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Live-attenuated vaccination with simian immunodeficiency virus (SIV) SIVmac239Δnef is the most successful vaccine product tested to date in macaques. However, the mechanisms that explain the efficacy of this vaccine remain largely unknown. We utilized an ex vivo viral suppression assay to assess the quality of the immune response in SIVmac239Δnef-immunized animals. Using major histocompatibility complex-matched Mauritian cynomolgus macaques, we did not detect SIV-specific functional immune responses in the blood by gamma interferon (IFN-γ) enzyme-linked immunospot assay at select time points; however, we found that lung CD8+ T cells, unlike blood CD8+ T cells, effectively suppress virus replication by up to 80%. These results suggest that SIVmac239Δnef may be an effective vaccine because it elicits functional immunity at mucosal sites. Moreover, these results underscore the limitations of relying on immunological measurements from peripheral blood lymphocytes in studies of protective immunity to HIV/SIV.Despite over 25 years of intensive research, efforts to develop a successful prophylactic HIV vaccine have failed (6, 39). The extraordinary difficulty of developing an HIV vaccine underscores the fact that the elements comprising an effective immune response directed against HIV are poorly understood. Simian immunodeficiency virus (SIV) infection of Mauritian cynomolgus macaques (MCM) provides the best model for unraveling the correlates of protection against SIV. With SIV infection of MCM, we can select the timing, route, dose, and sequence of the infecting virus. Additionally, the limited genetic diversity of MCM facilitates selection of genetically matched individuals that can be monitored throughout the acute phase of infection and enables more frequent and invasive sampling, especially of mucosal sites.Macaques infected with live-attenuated SIV, like SIVmac239Δnef, exhibit robust protection from pathogenic SIV infection (8, 10, 20, 25, 29, 35, 40, 44, 49, 53). While previous studies have included considerable heterogeneity in the strain of attenuated SIV, challenge strain, and macaque species used, they demonstrate collectively the broad spectrum of attenuated SIVs that effectively protect macaques against pathogenic challenge. Several studies have also shown that attenuated SIV effectively protects cynomolgus macaques against pathogenic challenge using an SIVmac239C8 virus (1-3). Like SIVmac239Δnef, this virus has a deletion in the nef gene, but this deletion is a considerably smaller 12-bp deletion than the 182-bp deletion in SIVmac239Δnef (24). Importantly, there are no studies that establish the protective efficacy of SIVmac239Δnef in MCM. Nevertheless, peak SIVmac239Δnef viral loads in MCM parallel the range established in rhesus macaques, between 3.2 × 103 and 9.4 × 105 (35), but fall below peak loads established in a separate study (8). The differences observed between the rhesus macaque study and our own could be due to differences in challenge dose. Long-term control of SIVmac239Δnef in MCM is also similar to that in rhesus macaques (35). It is critical to understand why live-attenuated SIV vaccines are so effective, with the ultimate goal of using these principals to develop a vaccine that is safe for use in humans.There are several plausible explanations for why live-attenuated SIV vaccines provide effective protection against challenge with pathogenic SIV. These explanations range from viral interference to a robust vaccine-elicited immune response (19, 43, 45, 47). We currently understand several aspects of live-attenuated vaccination with SIVmac239Δnef. First, there is an inverse relationship between the degree of attenuation and the level of protection (21). This relationship suggests that vigorous viral replication is important for the generation of an effective anti-SIV immune response. Second, the greater the sequence diversity between the vaccine strain and the challenge strain, the weaker is the protection provided by the vaccine (53). This demonstrates that an adaptive immune response that recognizes similar epitopes or virus features between the vaccine and challenge strains is necessary for protection in this model. Finally, vaccination with live-attenuated SIV requires a 15- to 20-week induction phase to achieve protection in the majority of animals (8). Thus, there is a direct relationship between the time postvaccination and the degree of protection between 0 and 20 weeks postvaccination. This temporal relationship suggests that a fully developed memory response is required to protect against pathogenic SIV challenge. Together, these observations argue that SIV-specific CD8+ T-lymphocyte responses might be important in protection as these responses would be less useful in the setting of heterologous virus challenge and require both robust viral replication and time to develop. Such responses, however, can be weak to nonexistent in the blood of vaccinated animals and frequently do not correlate with disease progression, leading some investigators to question their importance in protective immunity (25, 29, 45, 46). We hypothesize that continued replication of live-attenuated SIV in the mucosal tissues may lead to effective, compartmentalized memory T-cell responses that are important in controlling pathogenic SIV challenge.It is possible that prophylactic mucosal immunity is required to prevent viral replication soon after SIV infection and to minimize the destruction of mucosal immune cells that occurs within the first 3 weeks of SIV infection (9, 22, 26, 30). Initial depletion of effector memory CD4+ T cells in the gut-associated lymphoid tissue (GALT) combined with continuous viral replication leads to prolonged immune activation, eventual depletion of central memory CD4+ T cells, and the development of AIDS. An effective mucosal immune response elicited by live-attenuated SIV vaccination may prevent the initial CD4+ T-cell depletion from the gut. Several recent studies confirm a critical protective role for CD8+ T cells in the genital tract after vaccination with SHIV89.6, demonstrating that a mucosal immune response is capable of protecting against or ameliorating SIV infection (14-16, 48). Another study has also demonstrated the presence of high-frequency, polyfunctional T-cell responses in the mucosal tissues of elite controllers, i.e., individuals who maintain plasma viral loads below 75 copies/ml, compared to blood from the same individual, tissues of noncontrollers, and antiretroviral drug-treated patients. This study also provides a correlation between mucosal CD8+ T-cell responses and HIV control (12).While studying gut mucosal tissues is clearly an important part of understanding HIV/SIV pathology, there are several challenges to this undertaking. First, accessing gut tissues requires invasive sampling procedures, which are primarily limited to biopsy or time-of-death studies. Biopsies are often limited in number throughout the life span of an animal, while routine necropsy is cost-prohibitive for macaque studies. Second, these tissues are nonsterile. The digestive tract is teeming with floras that contaminate experiments requiring long-term cell culture. Finally, biopsies of mucosal tissues yield very few cells. These low cell numbers make ex vivo experiments very difficult or impossible to perform. Investigators have developed techniques to assess gut mucosal lymphocyte function by expanding these cells in vitro under sterile conditions with antibiotics and then using them in enzyme-linked immunospot assays (ELISPOT) or intracellular cytokine secretion (ICS) assays (18, 42). However, these experiments still suffer from two problems: (i) cells are altered in vitro, which may change their functional capacity; and, (ii) these experiments still rely on indirect measures of CD8+ T-cell function. These difficulties have limited research on mucosal CD8+ T-cell immunity during SIV infection.In light of these challenges, we decided to focus on the lung mucosal tissue, using CD8+ T cells isolated from bronchoalveolar lavage fluid (BAL). BAL samples lung mucosa where there are a large number of resident lymphocytes that encounter respiratory pathogens. Furthermore, BAL provides a minimally invasive sampling of a mucosal tissue that can be performed frequently, and BAL harbors effector T cells similar to GALT (32). These factors make the lung an ideal site for sampling mucosal CD8+ T cells.We modified an ex vivo viral suppression assay that tests the ability of CD8+ T cells to prevent viral replication in MCM (7, 27, 28, 36, 51, 54, 55). Using this approach, we compared the suppressive capacity of CD8+ T cells isolated from lung and blood, and we found that CD8+ T cells from the lung are more effective at suppressing viral replication than CD8+ T cells from the blood. This assay does not manipulate lung lymphocytes in vitro and provides a direct measure of CD8+ T-cell function. Furthermore, our data support the idea that CD8+ T cells in blood and mucosal tissue are not functionally equivalent, that blood lymphocytes are not a perfect surrogate for mucosal lymphocytes, and that mucosal T cells attenuate SIV replication to a greater extent than blood T cells.  相似文献   
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Introduction

We investigated the relationship of circulating tumor cells (CTCs) in non-small cell lung cancer (NSCLC) with tumor glucose metabolism as defined by 18F-fluorodeoxyglucose (FDG) uptake since both have been associated with patient prognosis.

Materials & Methods

We performed a retrospective screen of patients at four medical centers who underwent FDG PET-CT imaging and phlebotomy prior to a therapeutic intervention for NSCLC. We used an Epithelial Cell Adhesion Molecule (EpCAM) independent fluid biopsy based on cell morphology for CTC detection and enumeration (defined here as High Definition CTCs or “HD-CTCs”). We then correlated HD-CTCs with quantitative FDG uptake image data calibrated across centers in a cross-sectional analysis.

Results

We assessed seventy-one NSCLC patients whose median tumor size was 2.8 cm (interquartile range, IQR, 2.0–3.6) and median maximum standardized uptake value (SUVmax) was 7.2 (IQR 3.7–15.5). More than 2 HD-CTCs were detected in 63% of patients, whether across all stages (45 of 71) or in stage I disease (27 of 43). HD-CTCs were weakly correlated with partial volume corrected tumor SUVmax (r = 0.27, p-value = 0.03) and not correlated with tumor diameter (r = 0.07; p-value = 0.60). For a given partial volume corrected SUVmax or tumor diameter there was a wide range of detected HD-CTCs in circulation for both early and late stage disease.

Conclusions

CTCs are detected frequently in early-stage NSCLC using a non-EpCAM mediated approach with a wide range noted for a given level of FDG uptake or tumor size. Integrating potentially complementary biomarkers like these with traditional patient data may eventually enhance our understanding of clinical, in vivo tumor biology in the early stages of this deadly disease.  相似文献   
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The production of fully immunologically competent humanized mice engrafted with peripheral lymphocyte populations provides a model for in vivo testing of new vaccines, the durability of immunological memory and cancer therapies. This approach is limited, however, by the failure to efficiently engraft human B lymphocytes in immunodeficient mice. We hypothesized that this deficiency was due to the failure of the murine microenvironment to support human B cell survival. We report that while the human B lymphocyte survival factor, B lymphocyte stimulator (BLyS/BAFF) enhances the survival of human B cells ex vivo, murine BLyS has no such protective effect. Although human B cells bound both human and murine BLyS, nuclear accumulation of NF-kappaB p52, an indication of the induction of a protective anti-apoptotic response, following stimulation with human BLyS was more robust than that induced with murine BLyS suggesting a fundamental disparity in BLyS receptor signaling. Efficient engraftment of both human B and T lymphocytes in NOD rag1(-/-) Prf1(-/-) immunodeficient mice treated with recombinant human BLyS is observed after adoptive transfer of human PBL relative to PBS treated controls. Human BLyS treated recipients had on average 40-fold higher levels of serum Ig than controls and mounted a de novo antibody response to the thymus-independent antigens in pneumovax vaccine. The data indicate that production of fully immunologically competent humanized mice from PBL can be markedly facilitated by providing human BLyS.  相似文献   
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Umbilical cord blood (UCB) is increasingly being used for human hematopoietic stem cell (HSC) transplantation in children but often requires pooling multiple cords to obtain sufficient numbers for transplantation in adults. To overcome this limitation, we have used an ex vivo two-week culture system to expand the number of hematopoietic CD34(+) cells in cord blood. To assess the in vivo function of these expanded CD34(+) cells, cultured human UCB containing 1 x 10(6) CD34(+) cells were transplanted into conditioned NOD-scid IL2rgamma(null) mice. The expanded CD34(+) cells displayed short- and long-term repopulating cell activity. The cultured human cells differentiated into myeloid, B-lymphoid, and erythroid lineages, but not T lymphocytes. Administration of human recombinant TNFalpha to recipient mice immediately prior to transplantation promoted human thymocyte and T-cell development. These T cells proliferated vigorously in response to TCR cross-linking by anti-CD3 antibody. Engrafted TNFalpha-treated mice generated antibodies in response to T-dependent and T-independent immunization, which was enhanced when mice were co-treated with the B cell cytokine BLyS. Ex vivo expanded CD34(+) human UCB cells have the capacity to generate multiple hematopoietic lineages and a functional human immune system upon transplantation into TNFalpha-treated NOD-scid IL2rgamma(null) mice.  相似文献   
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