Thesis (Ph. D.)--University of Washington, 1998. / Vita. Includes bibliographical references (leaves [88]-114).

Thesis (Ph. D.)--University of Washington, 1997. / Vita. Includes bibliographical references (leaves [78]-93).

Chronic inflammation is associated with carcinoma development in several clinical settings, and we sought to investigate the role of T cells in this phenomenon using the DMBA/TPA two-stage chemical carcinogenesis protocol. We demonstrate that, paradoxical to models of immunosurveillance, wild-type (WT) mice have a markedly higher rate of tumor formation relative to strains lacking CD8+ T cells. Adoptive transfers of antibody-coated magnetic bead-enriched peripheral CD8+ T cells into TCRáâ-/- mice confirmed that the increased mean tumor area and progression to carcinoma was attributable to the presence of CD8+ T cells. All analyzed strains of mice in which the CD8 compartment was intact (WT, CD4-/-) showed significant increases in tumor susceptibility. Putative tumor-promoting (T-pro) cells (TCRáâ+CD8+CD44+CD62L- tumor infiltrating lymphocytes, TILs) were directly compared to their phenotypic equivalents in peripheral blood lymphocytes (PBLs). In WT and CD4-deficient mice, CD8+ TILs consistently revealed a markedly higher relative expression, by RT-PCR, of IFNã, TNFá and COX-2, and a striking decrease in expression of perforin. Cytokine-bead analysis (CBA) comparison of CD8+ and CD4+ TIL in tumors from WT mice confirmed the increased expression by the CD8+ TIL of IFNã and TNFá. To our knowledge, this is the first demonstration of increased carcinogenesis attributable to CD8+ TILs, characterized by their high IFNã, TNFá, and COX-2 production and defective perforin production relative to phenotypically equivalent PBLs. These studies may have mechanistic implications for the role of T cells in inflammation-associated carcinogenesis.

Diss. (sammanfattning) Stockholm : Karol. inst., 2004. / Härtill 4 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst., 2005. / Härtill 4 uppsatser.

Thesis (Ph.D.)--University of Alabama at Birmingham, 2007. / Title from PDF title page (viewed on Sept. 16, 2009). Includes bibliographical references.

Thesis (Ph. D.)--University of Washington, 2005. / Vita. Includes bibliographical references (leaves 92-100).

Made available in DSpace on 2015-10-06T13:03:07Z (GMT). No. of bitstreams: 0 Previous issue date: 2013-08-23. Added 1 bitstream(s) on 2015-10-06T13:18:56Z : No. of bitstreams: 1 000819087.pdf: 1423284 bytes, checksum: a89857bcef9822e82a34c2b6424c6064 (MD5) / Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) / A leishmaniose visceral é uma doença que causa manifestações clínicas variadas em cães, que podem apresentar desde alterações subclínicas a desordens generalizadas, incluindo alterações neurológicas. Há evidências do comprometimento das barreiras encefálicas, como a presença de infiltrado inflamatório com predomínio de linfócitos T CD3+ no sistema nervoso central. Deste modo, o objetivo deste trabalho foi determinar e comparar os imunofenótipos de linfócitos T no sangue periférico e no liquor e avaliar as lesões encefálicas em cães infectados. Verificou-se que os linfócitos T presentes em maior quantidade no liquor foram os duplos negativos (DN) e os duplos positivos (DP), com predomínio de TCRαβ. Também verificou-se que as células sanguíneas não diferiram das células do liquor em quantidade, o que indica que pode estar havendo um comprometimento da barreira hematoliquórica, permitindo que as células do sangue migrem para o liquor. Ocorreu também o predomínio de infiltrado linfohistioplasmocitário no encéfalo, principalmente em leptomeninges. Porém, não houve correlação entre a inflamação nessa área e as células T. Além disso, a correlação positiva entre a inflamação no subepêndima e as células T DN do liquor indica que essas células chegam no encéfalo também pelos vasos subependimários. Em conjunto, os resultados contribuem para explicar a inflamação observada no encéfalo de cães com leishmaniose, sendo que as células T DN podem ser responsáveis pela progressão neurológica da doença / Visceral leishmaniasis (VL) is a disease causing several clinical manifestations in dogs, that can present from subclinical to generalized disorders, including neurological disorders. There are evidences of cerebral barriers involvement, such as the presence of inflammatory infiltrate with predominance of CD3+ T cells in the brain of infected dogs. Therefore, the aim of this study was to determine and to compare the immunophenotypes of T lymphocytes in the peripheral blood and in the cerebrospinal fluid (CSF) of dogs with VL and evaluate the brain lesions. It was detected that the double negative (DN) and double positive (DP) T cells were present in higher percentage in the CSF, with predominance of TCRαβ. Besides, the amount of blood T cells did not differ from those observed in the CSF, indicating that the blood-CSF barrier may be damaged, allowing the migration of cells from the blood to the CSF. Moreover, inflammatory infiltrate with predominance of lymphohistioplasmacytic cells was observed, mainly in leptomeninges. However, there was no correlation between the intensity of the inflammation in this area and the T cells. Furthermore, the positive correlation between intensity of the inflammation in the subependimal area and DN T cells in the CSF indicates that these cells also may reach the brain through the subependymal vessels. Together, the results contribute to explain the inflammation observed in the brain of dogs with VL, where the DN T cells may contribute to the neurological progression of the disease

Resumo: A leishmaniose visceral é uma doença que causa manifestações clínicas variadas em cães, que podem apresentar desde alterações subclínicas a desordens generalizadas, incluindo alterações neurológicas. Há evidências do comprometimento das barreiras encefálicas, como a presença de infiltrado inflamatório com predomínio de linfócitos T CD3+ no sistema nervoso central. Deste modo, o objetivo deste trabalho foi determinar e comparar os imunofenótipos de linfócitos T no sangue periférico e no liquor e avaliar as lesões encefálicas em cães infectados. Verificou-se que os linfócitos T presentes em maior quantidade no liquor foram os duplos negativos (DN) e os duplos positivos (DP), com predomínio de TCRαβ. Também verificou-se que as células sanguíneas não diferiram das células do liquor em quantidade, o que indica que pode estar havendo um comprometimento da barreira hematoliquórica, permitindo que as células do sangue migrem para o liquor. Ocorreu também o predomínio de infiltrado linfohistioplasmocitário no encéfalo, principalmente em leptomeninges. Porém, não houve correlação entre a inflamação nessa área e as células T. Além disso, a correlação positiva entre a inflamação no subepêndima e as células T DN do liquor indica que essas células chegam no encéfalo também pelos vasos subependimários. Em conjunto, os resultados contribuem para explicar a inflamação observada no encéfalo de cães com leishmaniose, sendo que as células T DN podem ser responsáveis pela progressão neurológica da doença / Abstract: Visceral leishmaniasis (VL) is a disease causing several clinical manifestations in dogs, that can present from subclinical to generalized disorders, including neurological disorders. There are evidences of cerebral barriers involvement, such as the presence of inflammatory infiltrate with predominance of CD3+ T cells in the brain of infected dogs. Therefore, the aim of this study was to determine and to compare the immunophenotypes of T lymphocytes in the peripheral blood and in the cerebrospinal fluid (CSF) of dogs with VL and evaluate the brain lesions. It was detected that the double negative (DN) and double positive (DP) T cells were present in higher percentage in the CSF, with predominance of TCRαβ. Besides, the amount of blood T cells did not differ from those observed in the CSF, indicating that the blood-CSF barrier may be damaged, allowing the migration of cells from the blood to the CSF. Moreover, inflammatory infiltrate with predominance of lymphohistioplasmacytic cells was observed, mainly in leptomeninges. However, there was no correlation between the intensity of the inflammation in this area and the T cells. Furthermore, the positive correlation between intensity of the inflammation in the subependimal area and DN T cells in the CSF indicates that these cells also may reach the brain through the subependymal vessels. Together, the results contribute to explain the inflammation observed in the brain of dogs with VL, where the DN T cells may contribute to the neurological progression of the disease / Orientador: Gisele Fabrino Machado / Banca: Valéria Marçal Felix de Lima / Banca: Antonio Carlos Alessi / Mestre

Environ, 60 % des personnes atteintes d’un cancer auront au moins une séance de radiothérapie au cours de la prise en charge thérapeutique de leur maladie. Les doses de radiothérapie sont limitées en raison du risque important de fibrose séquellaire des tissus sains. Les rayonnements ionisants (RI) peuvent induire différents types de mort cellulaire y compris l'apoptose et la sénescence. Les cellules sénescentes ont une sensibilité réduite à l'apoptose et un phénotype sécrétoire inflammatoire. De plus, les RI peuvent induire la production d’espèces réactives de l’oxygène (ERO) qui provoquent des lésions de l'ADN dans les tissus non ciblés, et des effets systémiques associés à l'inflammation. Différentes équipes ont proposé des tests prédictifs de la radiosensibilité individuelle des patients basés sur l’évaluation du taux d'apoptose radio-induite des lymphocytes T CD4+/CD8+ (LT). Cependant, l’impact des différences de sensibilité à l’apoptose/sénescence des sous-populations de LT sur le taux d’apoptose n’a pas été étudié. Notre hypothèse est que la sensibilité à l’apoptose/sénescence radio-induite des LT circulants est associée à la sur/sous-représentation de sous-populations particulières de LT CD4+ dont les fonctions sont en rapport avec la survenue de fibrose. Nos résultats chez le donneur sain montrent que les LT CCR6+Th17 pro-fibrogéniques sont moins sensibles à l’apoptose et plus sensibles à la sénescence que les LT CCR6negTh et les Treg. Cette sénescence peut être préjudiciable car les lymphocytes CCR6+Th17 situés dans les tissus irradiés peuvent sécréter de l'IL-8 et du VEGF-A. La modulation des voies ERO/MAPK ou mTOR pourrait être une cible potentielle pour la prévention de la radiotoxicité induite par les CCR6+Th17 sénescents. Enfin, le ratio de cellules circulantes H2A.J+CCR6+Th17 sénescentes / CCR6+Treg pourrait être utilisé comme marqueur potentiel de la radiosensibilité individuelle. / On average, 60% of cancer patients have at least one radiation session during their care throughout the history of their disease. The doses of radiotherapy are limited because of the high risk of fibrosis-type side effects of healthy tissues. Ionizing radiation can induce a variety of cell death responses including apoptosis, but also senescence. Senescent cells have reduced sensitivity to apoptosis, and a pro-inflammatory secretory phenotype. In addition, ionizing radiations can induce the production of reactive oxygen species (ROS) that cause DNA damage in non-target tissues, and systemic effects associated with inflammation. In order to improve the personalization of radiotherapy, different teams proposed predictive tests of the individual radiosensitivity of patients by establishing a relationship between a low rate of radio-induced apoptosis of CD4+/CD8+ T lymphocytes (LT) and a high risk of secondary fibrosis. However, the impact of the differences in individual cell sensitivity to radiation-induced senescence on the ratio between LT cell subpopulations has not been studied. Our results on healthy donors show that pro-fibrogenic CCR6+ Th17 cells are less sensitive to apoptosis and more susceptible to senescence compared to CCR6neg LT. This senescence can be detrimental as irradiated CCR6+Th17 lymphocytes located in the irradiated tissue can secrete IL-8 and VEGF-A. Modulation of ROS/MAPK or mTOR signaling pathways could be potential targets for the prevention of this CCR6+Th17-induced radiotoxicity. Finally, the ratio of circulating H2A.J+ senescent CCR6+ Th17/CCR6+Treg cells may be used as a potential marker of individual radiosensitivity.