Design/Synthesis:Immunomodulators And Vaccine Constructs

Niaid Extramural Activities

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Abstract

These studies are aimed at developing an effective immunotherapeutic vaccine for treating HIV-infected, immunocompromised individuals. As a model for such patients, Drs. B. Golding, H. Golding and D. E. Scott and their staff (CBER, FDA) have employed MHC class II deficient (knockout) mice, since these mice have low CD4+ T cell numbers and are susceptible to opportunistic infections. We have continued to provide these investigators with covalent conjugates of synthetic peptides bound to heat-killed bacteria from Brucella abortus (BA). When injected into normal ) and class II deficient mice, these conjugates induced high levels of cytokines, IL-12, IFNgamma, associated with favorable Th1 type responses. In both types of mice, antibodies of IgA and predominantly Ig2a, Ig2b and Ig3 isotypes were elicited. Also, good cellular immunity was observed. A study was completed in which our conjugates with heat-killed B. abortus were employed to discern that dendritic cells (DC) are indeed major producers of IL-12 in spleens. However, our results challenge the notion that subsets of DC are destined to selectively induce Th1 or Th2 respsonses. Comparing responses to B. abortus and other pathogen carriers, demonstrated that the nature of the stimulating substance determines which DC subsets are activated to produce IL-12 (see, Huang et al., 2001). We have designed and prepared a number of antibody-dextran conjugates that have been employed by Dr. Patricia Mongini at NY University in experiments aimed at exploring how the mode of presentation of an antigen at the B cell surface affects activation thresholds and the cellular and biochemical events (apoptosis or S phase entry) that follow activation of resting, mature B cells. Using our co-conjugates of anti-IgM (surrogate for antigenic determinants) and anti-CD21 (surrogate for complement C3d, ligand for the CD21:CD19:CD81 B cell complex), Dr. Mongini demonstrated that T-dependent antibody responses can be significantly enhanced via polyvalent co-ligation of the B cell receptor with the CD21 complex as occurs when B cells are stimulated with an antigen-complement complex (see, Mongini et al., 2001).