An Examination of the Programs for Education of Gifted Children in United States

The purpose of this study was (1) to examine the provisions for gifted children made in the schools of the United States, (2) to consider the relative merits of the various procedures, and (3) to consider ways in which these procedures are applied, and (4) to describe the methods which the average teacher can use in her classroom

Mind the Gap: How Interspecies Variability in IgG and Its Receptors May Complicate Comparisons of Human and Non-human Primate Effector Function

The field of HIV research relies heavily on non-human primates, particularly the members of the macaque genus, as models for the evaluation of candidate vaccines and monoclonal antibodies. A growing body of research suggests that successful protection of humans will not solely rely on the neutralization activity of an antibody's antigen binding fragment. Rather, immunological effector functions prompted by the interaction of the immunoglobulin G constant region and its cognate Fc receptors help contribute to favorable outcomes. Inherent differences in the sequences, expression, and activities of human and non-human primate antibody receptors and immunoglobulins have the potential to produce disparate results in the observations made in studies conducted in differing species. Having a more complete understanding of these differences, however, should permit the more fluent translation of observations between model organisms and the clinic. Here we present a guide to such translations that encompasses not only what is presently known regarding the affinity of the receptor-ligand interactions but also the influence of expression patterns and allelic variation, with a focus on insights gained from use of this model in HIV vaccines and passive antibody therapy and treatment

Immunotherapy of colon cancer

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Biology, February 2010."February 2010." Cataloged from PDF version of thesis.Includes bibliographical references.A33 is a cell surface glycoprotein of colon epithelium with a long clinical history as a target in antibody-based cancer therapy. Despite being present in normal colon, radio-labeled antibodies against A33 are selectively retained by tumors at long time points. Accordingly, we have studied the trafficking and kinetic properties of the antigen to determine its promise in multi-step, pretargeted immunotherapy. In vitro, the localization, mobility, and persistence of the antigen were investigated, and this work has demonstrated that the antigen is both highly immobile and extremely persistent, properties which may contribute to the prolonged retention of the clinically administered antibodies, and their uncommon ability to penetrate solid tumors. Secondly, because poor tissue penetration is a significant obstacle to the development of successful antibody drugs for immunotherapy of solid tumors, we assess the contribution of antigen density and turnover rate by evaluating the distance to which antibodies penetrate spheroids when these properties are systematically varied. The results agree well with the quantitative modeling predictions, and demonstrate that dosing distal regions of tumors is best achieved by selecting slowly internalized targets that are not expressed above the level necessary for recruiting a toxic dose of therapeutic. Lastly, we describe the in vitro characteristics and report the promising in vivo biodistribution of a multi-step tumor targeting therapy utilizing a novel bispecific antibody which recognizes both the A33 antigen and a small molecule radiometal chelate. Following these studies, several protein engineering techniques are presented. First, a new method of conducting de novo protein engineering utilizing highly avid magnetic beads is described, in which extremely weak interactions can be captured from large library populations. Secondly, an in vitro assay which utilizes these highly avid magnetic beads is used to score the clinical immunogenicity of therapeutic protein drugs is presented. Finally, the use of sortase A as a means to generate fusion proteins posttranslationally is described. Taken together, this additional work demonstrates a productive intersection of basic research and protein engineering methods.by Margaret E. Ackerman.Ph.D

Enhanced Phagocytic Activity of HIV-Specific Antibodies Correlates with Natural Production of Immunoglobulins with Skewed Affinity for FcγR2a and FcγR2b

While development of an HIV vaccine that can induce neutralizing antibodies remains a priority, decades of research have proven that this is a daunting task. However, accumulating evidence suggests that antibodies with the capacity to harness innate immunity may provide some protection. While significant research has focused on the cytolytic properties of antibodies in acquisition and control, less is known about the role of additional effector functions. In this study, we investigated antibody-dependent phagocytosis of HIV immune complexes, and we observed significant differences in the ability of antibodies from infected subjects to mediate this critical effector function. We observed both quantitative differences in the capacity of antibodies to drive phagocytosis and qualitative differences in their FcγR usage profile. We demonstrate that antibodies from controllers and untreated progressors exhibit increased phagocytic activity, altered Fc domain glycosylation, and skewed interactions with FcγR2a and FcγR2b in both bulk plasma and HIV-specific IgG. While increased phagocytic activity may directly influence immune activation via clearance of inflammatory immune complexes, it is also plausible that Fc receptor usage patterns may regulate the immune response by modulating downstream signals following phagocytosis—driving passive degradation of internalized virus, release of immune modulating cytokines and chemokines, or priming of a more effective adaptive immune response

Boosting of HIV Envelope Cd4 Binding Site Antibodies with Long Variable Heavy Third Complementarity Determining Region in the Randomized Double Blind Rv305 Hiv-1 Vaccine Trial

The canary pox vector and gp120 vaccine (ALVAC-HIV and AIDSVAX B/E gp120) in the RV144 HIV-1 vaccine trial conferred an estimated 31% vaccine efficacy. Although the vaccine Env AE.A244 gp120 is antigenic for the unmutated common ancestor of V1V2 broadly neutralizing antibody (bnAbs), no plasma bnAb activity was induced. The RV305 (NCT01435135) HIV-1 clinical trial was a placebo-controlled randomized double-blinded study that assessed the safety and efficacy of vaccine boosting on B cell repertoires. HIV-1- uninfected RV144 vaccine recipients were reimmunized 6–8 years later with AIDSVAX B/E gp120 alone, ALVAC-HIV alone, or a combination of ALVAC-HIV and AIDSVAX B/E gp120 in the RV305 trial. Env-specific post-RV144 and RV305 boost memory B cell VH mutation frequencies increased from 2.9% post-RV144 to 6.7% post-RV305. The vaccine was well tolerated with no adverse events reports

Biophysical and Functional Characterization of Rhesus Macaque IgG Subclasses

Antibodies raised in Indian rhesus macaques [Macaca mulatta (MM)] in many preclinical vaccine studies are often evaluated in vitro for titer, antigen-recognition breadth, neutralization potency, and/or effector function, and in vivo for potential associations with protection. However, despite reliance on this key animal model in translation of promising candidate vaccines for evaluation in first in man studies, little is known about the properties of MM immunoglobulin G (IgG) subclasses and how they may compare to human IgG subclasses. Here, we evaluate the binding of MM IgG1, IgG2, IgG3, and IgG4 to human Fc gamma receptors (FcgammaR) and their ability to elicit the effector functions of human FcgammaR-bearing cells, and unlike in humans, find a notable absence of subclasses with dramatically silent Fc regions. Biophysical, in vitro, and in vivo characterization revealed MM IgG1 exhibited the greatest effector function activity followed by IgG2 and then IgG3/4. These findings in rhesus are in contrast with the canonical understanding that IgG1 and IgG3 dominate effector function in humans, indicating that subclass-switching profiles observed in rhesus studies may not strictly recapitulate those observed in human vaccine studies

Desensitization of the dopaminergic system in bovine retina following incubation with high potassium

The effect of potassium depolarization on dopamine D1 receptor activity in bovine retina was investigated. Preincubation of bovine retinas in buffer containing high KC1 (56 mM) as compared to a low KC1 control buffer resulted in a significant decrease in dopamine-stimulated adenylate cyclase with no change in basal or GTP-stimulated adenylate cyclase activity. The apparent Vmax for dopamine was decreased from 102 +/- 15 pmol/min/mg protein in retinas preincubated in high KC1 to 71 +/- 11 pmol/min/mg protein in control retinas (n = 5). The apparent Ka for dopamine stimulation of the enzyme did not change. The potassium-induced desentization could be blocked by preincubation with the dopamine antagonist cis-flupenthixol suggesting that the desentization was caused by the release of dopamine. The rapid desentization was not accompanied by a change in D1 receptor density as assessed by binding of [3H]SCH23390 nor in agonist binding as assessed by competition of the selective D1 agonist, SKF38393, for [3H]SCH23390 binding. The potassium-induced desentization was mimicked by preincubation of retinas in control medium containing isobutylmethylxanthine or dibutyryl cyclic AMP. Incubation of retinas in 56 mM KC1 also fed to a decrease in activation of adenylate cyclase by vasoactive intestinal polypeptide. These results strongly suggest that potassium depolarization leads to a very rapid heterologous desentization of adenylate cyclase in bovine retinas.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/28516/1/0000313.pd

Mucosal Immunity: The Forgotten Arm of the Immune System.

The 2017 Stanley A. Plotkin Lecture in Vaccinology was delivered by Professor Peter F. Wright at the Pediatric Academic Societies Annual Meeting in San Francisco, California, in May 2017. The presentation provided an overview of the mucosal immune system as it applies to vaccinology. Specifically, Professor Wright's lecture highlighted the remarkable opportunities for mucosal immunity research afforded by having both topically administered live vaccines and systemically administered inactivated vaccines available for the same pathogen. Using influenza and poliovirus case studies, Professor Wright described the use of live attenuated vaccines for human challenges and discussed how recent technological advancements in immunological assays have ushered in a new era for investigating the correlates of immune protection against wild-type infections at mucosal sites

A Pilot Study of the Effects of Mycoplasma ovipneumoniae Exposure on Domestic Lamb Growth and Performance

Mycoplasma ovipneumoniae is a globally distributed pathogen that has been associated with pneumonia in both domestic and wild Caprinae. It is closely related to M. hyopneumoniae, a respiratory pathogen of swine that is associated with decreased growth rates of pigs as well as clinical respiratory disease. In order to assess the effects of M. ovipneumoniae on lamb performance, we generated a cohort of lambs free of M. ovipneumoniae by segregation of test negative ewes after lambing, then compared the growth and carcass quality traits of M. ovipneumoniae-free and -colonized lambs from weaning to harvest. Some signs of respiratory disease were observed during the feeding trial in both lamb groups, but the M. ovipneumoniae-exposed group included more affected lambs and higher average disease scores. At harvest, lungs of lambs in both groups showed few grossly visible lesions, although the M. ovipneumoniae-exposed group did exhibit increased microscopic lung lesions (P\u3c0.05). In addition, M. ovipneumoniae exposed lambs produced lower average daily gains (P\u3c0.05), and lower yield grade carcasses (P\u3c0.05) compared to those of non-exposed lambs. The results demonstrated the feasibility of test and segregation for elimination of M. ovipneumoniae from groups of sheep and suggested that this pathogen may impair lamb growth and productivity even in the absence of overt respiratory disease