Browsing by Subject "Immunity, Cellular"
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Item Open Access Association between cell-mediated demyelination and astrocyte stimulation.(Prog Brain Res, 1992) Smith, ME; Sommer, MAItem Open Access B-lymphocyte effector functions in health and disease.(2010) DiLillo, David JohnB cells and humoral immunity make up an important component of the immune system and play a vital role in preventing and fighting off infection by various pathogens. B cells also have been implicated in the pathogenesis of autoimmune disease. However, the various functions that B cells perform during the development and maintenance of autoimmune conditions remain unclear. Therefore, the overall goal of this dissertation was to determine what roles B cells play during autoimmune disease. In the Chapter 3 of this dissertation, the function of B cells was assessed during tumor immunity, a model of immune system activation and cellular immunity. To quantify B cell contributions to T cell-mediated anti-tumor immune responses, mature B cells were depleted from wild type adult mice using CD20 monoclonal antibody (mAb) prior to syngeneic B16 melanoma tumor transfers. Remarkably, subcutaneous (s.c.) tumor volume and lung metastasis were increased two-fold in B cell-depleted mice. Effector-memory and interferon (IFN)γ or tumor necrosis factor (TNF)α-secreting CD4+ and CD8+ T cell induction was significantly impaired in B cell-depleted mice with tumors. Tumor antigen (Ag)-specific CD8+ T cell proliferation was also impaired in tumor-bearing mice that lacked B cells. Thus, B cells were required for optimal T cell activation and cellular immunity in this in vivo non-lymphoid tumor model. In Chapter 4 of this dissertation, the roles that B cells play during immune responses elicited by different allografts were assessed, since allograft rejection is thought to be T cell-mediated. The effects of B cell-depletion on acute cardiac rejection, chronic renal rejection, and skin graft rejection were compared using CD20 or CD19 mAbs. Both CD20 and CD19 mAbs effectively depleted mature B cells, while CD19 mAb treatment depleted plasmablasts and some plasma cells. B cell depletion did not affect acute cardiac allograft rejection, although CD19 mAb treatment prevented allograft-specific IgG production. Nonetheless, CD19 mAb treatment significantly reduced renal allograft rejection and abrogated allograft-specific IgG development, while CD20 mAb treatment did not. By contrast, B cell depletion exacerbated skin allograft rejection and augmented the proliferation of adoptively transferred alloAg-specific CD4+ T cells, demonstrating that B cells can also negatively regulate allograft rejection. Thereby, B cells can either positively or negatively regulate allograft rejection depending on the nature of the allograft and the intensity of the rejection response. Serum antibody (Ab) is, at least in part, responsible for protection against pathogens and tissue destruction during autoimmunity. In Chapter 5 of this dissertation, the mechanisms responsible for the maintenance of long-lived serum Ab levels were examined, since the relationship between memory B cells, long-lived plasma cells, and long-lived humoral immunity remains controversial. To address the roles of B cell subsets in the longevity of humoral responses, mature B cells were depleted in mice using CD20 mAb. CD20+ B cell depletion prevented humoral immune responses and class switching, and depleted existing and adoptively-transferred B cell memory. Nonetheless, B cell depletion did not affect serum Ig levels, Ag-specific Ab titers, or bone marrow (BM) Ab-secreting plasma cell numbers. Co-blockade of LFA-1 and VLA-4 adhesion molecules temporarily depleted long-lived plasma cells from the BM. CD20+ B cell depletion plus LFA-1/VLA-4 mAb treatment significantly prolonged Ag-specific plasma cell depletion from the BM, with a significant decrease in Ag-specific serum IgG. Collectively, these results indicate that BM plasma cells are intrinsically long-lived. Further, these studies now demonstrate that mature and memory B cells are not required for maintaining BM plasma cell numbers, but are required for repopulation of plasma cell-deficient BM. Thereby, depleting mature and memory B cells does not have a dramatic negative effect on pre-existing Ab levels. Collectively, the studies described in this dissertation demonstrate that B cells function through multiple effector mechanisms to influence the course and intensity of normal and autoreactive immune responses: the promotion of cellular immune responses and CD4+ T cell activation, the negative regulation of cellular immune responses, and the production and maintenance of long-lived Ag-specific serum Ab titers. Therefore, each of these three B cell effector mechanisms can contribute independently or in concert with the other mechanisms to clear pathogens or cause tissue damage during autoimmunity.Item Open Access Enhanced immune activation linked to endotoxemia in HIV-1 seronegative MSM.(AIDS (London, England), 2014-09) Palmer, Christine D; Tomassilli, Julia; Sirignano, Michael; Romero-Tejeda, Marisol; Arnold, Kelly B; Che, Denise; Lauffenburger, Douglas A; Jost, Stephanie; Allen, Todd; Mayer, Kenneth H; Altfeld, MarcusThis study assessed cellular and soluble markers of immune activation in HIV-1 seronegative MSM. MSM immune profiles were characterized by an increased expression of CD57 on T cells and endotoxemia. Endotoxin presence was linked to recent high-risk exposure and associated with elevated cytokine levels and decreased CD4+/CD8+ T cell ratios. Taken together, these data show elevated levels of inflammation linked to periods of endotoxemia resulting in a significantly different immune phenotype in a subset of MSM at a high risk of HIV-1 acquisition.Item Open Access Establishment of normative ranges of the healthy human immune system with comprehensive polychromatic flow cytometry profiling.(PloS one, 2019-01) Yi, John S; Rosa-Bray, Marilyn; Staats, Janet; Zakroysky, Pearl; Chan, Cliburn; Russo, Melissa A; Dumbauld, Chelsae; White, Scott; Gierman, Todd; Weinhold, Kent J; Guptill, Jeffrey TExisting normative flow cytometry data have several limitations including small sample sizes, incompletely described study populations, variable flow cytometry methodology, and limited depth for defining lymphocyte subpopulations. To overcome these issues, we defined high-dimensional flow cytometry reference ranges for the healthy human immune system using Human Immunology Project Consortium methodologies after carefully screening 127 subjects deemed healthy through clinical and laboratory testing. We enrolled subjects in the following age cohorts: 18-29 years, 30-39, 40-49, and 50-66 and enrolled cohorts to ensure an even gender distribution and at least 30% non-Caucasians. From peripheral blood mononuclear cells, flow cytometry reference ranges were defined for >50 immune subsets including T-cell (activation, maturation, T follicular helper and regulatory T cell), B-cell, and innate cells. We also developed a web tool for visualization of the dataset and download of raw data. This dataset provides the immunology community with a resource to compare and extract data from rigorously characterized healthy subjects across age groups, gender and race.Item Open Access Single-shot Ad26 vaccine protects against SARS-CoV-2 in rhesus macaques.(Nature, 2020-10) Mercado, Noe B; Zahn, Roland; Wegmann, Frank; Loos, Carolin; Chandrashekar, Abishek; Yu, Jingyou; Liu, Jinyan; Peter, Lauren; McMahan, Katherine; Tostanoski, Lisa H; He, Xuan; Martinez, David R; Rutten, Lucy; Bos, Rinke; van Manen, Danielle; Vellinga, Jort; Custers, Jerome; Langedijk, Johannes P; Kwaks, Ted; Bakkers, Mark JG; Zuijdgeest, David; Rosendahl Huber, Sietske K; Atyeo, Caroline; Fischinger, Stephanie; Burke, John S; Feldman, Jared; Hauser, Blake M; Caradonna, Timothy M; Bondzie, Esther A; Dagotto, Gabriel; Gebre, Makda S; Hoffman, Emily; Jacob-Dolan, Catherine; Kirilova, Marinela; Li, Zhenfeng; Lin, Zijin; Mahrokhian, Shant H; Maxfield, Lori F; Nampanya, Felix; Nityanandam, Ramya; Nkolola, Joseph P; Patel, Shivani; Ventura, John D; Verrington, Kaylee; Wan, Huahua; Pessaint, Laurent; Van Ry, Alex; Blade, Kelvin; Strasbaugh, Amanda; Cabus, Mehtap; Brown, Renita; Cook, Anthony; Zouantchangadou, Serge; Teow, Elyse; Andersen, Hanne; Lewis, Mark G; Cai, Yongfei; Chen, Bing; Schmidt, Aaron G; Reeves, R Keith; Baric, Ralph S; Lauffenburger, Douglas A; Alter, Galit; Stoffels, Paul; Mammen, Mathai; Van Hoof, Johan; Schuitemaker, Hanneke; Barouch, Dan HA safe and effective vaccine for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may be required to end the coronavirus disease 2019 (COVID-19) pandemic1-8. For global deployment and pandemic control, a vaccine that requires only a single immunization would be optimal. Here we show the immunogenicity and protective efficacy of a single dose of adenovirus serotype 26 (Ad26) vector-based vaccines expressing the SARS-CoV-2 spike (S) protein in non-human primates. Fifty-two rhesus macaques (Macaca mulatta) were immunized with Ad26 vectors that encoded S variants or sham control, and then challenged with SARS-CoV-2 by the intranasal and intratracheal routes9,10. The optimal Ad26 vaccine induced robust neutralizing antibody responses and provided complete or near-complete protection in bronchoalveolar lavage and nasal swabs after SARS-CoV-2 challenge. Titres of vaccine-elicited neutralizing antibodies correlated with protective efficacy, suggesting an immune correlate of protection. These data demonstrate robust single-shot vaccine protection against SARS-CoV-2 in non-human primates. The optimal Ad26 vector-based vaccine for SARS-CoV-2, termed Ad26.COV2.S, is currently being evaluated in clinical trials.