Using natural antibodies to improve vaccines

Summary

Principal Investigator: JOHN J IACOMINI
Affiliation: Harvard University
Country: USA
Abstract: DESCRIPTION (provided by applicant): Natural antibodies play a major role in providing protective host immunity. A significant portion of natural antibodies present in all humans, apes and Old World primates are specific for the carbohydrate antigen Gal11-3Gal21-4GlcNAc-R, or 1Gal. Indeed, 1Gal-specific natural antibodies comprise one to eight percent of circulating immunoglobulin in humans. Based on the universal high-titer presence of these antibodies, we hypothesized that it might be possible to utilize this pre-existing antigen-specific repertoire to augment the immunogenicity of antigens in order to improve the efficacy of vaccines. To test this hypothesis, we used 1Gal-deficient mice (GT0 mice), which like humans produce 1Gal-specific natural antibodies, to analyze whether conjugation of a poorly immunogenic antigen, such as bovine serum albumin (BSA), to 1Gal could affect its immunogenicity in vivo. Immunization of GT0 mice with BSA conjugated to 1Gal (1Gal-BSA) led to a T and B cell response to BSA that was significantly greater than that observed following immunization of control mice without the need for adjuvant. The ability to produce 1Gal-specific antibodies also led to an enhanced cytotoxic T lymphocyte anti-virus response following challenge of mice with murine leukemia virus- transformed cell lines expressing 1Gal. These data suggest that pre-existing 1Gal-specific antibodies encoded for in the natural antibody repertoire can be used to increase B and T cell responses to poorly immunogenic antigens that have been modified to express 1Gal epitopes without the need for adjuvant. The central hypothesis of this proposal is therefore that this pre-existing antibody repertoire can be used to improve vaccine strategies for pathogens. The specific aims are: to determine the mechanism by which 1Gal-specific natural antibodies increase the immunogenicity of antigens modified to express 1Gal;determine if pre-existing 1Gal-specific natural antibodies can be used to improve vaccines for pathogens, and;determine the effectiveness of immunization with 1Gal-modified antigens in immunocompromised hosts. PUBLIC HEALTH RELEVANCE: The development of novel immunization strategies against emerging pathogens remains a high public health priority throughout the world. In this proposal we will examine whether pre-existing natural antibody specificities can be used to develop potentially novel vaccine strategies.
Funding Period: -------------------2 - ------------------20
more information: NIH RePORT

Top Publications

  1. pmc Induction of transplantation tolerance to fully mismatched cardiac allografts by T cell mediated delivery of alloantigen
    Chaorui Tian
    Brigham and Women s Hospital and Children s Hospital Boston, Harvard Medical School, Boston, MA, USA
    Clin Immunol 136:174-87. 2010
  2. pmc Costimulation-dependent expression of microRNA-214 increases the ability of T cells to proliferate by targeting Pten
    Peter T Jindra
    Transplantation Research Center, Renal Division, Brigham and Women s Hospital, Harvard Medical School, Boston, MA 02115, USA
    J Immunol 185:990-7. 2010
  3. pmc The PD-1 pathway in tolerance and autoimmunity
    Loise M Francisco
    Department of Pathology, Harvard Medical School, Brigham and Women s Hospital, Boston, MA 02115, USA
    Immunol Rev 236:219-42. 2010

Detail Information

Publications3

  1. pmc Induction of transplantation tolerance to fully mismatched cardiac allografts by T cell mediated delivery of alloantigen
    Chaorui Tian
    Brigham and Women s Hospital and Children s Hospital Boston, Harvard Medical School, Boston, MA, USA
    Clin Immunol 136:174-87. 2010
    ..Thus, delivery of alloantigen by mature T cells induces tolerance to fully allogeneic organ allografts in non-myeloablatively conditioned recipients, representing a novel approach for tolerance induction in transplantation...
  2. pmc Costimulation-dependent expression of microRNA-214 increases the ability of T cells to proliferate by targeting Pten
    Peter T Jindra
    Transplantation Research Center, Renal Division, Brigham and Women s Hospital, Harvard Medical School, Boston, MA 02115, USA
    J Immunol 185:990-7. 2010
    ..Thus, the requirement for T cell costimulation is, in part, related to its ability to regulate expression of miRNAs that control T cell activation...
  3. pmc The PD-1 pathway in tolerance and autoimmunity
    Loise M Francisco
    Department of Pathology, Harvard Medical School, Brigham and Women s Hospital, Boston, MA 02115, USA
    Immunol Rev 236:219-42. 2010
    ..Thus, this review also discusses how the PD-1 pathway regulates a number of autoimmune diseases and the therapeutic potential of PD-1: PD-L modulation...