This project is directed toward the design and synthesis of immunogens and immun-modulators for collaborative studies in basic and applied immunology. Much of this work has been focused upon (1) studying mechanisms of activation of B cells through their specific antigen-binding receptors (membrane immunoglobulins), (2) developing novel and highly effective ways to stimulate specific humoral and cellular immune responses, and (3) translating these findings into potentially practical approaches to the immunization of humans against infectious diseases (e.g., malaria, AIDS, diphtheria-pertussis-tetanus, and H. influenzae Type b infections). Emphasis has been placed on studying the effects of polyvalent presentation of biologically active molecules (antibodies, peptides, polysaccharides, ligands, haptens, etc.), covalently linked to soluble high molecular weight polymers, on cell cultures or experimental animals. Soluble conjugates permit study of dose-response relationships and the quantitation of signal amplification due to multivalence by direct comparison with unconjugated effector molecules. An example has been collaborative studies on B cell activation by means of anti- immunoglobulins multiply coupled to high molecular weight dextran to serve as panclonal surrogates for hapten-specific type-2 thymus independent immunogens. New reagents and methods have been developed in this Section for synthesizing conjugates used for investigating novel approaches to synthetic vaccines. Enhanced humoral immune responses have been observed to heterodimers of antigen and anti-membrane proteins and to polyvalent conjugates of antigens with soluble, high molecular weight polymers (e.g., dextran). Rapid, large, specific antibody responses have been elicited with these constructs which were effective without adjuvant. Conjugates based on lipopolysaccharide from B. abortusas a carrier and adjuvant are being actively investigated as potential therapeutic vaccines for treating AIDS. Collaborative studies have been initiated on the biological responses, in vitro and in vivo, to synthetic peptides linked to polymer carriers. The sequences are taken from the large, adhesive glycoprotein, thrombospondin, that interacts with cells and matrix structures, serving as both a positive and negative modulator of motility, adhesion and proliferation. The goal is to develop selective biological response modifiers for controlling tumor metastases and various lymphocyte functions.
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| Wofsy, C; Vonakis, B M; Metzger, H et al. (1999) One lyn molecule is sufficient to initiate phosphorylation of aggregated high-affinity IgE receptors. Proc Natl Acad Sci U S A 96:8615-20 |
