Impact of Allograft Injury Time of Onset on the Development of Chronic Lung Allograft Dysfunction After Lung Transplantation

Abstract

The impact of allograft injury time-of-onset on the risk of chronic lung allograft dysfunction (CLAD) remains unknown. We hypothesized that episodes of late-onset (≥6 months) allograft injury would produce an augmented CXCR3/ligand immune response, leading to increased CLAD. In a retrospective single-center study, 1894 transbronchial biopsies from 441 lung transplant recipients were reviewed for the presence of acute rejection (AR), lymphocytic bronchiolitis (LB), diffuse alveolar damage (DAD) and organizing pneumonia (OP). The association between the time-of-onset of each injury pattern and CLAD was assessed using multivariable Cox models with time-dependent covariates. BAL CXCR3 ligand concentrations were compared between early and late-onset injury patterns using linear mixed-effects models. Late-onset DAD and OP were strongly associated with CLAD: adjusted HRs 2.8 95%CI 1.5-5.3 and 2.0 95%CI 1.1-3.4, respectively. The early-onset form of these injury patterns did not increase CLAD risk. Late-onset LB and AR predicted CLAD in univariable models, but lost significance after multivariable adjustment for late DAD and OP. AR was the only early-onset injury pattern associated with CLAD development. Elevated BAL CXCR3 ligand concentrations during late-onset allograft injury parallel the increase in CLAD risk and support our hypothesis that late allograft injuries result in a more profound CXCR3/ligand immune response.

Telomere Dysfunction Drives Chronic Lung Allograft Dysfunction Pathology

“…We speculate that senescence reprogramming due to telomere dysfunction in club cells leads to release of an array of cytokines and chemokines that attract immune cells to the lung. Elevated numbers of T cells and NK cells could reflect a direct response to cell stress (37) or be due to T-cell attracting chemokines released by senescent club cells, such as CXCL-9, CXCL-10 and CXCL-11, that are commonly elevated in airway inflammation (38) and CLAD (39,40). Elevated levels of lymphocytes in lungs of SCGB1a1-cre TRF1 F/F transgenic mice suggests that telomere dysfunction in club cells could even contribute to the inflammatory changes seen in CLAD.…”

Chronic Lung Allograft Dysfunction: Evolving Concepts and Therapies

“…In a recent single-center cohort study, we showed that late onset (at least 6 months posttransplant) LB is a risk factor for BOS, but not RAS. 128 However, in another study, LB was a risk factor for both BOS and RAS, and severe LB was more common in RAS than BOS. 149 As previously noted, the major risk factor for RAS is DAD, 114,115 and possibly OP as well.…”

“…115 Furthermore, BAL fluid concentrations of these chemokines are increased during injury, and the levels associate with the subsequent development of CLAD. 115,[128][129][130] CXCR3 chemokine ligands are also increased during community-acquired respiratory viral infection, and high levels predicted worse allograft function 6 months after recovery from the infection. 131 These studies suggest that CXCR3/ligand biology during allograft injury may set up the scenario for progression to CLAD by recruiting cytotoxic lymphocytes to the graft.…”

CCR4 expression on host T cells is a driver for alloreactive responses and lung rejection

“…This is particularly concerning when compared with other solid organ transplants such as liver, kidney, and heart that have 5-year survival rates of at least 70% (1)(2)(3)(4)(5)(6). Lung transplant recipients also have much higher rates of rejection, the main risk factor for limited lung allograft survival (7)(8)(9)(10)(11)(12)(13)(14)(15). Rejection is classically considered a consequence of an immune response to donor alloantigens that results in allograft dysfunction (7)(8)(9)(10)(11)(12)(13)(14)(15).…”

“…Lung transplant recipients also have much higher rates of rejection, the main risk factor for limited lung allograft survival (7)(8)(9)(10)(11)(12)(13)(14)(15). Rejection is classically considered a consequence of an immune response to donor alloantigens that results in allograft dysfunction (7)(8)(9)(10)(11)(12)(13)(14)(15). However, many of the molecular factors involved in the initiation of the alloresponse that leads to rejection remain largely unknown.…”