crohn. Verificou-se ainda que o genótipo AG da interleucina 1 foi associado com o desenvolvimento de retocolite ulcerativa idiopática. Os resultados sugerem que os polimorfismos de única base do fator de necrose tumoral alfa e da interleucina 1 estão envolvidos com a retocolite ulcerativa idiopática e podem contribuir para a patogênese na população brasileira estudada. / Inflammatory bowel disease describes a heterogeneous group of chronic inflammatory diseases of the gastrointestinal tract. The two main types of inflammatory bowel disease are ulcerative colitis and Crohn disease. The pathogenesis of the disease is characterized by unpredictable attacks of inflammation of the intestine, besides involving an interaction between genetic, environmental and immunological factors. Clinical and epidemiological aspects were investigated and the polymorphisms of genes of the immune response in Brazilian patients with inflammatory bowel disease in different anatomic-clinical forms were analyzed. A total of 101 patients were analyzed (43 - ulcerative colitis and 58 - Crohn disease) for the tumour necrosis factor alpha (TNF-α -308 G/A; rs1800629), interleukin-10 (IL-10 -1082 G/A; rs1800896), caspase activation and recruitment domains 15/ NOD like receptor 2 (CARD15/NOD2; rs2066844 and rs2066845), NOD like receptor pyrin domain containing – NLRP1 (rs12150220), NLRP3 (rs35829419) and interleukin-1beta (IL-1β 511T/C; rs16944) genes polymorphisms. The anatomic-clinical form of Crohn disease predominant was the fistulizing (29.31%), followed by inflammatory (27.58%) and stricturing (27.58%). A control group was composed by 91 healthy subjects group. NOD like receptor pyrin domain containing 1 and 3 and caspase activation and recruitment domains 15/ NOD like receptor 2 genes R702W and G908R variants were not associated to inflammatory bowel disease susceptibility. With respect to the polymorphism of interleukin-10, no statistical difference was found between the genotypes and alleles for inflammatory bowel disease compared to controls. Tumour necrosis factor alpha showed a statistically significant association between ulcerative colitis patients and controls which suggests that the presence of A allele predisposes the onset of ulcerative colitis but not Crohn disease. It was found yet that AG genotype of interleukin-1beta was associated with the development of ulcerative colitis. The results suggest that the tumour necrosis factor alpha and interleukin-1beta single nucleotide polymorphisms are involved with ulcerative colitis and may be contributing to pathogenesis in Brazilian population.

5 Abstract Interleukin-2 possesses strong stimulatory activity for activated T and NK cells and thus it is an attractive molecule for immunotherapy. However, its unfavourable pharmacological properties, extremely short half-life and severe toxicities associated with high-dose IL-2 are the most serious and limiting drawbacks. Moreover, IL-2 has been also implicated in the homeostasis of T regulatory cells where it plays a decisive role as an essential growth factor of these cells. Several different approaches to improve the therapeutic potential of IL-2 have been studied. Recently described IL-2/anti-IL-2 mAb immunocomplexes which show much higher and selective biological activity in contrast with free IL-2 in vivo are probably the most promising of them. In this study, we compared the biological activity of free IL-2 with IL-2/anti-IL-2 mAb immunocomplexes in order to demonstrate their benefits over free IL-2. We also demonstrated that IL-2/anti-IL-2 mAb immunocomplexes possess noticeable antitumor activity in two syngeneic mouse tumor models, namely EL4 T lymphoma and B16F10 melanoma, if administered early in tumor progression. Therefore, we justified potential use of IL-2/anti-IL-2 mAb immunocomplexes in tumor immunotherapy. We covalently conjugated IL-2 to synthetic semitelechelic polymeric carrier based...