TLR Activation Prevents Hematopoietic Chimerism Induced by Costimulation Blockade: A Dissertation

Abstract

Costimulation blockade based on a donor-specific transfusion and anti-CD154 mAb is effective for establishing mixed allogeneic hematopoietic chimerism and inducing transplantation tolerance. Despite its potential, recent evidence suggests that the efficacy of costimulation blockade can be reduced by environmental perturbations such as infection or inflammation that activate toll-like receptors (TLR). TLR agonists prevent costimulation blockade-induced prolongation of solid organ allografts, but their effect on the establishment of hematopoietic chimerism has not been reported. In this dissertation, we hypothesized that TLR activation during costimulation blockade would prevent the establishment of mixed hematopoietic chimerism and shorten skin allograft survival. To test this hypothesis, costimulation blockade-treated mice were co-injected with TLR2 (Pam3Cys), TLR3 (poly I:C), or TLR4 (LPS) agonists and transplanted with allogeneic bone marrow and skin grafts. Supporting our hypothesis, we observed that TLR agonists administered at the time of costimulation blockade prevented the establishment of mixed hematopoietic chimerism and shortened skin allograft