The Role of Innate Immunity in Acute Allograft Rejection after Lung Transplantation

Abstract

Although innate immunity is crucial to pulmonary host defense and can initiate immune and inflammatory responses independent of adaptive immunity, it remains unstudied in the context of transplant rejection. To investigate the role of innate immunity in the development of allograft rejection, we assessed the impact of two functional polymorphisms in the toll-like receptor 4 (TLR4) associated with endotoxin hyporesponsiveness on the development of acute rejection after human lung transplantation. Patients and donors were screened for the TLR4 Asp299Gly and Thr399Ile polymorphisms by polymerase chain reaction using sequence-specific primers. The rate of acute rejection at 6 months was significantly reduced in recipients, but not in donors, with the Asp299Gly or Thr399Ile alleles as compared with wild type (29 vs. 56%, respectively, p = 0.05). This association was confirmed in Cox proportional hazards and multivariate logistic regression models. Our results suggest activation of innate immunity in lung transplant recipients through TLR4 contributes to the development acute rejection after lung transplantation. Therapies directed at inhibition of innate immune responses mediated by TLR4 may represent a novel and effective means to prevent acute rejection after lung transplantation.

Transcript Signatures of Lymphocytic Bronchitis in Lung Allograft Biopsy Specimens

“…It is also consistent with the recent appreciation of sub-types of acute allograft rejection featuring differences in immune activation and cellular proliferation indistinguishable by light microscopy, 35 recognition of a chronic onset form of BOS not strongly linked to acute rejection, 36 and involvement of innate as well as adaptive immune mechanisms in rejection. 37 These data not only shed light on the feasibility and diagnostic implications of measuring multiple transcripts in bronchoscopic biopsies but also provide clues about the mechanism. The finding that type I collagen, MMP, and fibronectin transcripts increase with increasing grades of lymphocytic bronchitis is especially meaningful because these gene products are associated with tissue remodeling and fibrosis, as in OB.…”

Toll-Like Receptor 4 Gene Polymorphisms and Preeclampsia: Lack of Association in a Caucasian Population

“…Interestingly, the Asp299Gly variant decreased the susceptibility to rheumatoid arthritis (32) and late-onset Alzheimer's disease (33). Moreover, both polymorphisms decreased the risk of diabetic neuropathy in patients with type 2 diabetes (34), as well as of acute allograft rejection after lung transplantation (35).…”

Lung Transplantation: Opportunities for Research and Clinical Advancement

“…Using polymerase chain reaction allelic discrimination assays, specific TLR4 polymorphisms at Asp299 and Thr399 alleles in the recipient were associated with a lower incidence of rejection (29% rate of rejection in TLR4 mutants vs. 56% rate of rejection in wild-type recipient) (103). In contrast, no effect was seen with the 299/399 polymorphisms on rejection by donor genotype.…”