Immunomodulation and immunotherapy

Abstract

Background: Antibody-mediated immunity (AMI) was first described in 1890 by Behring and Kitasato when they observed that the transfer of sera from an immunized to a naïve host protected the latter against the effects of diphtheria and tetanus toxins. The experiments by Behring and Kitasato defined the central procedure that is still being used today for evaluating the efficacy of AMI (reviewed by Casadevall, A.-J. Immunol. Methods 291:1-10, 2004). After being a central piece in the development of immunology in the early 20 th century, the study of the functional aspects of AMI declined in the 1960s. The role of antibodies was taken as completely understood, and with the discovery of T cells, there was increased interest on cell-mediated immunity, which with the rediscovery of innate immunity, steered immunological research away from AMI. By the late 1980s, however, the development of monoclonal antibody (mAb) technology, the discovery of Fc receptors, and generation of mice with defined genetic deficiencies made possible studies that rekindled the interest on the basic mechanisms of AMI (reviewed by Casadevall and Pirofski. Infect. Immun. 72: 6191-6196, 2004). The relationship between antigen-specific immunoglobulin concentration and protection remains poorly understood for the majority of pathogens. There is conclusive evidence, however, that humoral immunity can modify the course of infection caused by some pathogenic fungi. Immunotherapy studies, especially of cryptococcosis are most advanced. C. neoformans has a polysaccharide capsule which is essential for its virulence, and mAbs reactive with GXM can protect against experimental cryptococcosis. The efficacy of these monoclonal antibodies against GXM is associated with several parameters such as isotype, recognized epitope, dose and infective inoculum. Antibodies in paracoccidioidomycosis (PCM) have been associated to severe disease, whereas protection has always been attributed to cellular immune response. Mattos Grosso et al., (Infect. Immun. 71: 6534-6542, 2003) showed that mAbs to gp70 abolished granuloma formation in the lungs of mice intratracheally infected. In the present work a panel of mAbs directed to peptide epitopes of the gp43 was evaluated in vivo. Methods: Four anti-gp43 IgG2a mAbs (32H, 19G, 17D and 10D) and two IgG2b mAbs (3E and 21F) were analyzed. As a control, an irrelevant mAb (A4) was used. Twenty four hours before the mice were intratracheally infected with 3x10 5 yeast cells of Pb18, 1 mg of mAb was injected intraperitoneally per animal. Groups of mice were sacrificed 15 and 30 days after the infection and colony forming units (CFU) from the lungs were counted. Results: Significant reduction in the lung CFUs was observed after 15 days with all mAbs tested with the exception of mAb 32H (IgG2a). However, after 30 days of infection, mAbs 19G and 10D (IgG 2a) and 3E (IgG 2b) were able to control the disease whereas mAbs 32H and 17D (IgG2a) and 21F (IgG2b) caused a significant increase in the number of lung CFUs. Discussion: Specific anti...