Acute rejection

Abstract

Despite induction immunosuppression and the use of aggressive maintenance immunosuppressive regimens, acute allograft rejection following lung transplantation is still a problem with important diagnostic and therapeutic challenges. As well as causing early graft loss and mortality, acute rejection also initiates the chronic alloimmune responses and airway-centred inflammation that predispose to bronchiolitis obliterans syndrome (BOS), also known as chronic lung allograft dysfunction (CLAD), which is a major source of morbidity and mortality after lung transplantation. Cellular responses to human leukocyte antigens (HLAs) on the allograft have traditionally been considered the main mechanism of acute rejection, but the influence of humoral immunity is increasingly recognised. As with other several other solid organ transplants, antibody-mediated rejection (AMR) is now a well-accepted and distinct clinical entity in lung transplantation. While acute cellular rejection (ACR) has defined histopathological criteria, transbronchial biopsy is less useful in AMR and its diagnosis is complicated by challenges in the measurement of antibodies directed against donor HLA, and a determination of their significance. Increasing awareness of the importance of non-HLA antigens further clouds this issue. Here, we review the pathophysiology, diagnosis, clinical presentation and treatment of ACR and AMR in lung transplantation, and discuss future potential biomarkers of both processes that may forward our understanding of these conditions.

Lung Transplantation and Precision Medicine

“…In addition to clinical findings and transbronchial biopsies, diagnosis of AMR can be suspected when donor-specific antibodies (DSA) are found in the blood [51,57]. Also, there is a form of AMR known as hyperacute rejection, which occurs minutes to hours after transplantation and is mediated by preformed antibodies directed toward donor HLA and ABO molecules [58]. Another cause of ALAD is azithromycin responsive allograft dysfunction (ARAD), which was previously also referred to as neutrophilic reversible allograft dysfunction (NRAD) or azithromycin responsive BOS [32].…”

Bronchoalveolar lavage cytokines are of minor value to diagnose complications following lung transplantation

“…During the first postoperative year, ACR affects 28% of LTRs at least once, necessitating treatment with steroid augmentation [1,6]. Symptoms of ACR are nonspecific, including dyspnea, cough, sputum production, fever and/or hypoxia [7,8]. Non-invasive tests like pulmonary function testing and chest imaging are useful indicators for potential complications, but have no discriminatory value between ACR and infection [9].…”

“…Cytokines are furthermore implicated in rejection after organ transplantation and induction of fibrotic pathways [20]. ACR is driven by T cell recognition of foreign major histocompatibility complexes [8,21]. Cytokines play a key role in this process by stimulating proliferation, chemotaxis and activation of cytotoxic T lymphocytes, neutrophils and alveolar macrophages AM [22][23][24].…”

Gene signatures common to allograft rejection are associated with lymphocytic bronchitis

“…By the time CLAD is diagnosed by spirometry, it may be too late to initiate certain interventions. Because acute cellular rejection (ACR) pathologies have been associated with increased CLAD risk, biomarkers of ACR may help identify incipient CLAD prior to frank lung function decline …”