- Dr Daniel Goldstein, Principal Investigator
- Prof. Philip Askenase, Collaborator
- Prof. Richard Flavell, Collaborator
- Yale University School of Medicine, New Haven, USA
- Role of Innate B1 Lymphocytes in Neonatal Transplant Tolerance
Transplantation is a very effective therapy for many end-stage diseases. The success of this therapy has largely been due to medications, which patients must take chronically, that suppress the immune system to avoid rejection of the transplanted organ. However, since these medications also suppress immune responses against infections and malignancy, transplant recipients are at high risk of infection and cancer. Therefore, protocols that can induce immune tolerance (i.e., the ability to manipulate a patient’s immune response so that the organ is no longer perceived as foreign and infections and tumors can be fought off without the need of chronic immunosuppressants) would represent a breakthrough in the field.
In this proposal, we will use a neonatal murine skin transplant model to understand the mechanisms of immune tolerance. This model is particularly relevant because immune tolerance is more readily acquired in the neonate as compared to the adult. Although important insights have been made using this experimental system, all of the studies were performed prior to the appreciation of the innate immune system. The innate immune system acts as a rapid, non-specific “first-response” component in the presence of foreign antigens, whereas the adaptive response is slow but specific to the noxious stimulus. Our prior work indicates that the innate system plays an important role in detecting the presence of transplants. However, the impact of innate immunity on transplant tolerance is largely unknown. Given that our preliminary data indicate that innate immune activated neonatal B cells possess unique immunoregulatory properties, this proposal will test the hypothesis that innate immune activated recipient B-1 cells are critical for the induction of neonatal transplant tolerance. We will use both molecular (i.e., antibody inhibition of specific pathways) and genetic (i.e., use of mice with defined genetic deletions) approaches. If our anticipated results indicate that neonatal innate activated B-1 cells are critical for tolerance this may lead to new investigations of tolerance induction in adults that may bring us closer to clinical protocols that induce immune tolerance.