Training in Transplantation Immunology

Brigham And Women'S Hospital, Boston MA

Investigators

Abstract

DESCRIPTION (provided by applicant): The experimental objective of this proposal is to understand the role of innate immunity and cell trafficking in the pathogenesis of graft rejection in vascularized solid organ transplantation. In this proposal, our hypothesis is that donor dendritic cells in the graft are activated by innate stimuli promoting migration to the lymph node, where they present antigen and activate T cells. The activated T cells then migrate to the inflamed graft and produce effector functions that induce rejection. We will investigate the following Aims in a cardiac transplant model. To investigate the functions of innate stimuli mediated by Toll like receptors, we will use MyD88 deficient mice. Lack of MyD88 is associated with delayed rejection of cardiac grafts. To investigate the crucial functions of peripheral lymph nodes, we will use LTbeta-R deficient mice that have defective organogenesis of lymph nodes. After splenectomy, LTbeta-R deficient mice ultimately reject allografts with extremely prolonged kinetics. To track the migration of donor and recipient dendritic cells and lymphocytes, we will use transgenic mice that constitutively express the green fluorescent mice as donors and/or recipients. In AIM 1, we will analyze the MyD88-dependent innate immune activation of donor dendritic cells following transplantation. In AIM 2, we will analyze the lymph node dependent immune activation of recipient T cells following transplantation.