Adaptive and innate immune responses in a rat orthotopic lung transplant model of chronic lung allograft dysfunction

Abstract

Acute rejection and respiratory infections are major risk factors for chronic lung allograft dysfunction (CLAD) after lung transplantation. To shed light on the enigmatic etiology of CLAD, we test the following hypotheses using a new experimental model: (i) Alloimmune-independent pulmonary inflammation reactivates alloimmunity. (ii) Alloimmunity enhances the susceptibility of the graft toward pathogen-associated molecular patterns. Pulmonary Fischer 344 to Lewis rat allografts were treated with lipopolysaccharide (LPS), which consistently results in lesions typical for CLAD. Grafts, local lymph nodes, and spleens were harvested before (day 28) and after LPS application (days 29, 33, and 40) for real-time RT-PCR and immunohistochemistry. Mixed lymphocyte reactions were performed on day 33. Four weeks after transplantation, lung allografts displayed mononuclear infiltrates compatible with acute rejection and overexpressed most components of the toll-like receptor system. Allografts but not secondary lymphoid organs expressed increased levels of Th1-type transcription factors and cytokines. LPS induced macrophage infiltration as well as mRNA expression of pro-inflammatory cytokines and effector molecules of innate immunity. Unexpectedly, T-cell reactivity was not enhanced by LPS. We conclude that prevention of CLAD might be accomplished by local suppression of Th1 cells in stable grafts and by controlling innate immunity during alloimmune-independent pulmonary inflammation.

Machine Perfusion for Abdominal Organ Preservation: A Systematic Review of Kidney and Liver Human Grafts

“…Twenty-two studies [6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27] identified by the systematic search were included into the analysis (Table 2); fifteen were published papers and seven were abstracts. Ten were RCTs [6,11,12,15,16,18,19,21,24,25], seven studies were retrospective [7,8,9,10,17,22,23], and five were prospective [13,14,20,26,27]. Predominantly, the studies used a LifePort ® kidney transporter for hypothermic machine preservation; there was a large variation in cold storage solution type, with some studies not mentioning the specific cold storage preservation solution, but instead referring to local guidelines.…”

“…Twenty-two studies [6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27] comparing HMP and SCS described the incidence of DGF (Figure 3), and its duration (Figure 4), with a total of 7963 patients. The overall OR was 0.57 (0.45, 0.72, 95% CI), with p < 0.00001, favouring a statistically significantly lower prevalence of DGF in kidneys preserved by HMP.…”

Chronic lung allograft dysfunction post-lung transplantation: The era of bronchiolitis obliterans syndrome and restrictive allograft syndrome

“…We established a BOS model by inducing airway inflammation with LPS[ 30 , 42 ] and demonstrated the mechanism of fibrosis by direct TLR4-mediated stimulation of fibroblasts[ 46 ]. In an animal model of BOS where LPS was transtracheally administered, increased levels of Th1-type transcription factors and cytokines were only present in the grafts, but not in secondary lymphoid organs[ 43 ]. Although LPS induced macrophage infiltration, effector molecules of innate immunity, the expression of proinflammatory cytokine mRNAs, and T cell reactivity were not enhanced.…”

Comparative analysis of morphological and molecular motifs in bronchiolitis obliterans and alveolar fibroelastosis after lung and stem cell transplantation

“…Whilst for both LuTx and HSCT patients BO has been well documented in this context, AFE patterns have been described only recently . This phase‐like development of CLAD is supported by data from animal models, which also describe a sequence of an acute injury pattern with epithelial and vascular damage and subsequent activation of inflammatory, epithelial and mesenchymal cells as indispensable in the pathogenesis of CLAD . Of note, the actual nature of the early stimulus leading to CLAD seems to be less relevant than the specific local microenvironment .…”