Date of Award
Master of Science
Toll-like receptors (TLRs) are pattern recognition receptors (PRRs) that recognize pathogen-associated molecular patterns (PAMPs) and host-derived damaged associated molecular patterns (DAMPs). TLR signaling is required to generate immunity, but is undesirable in transplantation. TLRs activate downstream events, evoking inflammatory cytokines/chemokines causing innate immune attacks on grafts. Adaptive attacks occur when TLRs promote dendritic cell (DC) maturation, resulting in antigen-specific rejection. Thus, blocking TLRs may prevent both innate and adaptive immune rejection. In this study, TLR2, TLR4, and the adaptors were silenced in primary DCs and tissues. Furthermore, TLR-silenced-DCs were less mature than control-DCs, caused less T cell proliferation, and induced more regulatory T (Treg) cell production. In a cardiac allogeneic transplant model, mice treated with TLR-shRNA showed graft prolongation, and had less pathological damage. Recipients with prolonged-grafts had less mature DCs that induced less T cell proliferation, but had more Tregs. Therefore, blocking TLRs prolongs graft survival in allogeneic transplants.
Beduhn, Marianne, "PREVENTING ALLOGRAFT REJECTION BY SILENCING TOLL-LIKE RECEPTORS (TLRs)" (2009). Digitized Theses. 3872.