Genes that Mediate Tolerance to the Placental Allograft

Summary

Principal Investigator: BRUCE A BEUTLER
Abstract: All eutherian mammals tolerate the engraftment of histoincompatible tissue during pregnancy. Yet, the maternal immune system remains competent to repel infection or to reject other forms of tissue allograft. Selective anergy to the placenta is one of the central unsolved mysteries of immunology. Since the placenta developed in an ancestral species that was endowed with a competent adaptive immune system, it is reasonable to suppose that this organism developed a mechanism for the circumvention of adaptive immunity to the trophoblast, and further, that the same core mechanism persists in its descendants today. It may be taken as axiomatic that a discrete set of maternally expressed genes is required for the maintenance of tolerance, and further, that mutations affecting these genes could disrupt tolerance. To approach the question of tolerance to the placenta, we have initiated a program of saturation mutagenesis in mice, employing a screen to detect mutations that forbid allogeneic (but not syngeneic) pregnancy. Three dominant mutations have been identified among 3506 F1 and F3 mice screened as of this writing. These mutations, and others that emerge, will be mapped and ultimately resolved through positional cloning methods. The identification of the gene(s) required for maintenance of selective tolerance to the fetal allograft will have several important consequences. First, it might ultimately be possible to take advantage of the toleragenic system utilized during mammalian gestation to promote the survival of other types of allograft: an outcome that would have important ramifications in transplantation medicine. Second, a similar or identical molecular system might be important in the maintenance of tolerance to self, and defects of the system might represent primary lesions in certain autoimmune diseases. Third, failure of tolerance to the placental allograft might be responsible for recurrent abortion as witnessed in humans and other mammalian species. Fourth, circumvention of the toleragenic mechanism might be used to prevent normal gestation, leading to termination of pregnancy within a few days following implantation of the blastocyst.
Funding Period: 2003-05-01 - 2007-04-30
more information: NIH RePORT

Top Publications

  1. ncbi CD14 is required for MyD88-independent LPS signaling
    Zhengfan Jiang
    Department of Immunology, The Scripps Research Institute, 10550 N Torrey Pines Road, La Jolla, California 92037, USA
    Nat Immunol 6:565-70. 2005
  2. ncbi R-form LPS, the master key to the activation ofTLR4/MD-2-positive cells
    Michael Huber
    Molecular Immunology, Institute for Biology III, Albert Ludwigs University Freiburg, Freiburg, Germany
    Eur J Immunol 36:701-11. 2006
  3. pmc Adjuvant-enhanced antibody responses in the absence of toll-like receptor signaling
    Amanda L Gavin
    Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037 USA
    Science 314:1936-8. 2006

Scientific Experts

  • Michael Huber
  • Amanda L Gavin
  • Bruce Beutler
  • Zhengfan Jiang
  • Christopher Martin
  • Takayuki Ota
  • Kasper Hoebe
  • David Nemazee
  • Bao Duong
  • Xin Du
  • Sosathya Sovath
  • Christoph Kalis
  • Marina Freudenberg
  • Suzanne Mudd
  • Simone Keck
  • Louis Shamel
  • Chris Galanos
  • Philippe Georgel

Detail Information

Publications3

  1. ncbi CD14 is required for MyD88-independent LPS signaling
    Zhengfan Jiang
    Department of Immunology, The Scripps Research Institute, 10550 N Torrey Pines Road, La Jolla, California 92037, USA
    Nat Immunol 6:565-70. 2005
    ..Thus, the TLR4-MD-2 complex receptor can function in two separate modes: one in which full signaling occurs and one limited to MyD88-dependent signaling...
  2. ncbi R-form LPS, the master key to the activation ofTLR4/MD-2-positive cells
    Michael Huber
    Molecular Immunology, Institute for Biology III, Albert Ludwigs University Freiburg, Freiburg, Germany
    Eur J Immunol 36:701-11. 2006
    ....
  3. pmc Adjuvant-enhanced antibody responses in the absence of toll-like receptor signaling
    Amanda L Gavin
    Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037 USA
    Science 314:1936-8. 2006
    ..This may have important implications in the use and development of vaccine adjuvants...