Innate immunity influences long-term outcomes after human lung transplant.
BACKGROUND
Lung transplantation is characterized by very high rates of acute and chronic allograft rejection. We hypothesize that activation of innate immunity augments adaptive immunity, leading to rejection after lung transplantation. In support of this idea, we have recently demonstrated that lung recipients heterozygous for either of two functional polymorphisms (Asp299Gly or Thr399Ile) in Toll-like receptor 4 (TLR4) associated with endotoxin hyporesponsiveness have decreased acute rejection over the first 6 months after transplant.


OBJECTIVE
In the current analysis, we sought to extend our initial observations and investigate the effect of these TLR4 polymorphisms on post-transplant acute rejection beyond the first 6 months, bacterial infections, bronchiolitis obliterans syndrome, and survival.


METHODS
Genotyping was performed on 170 lung transplant recipients.


RESULTS
Recipients heterozygous for either Asp299Gly or Thr399Ile had significantly reduced frequency (p = 0.02) and incidence of acute rejection (p = 0.04) sustained over 3 years after transplant, but no differences were observed in the overall onset of bronchiolitis obliterans syndrome. A trend, however, toward reduced onset of bronchiolitis obliterans syndrome grade 2 or 3 was observed in TLR4 heterozygotes.


CONCLUSIONS
Our results demonstrate that activation of recipient innate immune responses through TLR4 has a significant and sustained effect on the development of acute lung rejection. Targeting innate immune signaling represents a promising area for future clinical studies in the prevention of lung allograft rejection.
Palmer
Scott M
SM
Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA. palme002@mc.duke.edu
Burch
Lauranell H
LH
Trindade
Anil J
AJ
Davis
R Duane
RD
Herczyk
Walter F
WF
Reinsmoen
Nancy L
NL
Schwartz
David A
DA
D000328:Adult; D015415:Biomarkers / Q000032:analysis; D001989:Bronchiolitis Obliterans / Q000175:diagnosis / Q000401:mortality / Q000601:surgery*; D015331:Cohort Studies; D005260:Female; D005500:Follow-Up Studies; D006084:Graft Rejection; D006085:Graft Survival; D006801:Humans; D007113:Immunity, Innate / Q000502:physiology*; D016040:Lung Transplantation / Q000009:adverse effects / Q000379:methods* / Q000401:mortality; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology*; D008875:Middle Aged; D011336:Probability; D016016:Proportional Hazards Models; D011956:Receptors, Cell Surface / Q000235:genetics / Q000276:immunology*; D012189:Retrospective Studies; D018570:Risk Assessment; D012680:Sensitivity and Specificity; D012720:Severity of Illness Index; D015996:Survival Rate; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014181:Transplantation Immunology / Q000502:physiology*; D016042:Transplantation, Heterotopic
D015415:Biomarkers; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors