African trypanosomes are protozoan blood parasites that infect both humans and livestock. BALB/c mice are highly susceptible to experimental infections by Trypanosoma congolense while C57BL/6 mice are relatively resistant, as measured by degree and pattern of parasitemia and survival time. Rapid death observed in highly susceptible BALB/c mice is due to a systemic inflammatory response syndrome (SIRS). A small subset of pathogenic, MHC class II-restricted CD4+ T cells, activated during the course of T. congolense infections, mediates early mortality in infected highly susceptible BALB/c mice via excessive synthesis of the cytokine IFN-gamma. Since these pathogenic T cells are matrixadherent, they could be distinguished from conventional Th1 cells. There is a possibility that this subpopulation of T cells has unique surface markers.<p> The complement system is highly activated in African trypanosomiasis, leading to persistent hypocomplementemia. Amplification of the alternative pathway of complement is faster in BALB/c mice than in C57BL/6 mice and the degradation of complement component C3b to complement component C3d, during the amplification of the alternative pathway of complement, proceeds faster in BALB/c than in C57BL/6 mice (Ogunremi et al., 1993). T. congolense-infected BALB/c mice have more immune complexes containing trypanosomal variant surface glycoprotein (VSG) than C57BL/6 mice in their plasma (Pan & Tabel, unpublished). T. congolense-infected BALB/c mice might have more VSG-C3d immune complexes than infected C57BL/6 mice. The receptor for complement component C3d is the cell surface molecule CR2, also referred to as CD21. It is known that CR2 is widely expressed on B lymphocytes and follicular dendritic cells. There is also some evidence that CR2 is expressed on a subpopulation of activated T cells. Binding of VSG-C3d immune complexes to the complement receptor CR2 might costimulate the CR2+ T cells to produce IFN-ã. I hypothesize that IFN-ã-producing T cells in T. congolense-infected BALB/c mice are CR2+ and that the CR2+ T cells increase in numbers in experimental murine T. congolense infections.<p> Kinetic studies were carried out by staining spleen cells of T. congolense-infected BALB/c mice for the presence of CR2 on T cells (CD3+ cells). Total numbers of spleen cells showed a 5-fold increase with progressive T. congolense infections. The total numbers of T cells in the spleen showed a 7-fold increase at day 8 post infection. The total numbers of CR2+ T cells in the spleen showed a 3 to 7-fold increase with progressive infection. Parallel studies on B lymphocytes (CD19+ cells) showed that absolute numbers of B cells in the spleen had a 5 to 6-fold increase with progressive infection. Absolute numbers of CR2+ B cells in the spleen showed a 4-fold increase at day 7 post infection. The total numbers of CR2+ cells in the spleen showed an increase while the mean numbers of CR2 molecules per cell showed a reduction with progressive infection.<p> These results show that CR2+ T cells in the spleen increase in numbers with progressive T. congolense infections in BALB/c mice. I suggest that CD4+CR2+ T cells might play a role in the pathogenesis of T. congolense infections.

African trypanosomes are protozoan blood parasites that infect both humans and livestock. BALB/c mice are highly susceptible to experimental infections by Trypanosoma congolense while C57BL/6 mice are relatively resistant, as measured by degree and pattern of parasitemia and survival time. Rapid death observed in highly susceptible BALB/c mice is due to a systemic inflammatory response syndrome (SIRS). A small subset of pathogenic, MHC class II-restricted CD4+ T cells, activated during the course of T. congolense infections, mediates early mortality in infected highly susceptible BALB/c mice via excessive synthesis of the cytokine IFN-gamma. Since these pathogenic T cells are matrixadherent, they could be distinguished from conventional Th1 cells. There is a possibility that this subpopulation of T cells has unique surface markers.<p> The complement system is highly activated in African trypanosomiasis, leading to persistent hypocomplementemia. Amplification of the alternative pathway of complement is faster in BALB/c mice than in C57BL/6 mice and the degradation of complement component C3b to complement component C3d, during the amplification of the alternative pathway of complement, proceeds faster in BALB/c than in C57BL/6 mice (Ogunremi et al., 1993). T. congolense-infected BALB/c mice have more immune complexes containing trypanosomal variant surface glycoprotein (VSG) than C57BL/6 mice in their plasma (Pan & Tabel, unpublished). T. congolense-infected BALB/c mice might have more VSG-C3d immune complexes than infected C57BL/6 mice. The receptor for complement component C3d is the cell surface molecule CR2, also referred to as CD21. It is known that CR2 is widely expressed on B lymphocytes and follicular dendritic cells. There is also some evidence that CR2 is expressed on a subpopulation of activated T cells. Binding of VSG-C3d immune complexes to the complement receptor CR2 might costimulate the CR2+ T cells to produce IFN-ã. I hypothesize that IFN-ã-producing T cells in T. congolense-infected BALB/c mice are CR2+ and that the CR2+ T cells increase in numbers in experimental murine T. congolense infections.<p> Kinetic studies were carried out by staining spleen cells of T. congolense-infected BALB/c mice for the presence of CR2 on T cells (CD3+ cells). Total numbers of spleen cells showed a 5-fold increase with progressive T. congolense infections. The total numbers of T cells in the spleen showed a 7-fold increase at day 8 post infection. The total numbers of CR2+ T cells in the spleen showed a 3 to 7-fold increase with progressive infection. Parallel studies on B lymphocytes (CD19+ cells) showed that absolute numbers of B cells in the spleen had a 5 to 6-fold increase with progressive infection. Absolute numbers of CR2+ B cells in the spleen showed a 4-fold increase at day 7 post infection. The total numbers of CR2+ cells in the spleen showed an increase while the mean numbers of CR2 molecules per cell showed a reduction with progressive infection.<p> These results show that CR2+ T cells in the spleen increase in numbers with progressive T. congolense infections in BALB/c mice. I suggest that CD4+CR2+ T cells might play a role in the pathogenesis of T. congolense infections.

Made available in DSpace on 2014-10-09T12:53:55Z (GMT). No. of bitstreams: 0 / Made available in DSpace on 2014-10-09T14:09:29Z (GMT). No. of bitstreams: 0 / Tese (Doutoramento) / IPEN/T / Instituto de Pesquisas Energéticas e Nucleares - IPEN-CNEN/SP

Made available in DSpace on 2014-10-09T12:53:55Z (GMT). No. of bitstreams: 0 / Made available in DSpace on 2014-10-09T14:09:29Z (GMT). No. of bitstreams: 0 / O presente estudo teve como objetivo avaliar o efeito da inibição das cadeias inflamatórias reguladas pela ação do interferon-gama (IFN-&gamma;) e da enzima óxido nítrico sintase indutível (iNOS) no dano radioinduzido após exposição a dose letal (8 Gy) ou moderada a severa (4 Gy) nos tecidos hematopoiéticos (baço e medula) de modelos experimentais irradiados nestas doses. Grupos de camundongos isogênicos C57Bl/6j foram expostos à radiação correspondente a 4 ou 8 Gy em exposições de corpo inteiro em fonte panorâmica de 60Co. Da mesma forma, foram irradiados camundongos cuja expressão de IFN-&gamma; ou iNOS é ausente ou indetectável. Outros grupos receberam via oral por toda a duração do experimento um inibidor atividade de iNOS, aminoguanidina, ou via intraperitoneal uma quimiocina primordial promotora da hematopoiese, CXCL12, até o quarto dia após a exposição. Outra divisão experimental recebeu os dois agentes concomitantemente. Os animais foram sacrificados nos dias 2º, 4º e 8º após a irradiação, e fragmentos dos baços e fêmures foram preservados para histologia. Os esplenócitos e células não aderentes da medula óssea femoral foram removidos e divididos, fornecendo alíquotas para posterior RT-PCR e suspensões celulares apropriadas para ensaios de citometria de fluxo específicos para a detecção da freqüência de populações CD34+. Nestes mesmos dias de experimento, alíquotas de sangue caudal foram coletadas para contagem de hemácias e plaquetas periféricas. Os resultados mostraram que a ausência da produção de interferon-gama no local irradiado aumenta a sobrevivência e a quantidade de células progenitoras hematopoiéticas e que a ausência de iNOS ou seu bloqueio funcional diminuem a extensão do dano radioinduzido nos tecidos hematopoiéticos. Além disso, foi possível observar que a suplementação com CXCL12 sintética aumenta a freqüência do fenótipo CD34+ P.chave: radiação ionizante; medula óssea; óxido nítrico; aminoguanidina nos baços dos modelos testados, e que seu efeito parece antagonizar com a inibição da produção de NO pela aminoguanidina. / Tese (Doutoramento) / IPEN/T / Instituto de Pesquisas Energéticas e Nucleares - IPEN-CNEN/SP

京都大学 / 0048 / 新制・課程博士 / 博士(医科学) / 甲第21030号 / 医科博第91号 / 新制||医科||6(附属図書館) / 京都大学大学院医学研究科医科学専攻 / (主査)教授 生田 宏一, 教授 清水 章, 教授 竹内 理 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM