IGG CLASS AND FUNCTION OF ANTIPOLYSACCHARIDE ANTIBODIES

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DESCRIPTION: Anti-polysaccharide (PS) antibodies (Ab) are critical to host defense against encapsulated bacteria. The function of anti-PS Ab includes complement fixation and opsonization of bacteria for uptake and killing by phagocytes. The mammalian IgG anti-PS Ab response has delayed ontogeny and isotype restriction initially (IgG3 in mice, IgG2 in man). These antibodies class-switch predominately to IgG1 if the PS is conjugated to protein in both mouse and man. Defining the causes of this isotype restriction as well as the relative function of anti-PS antibodies of different IgG subclasses is crucial to better understanding immunity to PS-encapsulated bacteria and pathogenesis of human diseases such as IgG subclass deficiency. Precise evaluation of the effect of subclass on anti-PS antibody function is also important to improve serological correlates of immunity after vaccination with PS and PS-conjugate vaccines. The function of anti-PS Ab of different IgG subclasses remains unclear because to previous studies have used polyclonal affinity purified Ab exposed to chaotropic agents that alter Fc function. In addition, the use of monoclonal Ab with different antigenic specificities, and the lack of animal models of IgG subclass deficiency have limited the understanding of subclass-specific antibodies. In the current proposal the investigator will precisely define the role of IgG subclass in anti-PS Ab effector function, and determine the role of the constant region gene for the dominant anti-PS IgG subclass in immunity and in class switching that occurs when PS are conjugated to proteins. First, using variable region identical mouse/human chimeric Ab of all four human subclasses against P. aeruginosa (PA) LPS O-side chain, the investigator will determine differences in protective efficacy of Ab in animal models of PA infection and then define the mechanism of the observed functional differences. Second, he will make and characterize mouse/human chimeric antibodies against pneumococcal capsular PS to better define the role of IgG subclass in protection against pneumococcus, to improve serological correlates of protection and to determine if anti-PS subclass functional differences are epitope specific. Third, in order to determine the in vivo importance of the predominant anti-PS IgG subclass and to determine the importance of the heavy chain gene in anti-PS class switching, the investigator and his collaborators have successfully developed an IgG 3-deficient knockout mouse via 3 gene targeting and homologous recombination. These mice will now be evaluated for their ability to immunologically respond to PS, PS-protein conjugates, and encapsulated bacterial infections. These studies will determine which anti-PS IgG subclass functions most efficiently against PS-coated bacteria, better define the mechanism of functional differences between IgG subclasses and explore the relevance of these differences in vivo. These data will allow more rational strategies of active and passive immunization against PS-coated bacteria and improved treatment of IgG subclass deficiencies.