Design And Synthesis Of Immunomodulators And Vaccine Con

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Abstract

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 other cellular events (cell cycle progression and apoptosis) that follow activation of resting, mature human 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). This past year, we prepared double conjugates of anti-IgM and anti-CD21 on soluble, high molecular weight dextran that Dr. Mongini employed for studying the empact of co-engagement of the corresponding receptors in the presence of IL-4 on B cell expression of molecules critical for T cell activation, namely, CD80 and CD86. Significantly heightened expression (upregulation) was observed. Thus, co-clustering of B cell receptors and CD21 (CR2) plus added IL-4, following exposure to complement complexed with microbial or self antigens, will enhance B cell recruitment of T cell help. Conjugates of heat killed Brucella abortus (BA) with antigenic epitopes prepared in our lab allowed B. Golding et al., at CBER, FDA, to make further observations on the immune responses involving this strong, Th1-directing carrier. Intranasal immunization with BA-HIV V3 loop peptide conjugate elicited neutralizing antibodies and HIV-specific cytotoxic T cells at various mucosal surfaces in mice. Scott, Golding et al. reported that ovalbumin-Brucella conjuates (OVA-BA) injected into 1 week old mice imprinted a Th1 bias on much later encounters with this antigen presented with alum, a normally Th2-type, allergenic immunogen.