Browsing by Subject "immunology"
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Item Antibodies Recognizing Protective Pertussis Toxin Epitopes are Preferentially Elicited by Natural Infection Versus Acellular Immunization(2011-06) Sutherland, Jamie N.; Chang, Christine; Yoder, Sandra M.; Rock, Michael T.; Maynard, Jennifer A.; Sutherland, Jamie N.; Chang, Christine; Maynard, Jennifer A.Despite more than 50 years of vaccination, disease caused by the bacterium Bordetella pertussis persists, with rates increasing in industrialized countries over the past decade. This rise may be attributed to several factors, including increased surveillance, emergence of vaccine escape variants, waning immunity in adults, and the introduction of acellular subunit vaccines, which include chemically detoxified pertussis toxin (PTd). Two potently protective epitopes on pertussis toxin (PTx) are recognized by the monoclonal antibodies 1B7 and 11E6, which inhibit catalytic and cell-binding activities, respectively. In order to determine whether the PTx exposure route affects antibody responses to these epitopes, we analyzed sera from 30 adults with confirmed pertussis exposure and from 30 recently vaccinated adults for specific anti-PTx antibody responses and in vitro CHO cell neutralization titers. While overall titers against PTx and the genetically detoxified variant, PTg, containing the R9K and E129G substitutions, were similar in the two groups, titers against specific epitopes depended on the exposure route. Natural infection resulted in significantly higher titers of anti-PTx-subunit 1, 1B7-like, and 11E6-like antibodies, while acellular vaccination resulted in significantly higher titers of antibodies recognizing PTd. We also observed a correlation between in vitro protection and the presence of 1B7-like and 11E6-like antibodies. Notably, chemical detoxification, as opposed to genetic inactivation, alters the PTx tertiary and quaternary structure, thereby affecting conformational epitopes and recognition of PTx by 1B7 and 11E6. The lower levels of serum antibodies recognizing clinically relevant epitopes after vaccination with PTd support inclusion of PTg in future vaccines.Item Comparison of Lateral Flow Technology and Galactomannan and (1 -> 3)-Beta-D-Glucan Assays for Detection of Invasive Pulmonary Aspergillosis(2009-12) Wiederhold, Nathan P.; Thornton, Christopher R.; Najvar, Laura K.; Kirkpatrick, William R.; Bocanegra, Rosie; Patterson, Thomas F.; Wiederhold, Nathan P.We compared a lateral flow device to galactomannan and (1 -> 3)-beta-D-glucan assays to detect invasive aspergillosis in an established guinea pig model of pulmonary disease. The lateral flow device became positive earlier ( =day 3) than the (1 -> 3)-beta-D-glucan and galactomannan assays ( day 5), with all samples positive by each assay on day 7.Item Development of a model system to characterize antigen-specific T cell receptors based on TCR affinity and T cell function(2021) Xia, Amanda; Jiang, NingModern T cell cancer immunotherapies are based on the ability of cytotoxic T cells to recognize and attack infected cells. This process is activated by the T cell receptor (TCR) recognizing a peptide-bound major histocompatibility complex (pMHC) on the surface of target cells. It is of particular interest to target neoantigens, antigens derived from tumor-specific DNA mutations, to create a tumor-specific immune response. One method of broadening the T cell response is to genetically engineer the patient’s T cells to express neoantigen-specific TCRs isolated from healthy donors. It is important to understand how the affinity of the TCR-pMHC interaction relates to T cell function in the context of T cells expressing foreign TCR. Here, I created a model system to study human TCRs specific for cytomegalovirus (CMV) pp65, a commonly recognized CMV antigen. By transducing primary T cells with pp65-specific TCRs of known TCR affinity, I investigated how differences in TCR affinity related to T cell function. My model system demonstrated that transduced T cells could maintain high TCR expression over a sustained period and that the affinity of the TCR expressed positively correlated with cytokine production. This sets the foundation of a promising approach to study neoantigen-specific TCRs for the development of melanoma immunotherapy.Item Impaired Function of Antibodies to Pneumococcal Surface Protein A but not to Capsular Polysaccharide in Mexican American Adults with Type 2 Diabetes Mellitus(2012-09) Mathews, Christine E.; Brown, Eric L.; Martinez, Perla J.; Bagaria, Upasana; Nahm, Moon H.; Burton, Robert L.; Fisher-Hoch, Susan P.; McCormick, Joseph B.; Mirza, Sharper; Nahm, Moon H.The goal of the study was to determine baseline protective titers of antibodies to Streptococcus pneumoniae surface protein A (PspA) and capsular polysaccharide in individuals with and individuals without type 2 diabetes mellitus. A total of 561 individuals (131 individuals with diabetes and 491 without) were screened for antibodies to PspA using a standard enzyme-linked immunosorbent assay (ELISA). A subset of participants with antibodies to PspA were retested using a WHO ELISA to determine titers of antibodies to capsular polysaccharide (CPS) (serotypes 4, 6B, 9V, 14, 18C, 19A, 19F, and 23F). Functional activity of antibodies was measured by assessing their ability to enhance complement (C3) deposition on pneumococci and promote killing of opsonized pneumococci. Titers of antibodies to protein antigens (PspA) were significantly lower in individuals with diabetes than controls without diabetes (P = 0.01), and antibodies showed a significantly reduced complement deposition ability (P = 0.02). Both antibody titers and complement deposition were negatively associated with hyperglycemia. Conversely, titers of antibodies to capsular polysaccharides were either comparable between the two groups or were significantly higher in individuals with diabetes, as was observed for CPS 14 (P = 0.05). The plasma specimens from individuals with diabetes also demonstrated a higher opsonophagocytic index against CPS serotype 14. Although we demonstrate comparable protective titers of antibodies to CPS in individuals with and individuals without diabetes, those with diabetes had lower PspA titers and poor opsonic activity strongly associated with hyperglycemia. These results suggest a link between diabetes and impairment of antibody response.Item Long-Term Control Of Viral Replication In A Group O, Human Immunodeficiency Virus Type 1-Infected Individual(2014-06) Buckheit, R. W.; Sexauer, S. B.; Sedaghat, A. R.; Wilke, C. O.; Laeyendecker, O.; Basseth, C. R.; Blankson, J. N.; Wilke, Claus O.Item Optimized Adenovirus-Antibody Complexes Stimulate Strong Cellular and Humoral Immune Responses Against an Encoded Antigen in Naive Mice and Those with Preexisting Immunity(2012-01) Choi, Jin Huk; Dekker, Joe; Schafer, Stephen C.; John, Jobby; Whitfill, Craig E.; Petty, Christopher S.; Haddad, Eid E.; Croyle, Maria A.; Choi, Jin Huk; Dekker, Joe; Schafer, Stephen C.; John, Jobby; Whitfill, Craig E.; Petty, Christopher S.; Haddad, Eid E.; Croyle, Maria A.The immune response to recombinant adenoviruses is the most significant impediment to their clinical use for immunization. We test the hypothesis that specific virus-antibody combinations dictate the type of immune response generated against the adenovirus and its transgene cassette under certain physiological conditions while minimizing vector-induced toxicity. In vitro and in vivo assays were used to characterize the transduction efficiency, the T and B cell responses to the encoded transgene, and the toxicity of 1 x 10(11) adenovirus particles mixed with different concentrations of neutralizing antibodies. Complexes formed at concentrations of 500 to 0.05 times the 50% neutralizing dose (ND(50)) elicited strong virus-and transgene-specific T cell responses. The 0.05-ND(50) formulation elicited measurable anti-transgene antibodies that were similar to those of virus alone (P = 0.07). This preparation also elicited very strong transgene-specific memory T cell responses (28.6 +/- 5.2% proliferation versus 7.7 +/- 1.4% for virus alone). Preexisting immunity significantly reduced all responses elicited by these formulations. Although lower concentrations (0.005 and 0.0005 ND(50)) of antibody did not improve cellular and humoral responses in naive animals, they did promote strong cellular (0.005 ND(50)) and humoral (0.0005 ND(50)) responses in mice with preexisting immunity. Some virus-antibody complexes may improve the potency of adenovirus-based vaccines in naive individuals, while others can sway the immune response in those with preexisting immunity. Additional studies with these and other virus-antibody ratios may be useful to predict and model the type of immune responses generated against a transgene in those with different levels of exposure to adenovirus.Item Short Communication: Dynamic Constraints On The Second Phase Compartment Of Hiv-Infected Cells(2011-07) Spivak, A. M.; Rabi, S. A.; McMahon, M. A.; Shan, L.; Sedaghat, A. R.; Wilke, C. O.; Siliciano, R. F.; Wilke, Claus O.The cells responsible for the second phase decay of HIV-1 viremia following the initiation of antiretroviral therapy have yet to be identified. A dynamic model that considers where drugs act in the virus life cycle places constraints on candidate cell types. In this regard, the rapid drop in viremia in patients starting regimens containing the integrase inhibitor raltegravir is of particular interest. We show here that the time delay between reverse transcription and integration is short in differentiated macrophages, making these cells poor candidates for the second phase compartment under the assumptions of standard models of viral dynamics.