Abstract

<h3>Purpose</h3> Telomere dysfunction may persist in the immune system following lung transplantation for idiopathic pulmonary fibrosis (IPF) and impact responses to infections or donor antigens. Mechanistically, critically short telomeres can activate p53 and block cell proliferation. We hypothesized that p53 activation might be associated with the impaired proliferation to alloantigens for IPF lung transplant recipients. <h3>Methods</h3> We analyzed 5 IPF lung transplant recipients with telomere dysfunction and 6 age-matched non-IPF controls, 18 months after transplantation, and 4 healthy donors. We quantified CD8+ T cell proliferation to pooled, donor-derived, stimulated B cells (sBc) with or without treatment with KML001, a reagent that binds and erodes telomeres. Expression of p53 and proportions of Annexin V+ apoptotic cells were quantified by flow cytometry. Statistical comparisons were performed using 2-way ANOVA with Dunnett's post-test. <h3>Results</h3> IPF lung transplant recipients (Fig. A) demonstrated impaired CD8+ T cell proliferation relative to non-IPF patients (Fig. B) and healthy controls (Fig. C&D, P≤0.0002). This proliferation was further impaired by telomere erosion (Fig. C&E, P<0.0001). P53 expression was increased in cells responding to sBc stimulation (MFI change 183, 95% CI 159-207). Among T cells that did not proliferate to allo-stimulation (Fig. F), p53 expression was higher in IPF subjects versus non-IPF (P=0.049) or healthy referents (P=0.002). Apoptotic cells were not different between groups. <h3>Conclusion</h3> P53 upregulation is associated with impaired CD8+ T cell proliferation to alloantigens in lung transplant recipients with IPF and may mediate proliferative arrest in CD8+T cells for IPF lung transplant recipients. These findings may explain sensitivity of some recipients to p53 activators, such as mycophenolic acid, that may synergize with telomere dysfunction to drive cell cycle arrest and leukopenia.

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