Immunosenescence is the progressive loss of immune tissue that result from (i) functional, (ii) clonal or (iii) systemic changes to the cells or tissue that make up the immune system. While this process occurs gradually during the ageing process, there is overwhelming evidence to implicate HIV infection in driving all three aspects of immunosenescence by inducing high levels of immune activation. In the current literature, there is a dearth of data on the impact of HIV-2 infection or untreated perinatal HIV-1 infection in driving immunosenescence, and the key goal of this thesis is to mend this gap in knowledge. Both HIV-2 and paediatric HIV-1 infection provide excellent settings for verifying the mechanistic theories that relate to HIV-1-associated immunosenescence. The majority of HIV-2 infected individuals control their infection, which raises the question of how HIV-2 controllers are able to generate robust T-cell responses, when equivalent responses are rare in HIV-1 infected cohorts. Our hypothesis is that the former is an outcome of sustained or more robust homeostasis due to lower immune activation levels. Altogether, we show that primary immune resources are better preserved in HIV-2 than in HIV-1 infection - including more substantial HPC and naïve T-cell populations that correlate well with thymic output. The preservation of primary immune responses during HIV-2 infection is expected to contribute to robust effector functions and a younger phenotype of virus-specific memory T-cells. Accordingly, we show that HIV-2 specific memory T-cells reflect an earlier differentiated phenotype than HIV-1 specific T-cells, are highly polyfunctional and exhibit strong virus suppressive capabilities. In perinatally HIV-1 infected children - who by virtue of their age represent slow progressors - the presence of a hyperactive thymus may be sufficient to compensate against the early onset of immunosenescence and result in younger immune cell phenotypes. Yet, in measuring leucocyte telomere length and mtDNA content by qPCR, which qualify as biomarkers of senescence, we observed that leucocytes from vertically-infected Zimbabwean children present with shortened telomeres and an increase in mtDNA content, which signals the onset of advanced cellular senescence.

Elderly residents of nursing homes are at high risk of respiratory viral infection, mortality and frailty. It is a widely held view that the dysfunctional changes to the immune system that arise from ageing, known as immunosenescence are responsible for the increased risk of infection, mortality and frailty; however only sparse data exist to substantiate this. Furthermore, the majority of studies investigating these associations have excluded elderly nursing home residents, thus little is known about immune phenotypes in this group. In this thesis, I first characterized immune phenotypes in elderly nursing home residents by comparing immune phenotypes in an elderly nursing home cohort to a group of younger healthy adults. I then explored how age, sex, frailty and nutrition influence immune phenotypes in the elderly group. I subsequently used different statistical analyses, including Cox proportional hazards modeling, hierarchical cluster analysis and multi-level modelling to identifying immune biomarkers predictive of clinical outcomes in elderly nursing home residents including respiratory viral infection, mortality and frailty. We found that high cytomegalovirus (CMV)-reactive CD4+ T-cells were associated with an increased risk of respiratory viral infection and high T-regulatory cells (T-regs) were associated with a reduced risk of respiratory viral infection. High CMV-reactive CD4+ T-cells were also associated with an increased risk of mortality within the subsequent 1-year in those aged 65-84 years but had no differential effect in those aged 85-104 years. Other immune phenotypes were not predictive of mortality. Higher naïve CD4+ T-cells and effector memory CD8+ T-cells predicted lower levels of frailty and higher central memory CD8+ T-cells predicted higher levels of frailty. These findings may help provide more focused care through targeted prevention. Furthermore, knowledge of these immune biomarkers provides insight into how immunosenescence may contribute to these clinical outcomes and will help guide future research into novel prevention strategies. / Thesis / Doctor of Philosophy (PhD)

Em animais, os protocolos de Treinamento Físico Crônico (TF) aeróbio de nível moderado têm sido relacionados com a melhora da capacidade do sistema imunológico, como por exemplo o aumento dos leucócitos e a maior produção de citocinas e de oxido nítrico. Durante o envelhecimento, ocorre uma desregulação do sistema imunológico, conhecido como Imunossenescência, a qual contribui para o aumento da suscetibilidade a infecções, câncer e autoimunidade, e redução da resposta vacinal. Assim, o presente estudo verificou os resultados do TF sobre o sistema imunológico, avaliando a capacidade fagocítica dos macrófagos peritoneais oriundos de animais jovens e idosos. MATERIAL E MÉTODOS: Foram utilizados ratos da linhagem Wistar com 60 dias (Jovens) e com 14 meses de idade (Idosos), divididos em quatro grupos: Jovens Sedentários (JS) e Treinados (JT), e Idosos Sedentários (IS) e Treinados (IT). O protocolo de TF foi realizado através do exercício de nível por meio de natação por 45 minutos, três vezes na semana, por oito semanas consecutivas. Após, os macrófagos peritoneais foram desafiados em vitro, durante 30 e 120 minutos, com Escherichia Coli (E. coli) ou Candida albicans (C. albicans), previamente corados com FITC. Células com microrganismos internalizados foram quantificadas por meio de microscopia de fluorescência. RESULTADOS: Após o protocolo de EF, o percentual de macrófagos peritoneais com microrganismos internalizados, obtidos a partir dos ratos jovens ou idosos, foi maior (p < 0,05) em relação aos sedentários. Estes achados foram verificados tanto após desafio com bactérias E. coli quanto com fungos C. albicans, e independente do período de desafio. Os valores obtidos em 120 minutos foram superiores que aqueles correspondentes aos 30 minutos de desafio. Após o EF, os valores percentuais de macrófagos com microrganismos internalizados foram maiores entre os idosos que aqueles observados entre os jovens, independente do período de desafio (p < 0,05). Estas diferenças etárias também ocorreram entre os animais sedentários. CONCLUSÕES: O exercício físico aeróbio em nível moderado foi capaz de alterar a função fagocítica dos macrófagos. A maior internalização de microrganismos por parte dos macrófagos oriundos dos idosos, em relação aos jovens, pode refletir um estado prévio de ativação celular, em função do aumento da atividade inflamatória basal observado em idosos (inflammaging). / In animals, the aerobic physical training (PT) of moderate level have been related with the improvement of the immunologic system capacity, like the increase of leukocytes and a higher production of cytokines and nitric oxide. While ageing, there is a deregulation of the immunologic system, known as Immunosenescence, which contributes to the increasing of the susceptibility to infections, cancer and autoimmunity, and the vaccine response. Thus, the present study examined the results of PF on the immune system, evaluating the phagocytic capacity of peritoneal macrophages derived from young and old animals. Material and Methods: Young (60-day old) and old (14-month old) Wistar mice were divided in four different groups: Sedentary Youngsters (SY) and Trained Youngsters (TY), Sedentary Elderly (SE) and Trained Elderly (TE). The physical training was based in an moderate aerobic PE protocol through swimming sessions of 45 minutes each, three times a week, for eight consecutive weeks. After that, the peritoneal macrophages were challenged in vitro, during 30 to 120 minutes, with Escherichia Coli (E.coli) or Candida albicans (C.albicans), previously dyed with FITC. Internalized microorganism cells were quantified through fluorescence microscopy. Results:After the PE protocol, the percentage of peritoneal macrophage with internalized microorganisms, from young and old mice, was higher (p<0,05) related to the sedentary. These findings were verified either after the challenge with E. coli bacteria or with C. albicans fungi, independently of the challenge time. The values obtained in 120 minutes were higher than those obtained in the 30 minutes of challenge. After the PE, the percentage values of macrophage with internalized microorganisms were higher among the elderly than those observed among the youngsters, independently of the challenge time (p < 0,05). These age differences also occurred among the sedentary animals. Conclusions: The aerobic physical exercise in a moderate level was able to alter the phagocytic function of the macrophages. The greater internalization of microorganisms in macrophages from the elderly, compared to youngsters, may reflect a previous state of cell activation, due to the increase of of the basal inflammatory activity observed in the elderly (inflammaging).

Em animais, os protocolos de Treinamento Físico Crônico (TF) aeróbio de nível moderado têm sido relacionados com a melhora da capacidade do sistema imunológico, como por exemplo o aumento dos leucócitos e a maior produção de citocinas e de oxido nítrico. Durante o envelhecimento, ocorre uma desregulação do sistema imunológico, conhecido como Imunossenescência, a qual contribui para o aumento da suscetibilidade a infecções, câncer e autoimunidade, e redução da resposta vacinal. Assim, o presente estudo verificou os resultados do TF sobre o sistema imunológico, avaliando a capacidade fagocítica dos macrófagos peritoneais oriundos de animais jovens e idosos. MATERIAL E MÉTODOS: Foram utilizados ratos da linhagem Wistar com 60 dias (Jovens) e com 14 meses de idade (Idosos), divididos em quatro grupos: Jovens Sedentários (JS) e Treinados (JT), e Idosos Sedentários (IS) e Treinados (IT). O protocolo de TF foi realizado através do exercício de nível por meio de natação por 45 minutos, três vezes na semana, por oito semanas consecutivas. Após, os macrófagos peritoneais foram desafiados em vitro, durante 30 e 120 minutos, com Escherichia Coli (E. coli) ou Candida albicans (C. albicans), previamente corados com FITC. Células com microrganismos internalizados foram quantificadas por meio de microscopia de fluorescência. RESULTADOS: Após o protocolo de EF, o percentual de macrófagos peritoneais com microrganismos internalizados, obtidos a partir dos ratos jovens ou idosos, foi maior (p < 0,05) em relação aos sedentários. Estes achados foram verificados tanto após desafio com bactérias E. coli quanto com fungos C. albicans, e independente do período de desafio. Os valores obtidos em 120 minutos foram superiores que aqueles correspondentes aos 30 minutos de desafio. Após o EF, os valores percentuais de macrófagos com microrganismos internalizados foram maiores entre os idosos que aqueles observados entre os jovens, independente do período de desafio (p < 0,05). Estas diferenças etárias também ocorreram entre os animais sedentários. CONCLUSÕES: O exercício físico aeróbio em nível moderado foi capaz de alterar a função fagocítica dos macrófagos. A maior internalização de microrganismos por parte dos macrófagos oriundos dos idosos, em relação aos jovens, pode refletir um estado prévio de ativação celular, em função do aumento da atividade inflamatória basal observado em idosos (inflammaging). / In animals, the aerobic physical training (PT) of moderate level have been related with the improvement of the immunologic system capacity, like the increase of leukocytes and a higher production of cytokines and nitric oxide. While ageing, there is a deregulation of the immunologic system, known as Immunosenescence, which contributes to the increasing of the susceptibility to infections, cancer and autoimmunity, and the vaccine response. Thus, the present study examined the results of PF on the immune system, evaluating the phagocytic capacity of peritoneal macrophages derived from young and old animals. Material and Methods: Young (60-day old) and old (14-month old) Wistar mice were divided in four different groups: Sedentary Youngsters (SY) and Trained Youngsters (TY), Sedentary Elderly (SE) and Trained Elderly (TE). The physical training was based in an moderate aerobic PE protocol through swimming sessions of 45 minutes each, three times a week, for eight consecutive weeks. After that, the peritoneal macrophages were challenged in vitro, during 30 to 120 minutes, with Escherichia Coli (E.coli) or Candida albicans (C.albicans), previously dyed with FITC. Internalized microorganism cells were quantified through fluorescence microscopy. Results:After the PE protocol, the percentage of peritoneal macrophage with internalized microorganisms, from young and old mice, was higher (p<0,05) related to the sedentary. These findings were verified either after the challenge with E. coli bacteria or with C. albicans fungi, independently of the challenge time. The values obtained in 120 minutes were higher than those obtained in the 30 minutes of challenge. After the PE, the percentage values of macrophage with internalized microorganisms were higher among the elderly than those observed among the youngsters, independently of the challenge time (p < 0,05). These age differences also occurred among the sedentary animals. Conclusions: The aerobic physical exercise in a moderate level was able to alter the phagocytic function of the macrophages. The greater internalization of microorganisms in macrophages from the elderly, compared to youngsters, may reflect a previous state of cell activation, due to the increase of of the basal inflammatory activity observed in the elderly (inflammaging).

No description available.

Thesis (MSc (Mathematical Sciences))--University of Stellenbosch, 2011. / Thesis presented in fulfilment of the adacemic requirements for the degree of Master of Science at the University of Stellenbosch. / Please refer to full text to view abstract.

BACKGROUND Aging is characterized by a progressive decline in immune surveillance that favors tumor development in older patients. One of the mechanisms used by malignant cells to escape immune surveillance is genetic or epigenetic modifications of tumor suppressor genes. Studies in B-cells and our previous report on the correlation between 6q deletion and progression into a T cell lymphoproliferative disease, identifying the BACH2 gene as a candidate tumor suppressor gene. Together, BACH2 and PRDM1 are described as having a fundamental role in oncogenesis, differentiation and apoptosis control of B and T lymphocytes during oxidative stress. Furthermore, several studies in mice model suggested that BACH2 gene is sensitive to DNA damage during aging and plays a role in the cellular senescence process. The impact of these genes in the immune response of the older adult is unclear. OUR HYPOTHESIS 1. Recent reports (including our previous study) on the transcription factor BACH2 and PRDM1 have highlighted their impact on immunological changes. It has been shown that BACH2 is highly sensitive to transcription-blocking DNA lesions in aged mice. Despite the growing interest in BACH's role, there have been many studies in mice models, studies on BACH2 in humans are still limited. This concept prompted us to investigate the variation of BACH2 and PRDM1 expression with age in major lymphocyte subsets from healthy individuals. 2. Apoptosis and senescence are two types of cellular response affected by cancer and aging processes, albeit through different mechanisms. Carcinogenesis is associated with a progressive reduction in the ability of the cells to trigger apoptosis and senescence. The lymphocytes apoptosis process and the markers of cell senescence were thus studied in both populations. 3. Chronic lymphocytic leukemia, one of the aging-related diseases, is characterized by the accumulation of “anergic” phenotypes in both B-cells and T-cells. In chronic lymphocytic leukemia, malignant cell anergy is associated with failure of inducing PRDM1 (BLIMP1), a critical regulator of differentiation into plasma cells, and that epigenetic modification account for such failure. We thus examined the expression of specific transcription factors BACH2 and PRDM1 in the leukemic lymphocytes subsets and compared the results with age-matched normal population. POPULATION & METHODS Blood samples were obtained from 60 healthy donors, aged from 20 to 90 years, and 41 untreated chronic lymphocytic leukemia were studied. Lymphocyte subsets (CD19+ B-cells, CD8 T-cells, CD4 T-cells, CD4 naïve T-cells, CD4 effector memory T-cells) were isolated for subsequent molecular analyses using the MACS Technology (Miltenyi), with the purity of each lymphocyte subpopulation between 95%-99%. BACH2, PRDM1, IL-4, IFNG, TP53, CDKN2A (p16INK4A), PDCD1 (PD-1) and CD274 (PD-L1) mRNA transcripts were quantified using qRT-PCR. BACH2 protein expression was examined by Western blotting. To investigate BACH2-target genes in apoptosis, we performed a “Human Apoptosis EpiTect ChIP qPCR Array” profiles including 84 key genes involved in programmed cell death. Etoposide was used to induce intracellular oxidative stress followed by cell apoptosis. Apoptotic cells were identified with the annexin-V-FITC apoptosis detection kit (BD Pharmingen). To measure ß-galactosidase by flow cytometry, we used Fluorescein-di-beta-D-galactopyranoside as a substrate for beta-galactosidase (Molecular Probes).RESULTS 1. BACH2 and PRDM1 gene expression were strongly correlated with age in healthy donor’s major lymphocyte subsets. BACH2 mRNA expression declined by age, with statistically significant differences observed in all lymphocyte subsets: CD4+, CD4+ naïve, CD4+ memory, CD8+ T-cells and CD19+ B-cells (p<0.0001, <0.0001, 0.0118, <0.0001 and 0.0004 respectively). In contrast, PRDM1 gene expression significantly increased with age in the same subpopulations. The phenotypic changes of immune lymphocytes are related to the BACH2 and PRDM1 gene expression. Along with the decline of BACH2, the older group had a severe decrease in number and quality of cytotoxic T-cells (p=0.0005 and <0.0001), while increasing the rate exhausted T-cells that highly expressed of PD-1 and PD-L1. Both PCCD1 (PD-1) and CD274 (PD-L1) gene expression had inversely correlated with BACH2 in the same lymphocyte subsets (p=0.0342; 0.0254 and 0.0429 respectively). Western blotting analysis demonstrated that BACH2 protein expressions in the T and B cell subpopulations significantly correlated with transcript expression. 2. Age-related BACH2 down-regulation enhanced the increasing of senescent cells and the resistance to apoptosis in the major lymphocyte subsets. We, further, found the correlation of BACH2 with senescence markers, such as p16INK4A (CDKN2A) and SA-β-GAL along with loss of CD28+ on T-lymphocytes. ChIP-qPCR Array demonstrated that BACH2 bound directly several genes involved in programmed cell death. A reduction in apoptosis was observed with age in CD4+ T-cells and CD19+ B-cells (p=0.03 in both subpopulations). As recently reported for BACH2-deficient mice, our data show that BACH2 down-regulation is strongly correlated with a decrease in CD4+ T-cell and CD19+ B-cell apoptosis (r=0.57 and 0.61). 3. Decreases in BACH2 mRNA expression were greater in CD4+ and CD8+ T-cells, as well as leukemic B-cell subpopulations from untreated CLL patients, compared with age-matched healthy donors (p=0.0006; 0.0003 and 0.0083, respectively). As expected, PRDM1 was significantly upregulated in the CD4+ and CD8+ T-cell subpopulations (p=0.003 and 0.001, respectively) from CLL patients but not their leukemic B-cells. CONCLUSION In this research work, we examined BACH2 and PRDM1 gene expression to investigate its potential as a predictive marker of aging. Our data suggest BACH2 and PRDM1 mRNA expression, in the inverse correlation, associated with the phenotypic changes of immune lymphocytes in aging. Age-related BACH2 down-regulation enhanced the increasing of exhausted phenotypes, senescent cells and resistance to cell apoptosis. BACH2 and PRDM1 could involve in cellular and immunological functions deterioration of the immunosenescence process. Further investigations on BACH2 and PRDM1 genetic mutations provide a better understanding of the role of the unbalanced expression of those genes in lymphocytes functions and survival according to age. / Doctorat en Sciences biomédicales et pharmaceutiques (Médecine) / info:eu-repo/semantics/nonPublished

Apesar de todo o avanço científico nas últimas décadas, a doença de Chagas ainda é um importante problema em saúde pública. A expectativa de vida no Brasil tem aumentado a cada ano e esse crescimento permite o surgimento de uma população idosa em risco de contrair essa doença. Diante disso, os objetivos deste trabalho foram avaliar a resposta imune em ratos Wistar senescentes, infectados pela cepa Y de T. cruzi. O presente estudo mostrou alterações na imunidade inata, quando avaliamos a população de macrófagos peritoneais, bem como a sinalização (expressão de RT1B) e da molécula coestimulatória (CD80) das células APC nos animais senis. A imunidade celular também foi reduzida, uma vez que os animais senis apresentaram uma diminuição significativa na porcentagem de linfócitos T CD4+ e T CD8+, quando comaprados aos jovens. Além disso, foi observado que o envelhecimento reduz a expressão da principal molécula de sinalização, o CD28+, responsável pela ativação de células T. Nos nossos estudos, o envelhecimento foi associado a um aumento no percentual de linfócitos CD4+CD25lowFOXP3+, que representam as células T regulatórias instáveis. Por outro lado, os animais senis não infectados apresentaram uma redução significante no percentual de linfócitos CD4+CD25highFOXP3+, as células T regulatórias estáveis. A senesescência, bem como, o processo infeccioso ocasionaram um aumento nos níveis de corticosterona e no percentual de esplenócitos em apoptose inicial e tardia em animais senis infectados. O envelhecimento também regulou negativamente a transição DN1-DN2, bem como, as subpopulações de timócitos DN3 e DN4 em animais senis, infectados ou não. Observou-se uma redução no percentual de timócitos viáveis nos animais senis, tanto controles quanto infectados. Com relação aos parâmetros do estresse oxidativo, a senilidade elevou os níveis de TBARS, reduziu a atividade da principal enzima antioxidante SOD e na concentração de 8-isoprostano. O substrato da enzima glutationa peroxidase GSH aumentou nesses animais senis, comparados aos jovens. A análise da produção de citocinas evidenciou um aumento nos níveis de TGF-? em animais senis. No 16° dia após a infecção, um aumento nos níveis de IL-12 foram observados apenas nos animais senis infectados. Entretanto, este mesmo grupo apresentou uma redução na produção de IL-2 no 9º dia após a infecção. As concentrações de IL-17 foram maiores nos animais senis infectados e controles, quando comparados aos animais jovens. Tanto a infecção por T. cruzi quanto o envelhecimento ocasionaram um aumento nos níveis de TNF-? nos animais jovens e senis infectados. Com o presente estudo, conseguimos avançar na compreensão dos mecanismos celulares e moleculares envolvidos nas modificações da imunidade ao longo da vida e seus reflexos frente à doença de Chagas. Inúmeras alterações foram observadas, incluindo resposta imune ineficiente, aumento do estresse oxidativo, bem como diminuição da atividade de enzimas antioxidantes e comprometimento no processo de maturação celular intratímica, os quais afetam etapas essenciais no desenvolvimento dos timócitos e exportação de células T para a periferia. Foi observado um desequilíbrio funcional do eixo neuroendócrino, bem como a diminuição da viabilidade celular. Além disso, as mudanças no perfil da produção de citocinas promoveram implicações diretas na competência imunológica desses animais. / Despite all the scientific advances in the last decades, Chagas disease is still an important public health problem. Every year, the life expectancy in Brazil has increased and this growth tops with the emergence of an elderly population at risk of contracting this disease. Therefore, the objectives of this study were to evaluate the immune response in senescent Wistar rats, infected with T. cruzi Y strain. Changes in innate immunity was observed in the population of peritoneal macrophages, as well as signaling (RT1B expression) and the costimulatory molecule (CD80) of APC cells in senile animals. Cellular immunity was also reduced, since senile animals showed a significant decrease in the percentage of CD4+ T and CD8+T lymphocytes when compared to young counterparts. A reduced expression of the major signaling molecule, CD28+, responsible for T cell activation was also observed as long as animals age. Aging was associated with an increase in the percentage of CD25+ CD25lowFOXP3+ lymphocytes, which represent T regulator cells. On the other hand, the uninfected senile animals presented a significant reduction in the percentage of CD4+ CD25highFOXP3+ lymphocytes. Senescence as well as the infectious process triggered an increase in corticosterone levels and in the percentage of splenocytes in early and late apoptosis in senile infected animals. Aging also negatively regulated the DN1-DN2 transition, as well as the subpopulations of thymocytes DN3 and DN4 in senile animals, infected or not. A reduction in the percentage of viable thymocytes was observed in control and infected senile animals. Regarding to oxidative stress, aging increased the levels of TBARS, reduced the activity of the main antioxidant enzyme SOD and the concentration of 8-isoprostane. Oppositely, aged animals displayed increased levels of the enzyme glutathione peroxidase GSH as compared to the young ones. The analysis of cytokine production evidenced an increase in TGF-? levels in senile animals. On the 16th day after infection, enhanced concentrations of IL-12 was observed only in senile infected animals. However, this same group showed a reduction in IL-2 production on the 9th day after infection. Senile and control animals displayed higher IL-17 concentrations when compared to young animals. Both T. cruzi infection and aging caused an increase in TNF-? levels in young and senile infected animals. The present study allowed us to better understand the cellular and molecular mechanisms involved in the immune response throughout life and its actions on Chagas\' disease. For that, several alterations were observed such as an inefficient immune response, increased oxidative stress, decreased antioxidant enzyme activity and impairment in the intratymic cell maturation process, impairing thymocyte development and the export of T cells to the periphery, as well decreased cell viability. A functional imbalance of the neuroendocrine axis was also observed, as well as changes in the profile of cytokine production directly impairing the immune competence in these animals.

The Swedish OCTO and NONA immune longitudinal studies were able to identify and confirm an immune risk profile (IRP) predictive of an increased 2-year mortality in very old individuals, 86–94 years of age. The IRP, was associated with persistent cytomegalovirus infection and characterized by inverted CD4/CD8 ratio and related to expansion of terminally differentiated effector memory T cells (TEMRA phenotype). In the present HEXA immune longitudinal study, we have examined a younger group of elderly individuals (n = 424, 66 years of age) in a population-based sample in the community of Jönköping, Sweden, to examine the relevance of findings previously demonstrated in the very old. Immunological monitoring that was conducted included T cell subsets and CMV-IgG and CMV-IgM serology. The result showed a prevalence of 15 % of individuals with an inverted CD4/CD8 ratio, which was associated with seropositivity to cytomegalovirus and increases in the level of TEMRA cells. The proportion of individuals with an inverted CD4/CD8 ratio was significantly higher in men whereas the numbers of CD3+CD4+ cells were significantly higher in women. In conclusion, these findings are very similar to those previously found by us in the Swedish longitudinal studies, suggesting that an immune profile previously identified in the very old also exists in the present sample of hexagenerians. Therefore, it will be important to examine clinical parameters, including morbidity and mortality, to assess whether the immune profile also is a risk profile associated with higher mortality in this sample of hexagenerians. / <p>Funding Agencies|Medical Research Council of South-East Sweden||</p>

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第18160号 / 医博第3880号 / 新制||医||1003(附属図書館) / 31018 / 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 生田 宏一, 教授 宮地 良樹 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM