Bacterial products in donor airways prevent the induction of lung transplant tolerance

Abstract

Lung transplantation is the only established lifesaving option for many patients suffering from end-stage pulmonary disease. The selection of appropriate lung donors is a critical element of the transplant process. Infiltrates on chest imaging studies and the presence of bacteria in the donor airways have long been considered contraindications to the use of lungs for transplantation. 1 Because of a scarcity in suitable lungs for transplantation and a rising waitlist mortality rate, strategies have been increasingly employed to expand the donor pool. To this end, one such approach is the use of extended criteria lung donors, which may harbor infections. The use of donor lungs with bacterial colonization or pneumonia, however, is controversial. Whereas some

Tolerance, immunosuppression, and immune modulation: impacts on lung allograft survival

“…Similarly, others have shown that bacterial and viral infections are associated with chronic rejection in the clinics [19,20]. A recent study by our group showed that the presence of a synthetic bacterial lipopeptide in donor airways was sufficient to prevent tolerance induction [11 ▪▪ ]. This response to bacterial lipopeptide was mediated by recipient-derived monocytes and induced expansion of CD8 + T cells within the lung graft.…”

“…Acute cellular rejection is primarily driven by T cell activation after recognition of donor alloantigens. Such T cell activation appears to be facilitated by innate immune pathways triggered by early graft injury [10,11 ▪▪ ,12]. Ischemia-reperfusion injury (IRI), a frequent complication after lung transplantation, is considered to be the principal mechanism leading to primary graft dysfunction (PGD).…”

Novel approaches for long-term lung transplant survival

“…CLAD occurs in up to half of recipients within five years of transplantation and represents the principal life-limiting factor for lung transplant patients ( 18 ). The development of CLAD is likely multifactorial and related to the complex interaction of immune and non-immune factors, including but not limited to acute rejection, pre-transplant allosensitization, bacterial infection and colonization, acute viral infection, and gastroesophageal reflux disease; in a subset of patients, no clear risk factors for CLAD are identified and it is presumed to result from chronic rejection ( 19 – 22 ). CLAD is marked by fibrotic remodeling within the pulmonary allograft, with described phenotypes include bronchiolitis obliterans syndrome (BOS), restrictive allograft syndrome (RAS), and a mixed BOS-RAS phenotype ( 23 ).…”

“…One primary difference is regulation of alloimmune responses at the level of the lung allograft, which is in contrast with other transplanted organs that depend on cell trafficking to secondary lymphoid organs for activation of allorecognition pathways ( 28 – 30 , 35 – 37 ). Early graft injury resulting from IRI and infection has been shown to activate innate immune pathways within the lung allograft, which in turn trigger alloantigen-specific T-cell expansion ( 19 , 25 , 38 ). During IRI, resident donor monocytes in the lung elaborate chemotactic and proinflammatory cytokines that facilitate neutrophil entry into lungs grafts, enhancing CD4 + T-cell responses to donor antigens and resulting in PGD ( 39 – 41 ).…”

Microbiota in heart and lung transplantation: implications for innate-adaptive immune interface

“…Infection in the donor lung prior to implantation can trigger several innate immunity responses. To this end, our group has recently shown that TLR2 activation triggered by a bacterial lipoprotein (Pam 3 Cys 4 ) that is present in the graft causes acute cellular rejection, which is mediated by recipient bone-marrow derived monocytes [28]. We have also recently demonstrated that low levels of LPS, which may be present in the graft following treatment of donor bacterial pneumonia, stimulate donor tissue-resident alveolar macrophages (TRAMs) to increase CXCL2 production, which in turn enhances neutrophil recruitment and leads to PGD [29].…”