Lung Transplant Recipients with Idiopathic Pulmonary Fibrosis and Telomere Dysfunction Have Impaired Donor-Specific Immune Responses

Abstract

Purpose Telomere dysfunction is linked to idiopathic pulmonary fibrosis (IPF) and worse outcomes following lung transplantation. The association of telomere dysfunction with both CMV infection and leukopenia post-transplant suggests impaired immunity, but telomere associations with allograft-specific immune responses are unknown. We hypothesized that impaired proliferation to donor antigens would be associated with both IPF as a transplant indication and decreased telomere length. Methods We analyzed peripheral blood mononuclear cells (PBMC) from 14 IPF lung transplant recipients, and 12 age-matched non-IPF controls, before and 24 months after transplantation, as well as PBMC from 9 healthy donors. The proportions of regulatory, CD4+ conventional, and CD8+ T cells proliferating in response to donor-derived, stimulated B cells (sBc) were quantified by flow cytometry. Proliferation was compared between IPF and non-IPF recipients by t-test. PBMC telomere length was measured by quantitative PCR and compared with proliferation to alloantigens by Pearson correlation. Results Pre-transplant, IPF lung transplant recipients demonstrated impaired CD8+ T cell proliferation to donor antigens, relative to non-IPF patients (P Conclusion IPF as an indication for lung transplant is associated with short leukocyte telomere length and impaired T cell responses to donor antigens. However, the rescue of proliferation by cytokine exposure suggests that infection could drive heterologous immunity and ensuing allograft dysfunction in this population. These findings may inform studies to optimize immunosuppression for lung transplant recipients with short telomeres.