Diss. (sammanfattning) Stockholm : Karol inst., 2003. / Härtill 5 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst., 2006. / Härtill 4 uppsatser.

Thesis (Ph. D.)--Cornell University, January, 2009. / Vita. Includes bibliographical references (leaves 79-86).

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2010.

Thesis (M. Phil.)--University of Hong Kong, 1992.

Thesis (doctoral)--University of Uppsala, 1983. / Bibliography: p. 32-37.

Thesis (Ph.D.)--University of California, San Francisco, 2004. / Includes bibliographical references. Also available online.

Thesis (Ph. D.)--Ohio State University, 2007. / Title from first page of PDF file. Includes bibliographical references (p. 273-291).

Neuroblastoma is an aggressive solid tumor that develops from immature cells of the nervous system and is almost exclusively diagnosed in infants and young children. Over the past decade a multitude of immune based therapies have been explored as therapeutic candidates for patients with neuroblastoma. The anti-GD2 monoclonal antibody, 3F8, and more recently, natural kill (NK) cell based therapies have been accepted as hopeful therapeutic options for patients with Neuroblastoma. These options however have many drawbacks including dose limiting pain, the development of tolerance, reliance on MHC mismatch and possible reliance on the invariant NK (iNK) cells population. Gamma Delta T cells, a subpopulation of T cells composed of a T cell receptor (TCR) with a gamma and a delta chain instead of an alpha and a beta; chain, have been shown to recruit a more robust immune response then both 3F8 and NK cells through their activation of antigen presenting cells (APCs) and non-reliance on MHC mismatch. Gamma Delta T cells are also able to recruit NK cells as well as other cytotoxic lymphocytes. For these reasons, it is believed that Gamma Delta T cell based treatment alone or in combination with an anti-GD2 monoclonal antibody may have a greater efficacy than either NK cells or an anti-GD2 monoclonal antibody alone. The intent of this thesis is to explore and evaluate the current state of Gamma Delta T cell based immunotherapy against the backdrop of NK cell based immunotherapy for neuroblastoma.

Immune response to M leprae is determinant to leprosy evolution and NK cells are important constituents of the innate immune response and can contribute to the adaptive response activation. The aim of this study was to evaluate the immunoexpression of NK cells markers CD16+ and CD56+ in skin lesions of patients with leprosy, before any treatment. A total of 54 skin biopsies of patients with leprosy were evaluated by immunohistochemistry using rabbit anti-human CD16a (clone SP189) from Spring Bioscience and mouse anti-human CD56 (clone 123C3) from DakoÂ, together with Envision Flex kit from DakoÂ. Nineteen cases were from tuberculoid (TT) clinical form, 14 were borderline (BT, BB, BL) and 20 were lepromatous (LL), while one case was from indeterminate form (I). Among them 31 (57,4%) were from male gender and 30 (55,5%) presented positive baciloscopy. The samples were collected at the âCentro de Dermatologia Dona LibÃniaâ in Fortaleza, CearÃ, Brazil, and were analysed at the âLaboratÃrio de TÃcnicas Cito-histopatolÃgicas Especiais do Departamento de Patologia e Medicina Legal da Universidade Federal do CearÃâ. Positive controls for the CD16 and CD56 expression were lung tissue and carcinoid tumor, respectively. Fisher, Chi-square, Kruskal-Wallis and Mann-Whitney tests were used to statistical analysis and a p value of <0.05 was considered significant. Differences were observed when expression of CD16+ cells was compared between tuberculoid and borderlines forms (p=0.0329), as also among gender comparisons (p=0.0129). The CD16+ cells in the three different clinical forms groups were also statistically different achieving a p value of 0.0085, and showing a higher median of expression of CD16+ in the TT group. These data suggests that a protective immune response against M. leprae in leprosy requires a balance between NK cells subgroups (CD16+ and CD56+) and that the tuberculoid form presents higher levels of CD16+ cells expression when compared to borderlines and LL forms. In addition, the study suggests that there are possible hormonal or genetic influences on the distribution of NK cell function markers. / A resposta imunolÃgica ao Mycobacterium leprae à componente determinante na evoluÃÃo da doenÃa. As cÃlulas Natural Killer (NK) sÃo constituintes importantes da resposta imune inata, podendo participar da ativaÃÃo da resposta adaptativa. Este estudo objetivou avaliar a imunoexpressÃo de marcadores de cÃlulas NK, CD16+ e CD56+, em lesÃes cutÃneas de pacientes com hansenÃase antes do tratamento, por imunoistoquÃmica. Foram analisadas 54 biÃpsias cutÃneas de lesÃes de paciente com hansenÃase. Sendo 19 casos da forma clÃnica tuberculÃide (TT), 14 da forma borderline (BT, BB e BL) e 20 da forma lepromatosa (LL) e 1 caso da forma clÃnica indeterminada (I). Destes pacientes 31 (57,4%) eram do gÃnero masculino, 30 (55,5%) eram baciloscopia positiva. As amostras foram provenientes do Centro de Dermatologia Dona LibÃnia e analisadas no LaboratÃrio de TÃcnicas Cito-histopatolÃgicas Especiais do Departamento de Patologia e Medicina Legal da Universidade Federal do CearÃ. Para a imunistoquÃmica foram utilizados os anticorpos monoclonais primÃrios: rabbit anti-human CD16a (clone SP189) da Spring Bioscience e o mouse anti-human CD56 (clone 123C3) da DakoÂ, juntamente com o kit Envision Flex da DakoÂ. Os controles positivos para CD16 e CD56 foram obtidos a partir de secÃÃes de tecidos de pulmÃes e tumor carcinÃide, respectivamente. Os testes de Fisher, Qui-quadrado, Kruskal-Wallis e Mann-Whitney foram utilizados para anÃlise estatÃstica, sendo considerado significante quando p<0,05. A comparaÃÃo entre a imunoexpressÃo de CD16+ em linfÃcitos teciduais da forma tuberculÃide em relaÃÃo Ãs formas borderlines apresentou diferenÃas estatÃsticas significantes (p=0,0329), como tambÃm em relaÃÃo ao gÃnero (p=0,0129). AtravÃs do teste Kruskal-Wallis, comparando os trÃs grupos das formas clinicas da doenÃa em relaÃÃo ao nÃmero de cÃlulas imunomarcadas com CD16+, foi observado que a mediana do grupo tuberculÃide foi maior, conferindo p=0,0085. Pode-se concluir que o estudo sugere que uma resposta imunolÃgica protetora na hansenÃase requer um equilÃbrio entre subgrupos de cÃlulas NK CD16+ e CD56+, e que a forma tuberculoide cursa com predomÃnio dessas cÃlulas NK citotÃxicas quando comparadas Ãs formas borderline e lepromatosas. Em adiÃÃo, o estudo sugere que hà possÃveis influÃncias hormonais ou genÃticas na distribuiÃÃo destes marcadores de funÃÃo de cÃlulas NK.