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INNATE IMMUNE RESPONSE IS ACTIVATED BY TLR 4 SIGNALING IN HUMAN LUNG TRANSPLANT RECIPIENTS.
S. Ramachandran, Ph.D, K. Parekh, M.D, F. Fernandez, M.D, A. Patterson, M.D and T. Mohanakumar, Ph.D. St. Louis MO, USA, Washington University School of Medicine, 63110, Surgery, Path.
Immunol.
Introduction: TLRs have been shown to play an important role in linking innate immunity to the adaptive immune responses. The objective of the study were: 1. To identify the role of TLRs in activation of the innate immune response (IIR) following human lung transplantation. 2. To determine the role of TLR in development of obliterative airway disease (OAD) using a murine heterotopic tracheal transplant model with TLR2 and TLR 4 knockout mice.
Methods: Expression of TLRs 2,3,4,5,6,7,8, 9, 10 TIRAP and TOLLIP were analyzed on bronchoalveolar lavage cells post-op day 1 following transplantation. Tracheal allografts from BALB/c were heterotopically transplanted into C57BL/6 (n=5) or TLR2 or TLR4 knockout (KO) mice. NF-kB activation were analyzed using TransAM™ NFkB Family Transcription Factor Assay Kit
Results: An increased activation of the innate immune response through the TLR4 (2-5 fold increase) signaling was observed in the BAL samples from human lung transplant recipients. TLR2 and TLR4 expression were up regulated in heterotopically transplanted wild type mice 3 days post transplant along with an increased activation of NF-kB (3 fold). A significant 6 and 3 fold decrease in NF-kB activation was also observed in TLR4 KO mice and TLR2 KO mice respectively.
Conclusion: TLR4 is a major pathway through which innate immunity is activated immediately following human lung transplantation. This is further supported by the finding that deficiency of TLR4 results in decreased activation of NF-kB in murine heterotopic tracheal transplant model of obliterative airway disease.