- Dr. Daniel R. Goldstein, Principal Investigator
- Dr. Ruslan Medzhitov, Collaborator
- Yale University, New Haven, USA
- Role of Innate Immunity inTransplantation Tolerance
Toll-like receptors are critical innate immune receptors that detect the presence of microbial invasion. Recent in vitro studies have demonstrated that Toll-like receptors can affect the function of T regulatory cells. However, the role of Toll-like receptors in immunological tolerance, specifically transplantation tolerance remains obscure. Our preliminary data provides evidence that signaling via the Toll-like receptor signal adaptor, MyD88, inhibits tolerance in the adult. Furthermore, we provide evidence that Toll-like receptor expression is reduced in the neonate.
Since neonatal tolerance models are critical for our understanding of the basic mechanisms of immune tolerance, we propose to examine whether Toll-like receptor immune function is reduced in the neonate and whether this effect is critical for neonatal transplantation tolerance by promoting the generation of functional regulatory T cells. Therefore, this proposal will determine whether reduced innate immune signaling via Toll-like receptors promotes immunological tolerance.
The information generated will provide a new paradigm in the field that is directly translatable to human allotransplantation and autoimmunity (i.e., the development of inhibitors of Toll-like receptors at the time of tolerance induction). Additionally, this proposal will provide critical information as to whether Toll-like receptor-dependent immune function is impaired in the neonate, a previously unexplored area. Acquisition of this knowledge has the potential to translate into improved therapies for neonatal and childhood infections and the development of more efficacious childhood vaccinations.