Sudhir Paul

..These concepts may be useful for developing novel vaccines that capitalize and improve on constitutive antibody functions for protection against microbes...

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..These findings suggest the feasibility of raising antigen-specific proteolytic antibodies on demand by covalent immunization...

..This article attempts to provide a rational basis for natural Ab catalysis, in the hope that understanding this phenomenon will stimulate medical and basic science advances in the field...

..These observations suggest that IgMs can selectively cleave gp120 by a nucleophilic mechanism and raise the possibility of their role as defense enzymes...

..The covalent reactivity of Abs with phosphonate esters suggests their ability to recapitulate the catalytic mechanism utilized by classical serine proteases...

..We present our view that catalytic antibodies are likely to emerge as more efficacious and safer immunotherapy reagents compared to traditional Abeta-binding antibodies...

..We summarize evidence supporting development of covalent immunization as the first vaccine strategy with the potential to induce an antibody response to a conserved HIV epitope that neutralizes genetically divergent HIV strains...

..Criteria appropriate for developing a CIVIG formulation with potential therapeutic utility are discussed, including isolation of the Abeta-specific catalytic subsets present in IgM and IgG from human blood...

..These observations show that VIP is a target for specific catalytic autoantibodies in autoimmune disease...

..In view of their superior catalytic activity, the VL domain IgVs may help attain clearance of medically important antigens more efficiently than natural Igs...

..The neutralizing activity was specifically inhibited by an electrophilic inhibitor of the catalytic activity. The existence of catalytic IgAs to gp120 in uninfected humans suggests their role in resistance to HIV...

..These results suggest a novel route to antigen-specific covalent targeting of pathogenic Abs...

..Reduced Abeta aggregation and neurotoxicity attributable to the catalytic function were evident. These findings provide a foundation for development of catalytic Igs for AD immunotherapy...

..We present models accounting for improved CD4-binding site recognition and broad HIV neutralizing activity of the mAbs, long sought goals in HIV vaccine development...

..These results reveal that the peptidyl phosphonate ester can serve as a probe for the antigen recognition and catalytic subsites of proteolytic antibodies...

..These observations suggest that mechanisms underlying B cell clonal selection favor the retention and improvement of catalytic activity in the IgA, but not the IgG compartment of the immune response...

..These findings suggest the feasibility of raising antibodies capable of long-lasting inactivation of antigens by electrophilic immunization...

..Our results suggest that catalytic IgM autoantibodies can help clear Abeta, and they open the possibility of using catalytic Abs for AD immunotherapy...

..To identify an HIV epitope suitable for vaccine development...

..The scFv neutralized R5 and X4-dependent HIV-1 strains from clades B, C, and D. The lupus repertoire may be useful as a source of neutralizing antibodies to HIV...

..These results suggest that electrophilic immunization induces a sufficiently robust nucleophilic Ab response to enhance the anti-microbial efficacy of candidate polypeptide vaccines...

..These observations indicate the existence of serine protease-like BCRs and secreted IgM Abs as innate immunity components with potential roles in B cell development and Ab effector functions...

..The pairing of such light chains with heavy chains capable of gp120(SAg) recognition represents a potential mechanism for generating protective Abs with enhanced HIV binding strength and anti-viral proteolytic activity...

..One of the 39 light chains studied hydrolyzed the Val197-Ser198 bond of the peptide with Km and kcat values of 223 +/- 7 microM and 0.087 +/- 0.001 min(-1)...

..These studies provide proof-of-principle that the catalytic activity of a light chain can be rendered antigen-specific by pairing with a noncovalently binding heavy chain subunit...

..Further study of the properties of the naturally occurring anti-SAg catalytic Igs should provide valuable guidance in designing a prophylactic vaccine that amplifies protective catalytic immunity to HIV...

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..These observations suggest the potential of EPs for specific and covalent targeting of proteins, and raise the possibility of nucleophile-electrophile pairing as a novel mechanism stabilizing protein-protein complexes...

..In reference to therapy of HIV infection, assurance is required that the Abs recognize the native conformation of gp120 expressed as a trimer on the virus surface...

..Short-lived but strong inhibition of cellular DNA synthesis was observed in the presence of the autoantibodies. We concluded that autoantibody responses to EGFR hold the potential of fulfilling a pathogenic role in autoimmune disease...

..The studies indicate broad and potent HIV neutralization by constitutive Abs as an innate, germline-encoded activity directed to the superantigenic CD4BD(core) epitope that is available for amplification for vaccination against HIV...

..Analysis of the cDNA sequences of these antibodies show clustered mutational patterns in the complementarity determining region, suggesting that variable domains are the products of antigen-driven B cell clonal maturation...

..47 vs 2.0 min(-1)). These observations suggest that the covalent reactivity of phosphonate monoesters contributes to their interactions with serine proteinases, including certain proteolytic antibodies...

..E-FVIII is a prototype reagent able to attain irreversible and specific inactivation of pathogenic Abs...

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..The depletion of VIP by specific antibodies in autoimmune disease may interfere with VIP regulation of T cells and inflammatory cells and result in further amplification of autoreactive immunological responses...

..Successful vaccine targeting of the CD4BD will require a sufficiently rigid immunogen that mimics the native epitope conformation and bypasses B cell checkpoints restricting synthesis of the neutralizing antibodies...

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..These finding suggest a novel mechanism whereby antibodies can induce a procoagulant state, i.e., prothrombin activation via cleavage of the molecule...

..These data suggest a potential defense function for constitutively produced catalytic antibodies to a putative superantigenic site of Efb, but an adaptive catalytic response appears to be proscribed...

..Finally, H-111 blocks HCV-like particle binding to and HCV virion infection of target cells, suggesting the involvement of this epitope in virus binding and entry...

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..Scientific theories are changeable entities, dependent on empirical data and interpretations of the data, and their growth is better served by keeping an open mind...

..We hypothesized that hydrolysis of VIP by circulating catalytic VIP antibodies will be increased in pregnancy in patients with asthma...

..These antibody light chains provide a novel route toward engineering efficient therapeutic antibodies capable of cleaving Abeta in vivo...

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..The level of VIP recognized by CD4 T cells thus is a major determinant of the relative contributions of Th subsets to the immune effector phenotype...

..Thus the ratio of two forms of T cell VPAC2 determines the net effect of VIP on IL-4 generation by activated Th2 cells...

..Artificial CAbs are likely to find increasing applications in research, clinical medicine, diagnostics and manufacturing...

..Novel vaccination strategies and HIV-1 neutralizing Abs will emerge from these studies if the physiological barriers to catalytic Ab synthesis can be bypassed. ..

..From these studies, we hope to identify the strengths and weaknesses of the Abs and immunogens relevant to HIV vaccination and therapy. ..

..Proteolytic anti-Abeta Abs capable of preventing the deposition of Abeta and cognitive decline would be candidates for passive immunotherapy of humans with AD. ..

..These studies may identify proteolytic antibodies suitable for further development as a topical HIVcide. ..

..The investigators expect the proposed studies to generate catalytic Fv constructs capable of permanent and efficient inactivation of EGFR, and to establish the validity of using catalytic Abs for tumor immunotherapy. ..

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..Successful execution of this project will provide insight to the genesis of chemically reactive Abs and potentially validate the use CRAs for inhibition and induction of antigen-specific catalytic Abs. ..

..From these studies, we hope to identify the strengths and weaknesses of the Abs and immunogens relevant to HIV vaccination and therapy. ..