The role of the immune system in lung transplantation: Towards improved long-term results

Over the past 35 years, lung transplantation has evolved from an experimental treatment to the treatment of choice for patients with end-stage lung disease. Beyond the immediate period after lung transplantation, rejection and infection are the leading causes of death. The risk of rejection after lung transplantation is generally higher than after other solid organ transplants, and this necessitates more intensive immunosuppression. However, this more intensive treatment does not reduce the risk of rejection sufficiently, and rejection is one of the most common complications after transplantation. There are multiple forms of rejection including acute cellular rejection, antibody-mediated rejection, and chronic lung allograft dysfunction. These have posed a vexing problem for clinicians, patients, and the field of lung transplantation. Confounding matters is the inherent effect of more intensive immunosuppression on the risk of infections. Indeed, infections pose a direct problem resulting in morbidity and mortality and increase the risk of chronic lung allograft dysfunction in the ensuing weeks and months. There are complex interactions between microbes and the immune response that are the subject of ongoing studies. This review focuses on the role of the immune system in lung transplantation and highlights different forms of rejection and the impact of infections on outcomes

Antibody-mediated rejection after lung transplantation

Antibody-mediated rejection (AMR) has been identified as a significant form of acute allograft dysfunction in lung transplantation. The development of consensus diagnostic criteria has created a uniform definition of AMR; however, significant limitations of these criteria have been identified. Treatment modalities for AMR have been adapted from other areas of medicine and data on the effectiveness of these therapies in AMR are limited. AMR is often refractory to these therapies, and graft failure and death are common. AMR is associated with increased rates of chronic lung allograft dysfunction (CLAD) and poor long-term survival. In this review, we discuss the history of AMR and describe known mechanisms, application of the consensus diagnostic criteria, data for current treatment strategies, and long-term outcomes. In addition, we highlight current gaps in knowledge, ongoing research, and future directions to address these gaps. Promising diagnostic techniques are actively being investigated that may allow for early detection and treatment of AMR. We conclude that further investigation is required to identify and define chronic and subclinical AMR, and head-to-head comparisons of currently used treatment protocols are necessary to identify an optimal treatment approach. Gaps in knowledge regarding the epidemiology, mechanisms, diagnosis, and treatment of AMR continue to exist and future research should focus on these aspects

Position paper: Models of post-transplant care for individuals with cystic fibrosis

There is no consensus on the best model of care for individuals with CF to manage the non-pulmonary complications that persist after lung transplant. The CF Foundation virtually convened a group of international experts in CF and lung-transplant care. The committee reviewed literature and shared the post-lung transplant model of care practiced by their programs. The committee then developed a survey that was distributed internationally to both the clinical and individual with CF/family audiences to determine the strengths, weaknesses, and preferences for various models of transplant care. Discussion generated two models to accomplish optimal CF care after transplant. The first model incorporates the CF team into care and proposes delineation of responsibilities for the CF and transplant teams. This model is reliant on outstanding communication between the teams, while leveraging the expertise of the CF team for management of the non-pulmonary manifestations of CF. The transplant team manages all aspects of the transplant, including pulmonary concerns and management of immunosuppression. The second model consolidates care in one center and may be more practical for transplant programs that have expertise managing CF and have access to CF multidisciplinary care team members (e.g., located in the same institution). The best model for each program is influenced by several factors and model selection needs to be decided between the transplant and the CF center and may vary from center to center. In either model, CF lung transplant recipients require a clear delineation of the roles and responsibilities of their providers and mechanisms for effective communication

Cystic Fibrosis Foundation consensus statements for the care of Cystic Fibrosis Lung Transplant Recipients

Cystic fibrosis (CF) is the indication for transplantation in approximately 15% of recipients worldwide, and Cystic Fibrosis Lung Transplant Recipients (CFLTRs) have excellent long-term outcomes. Yet, CFLTRs have unique comorbidities that require specialized care. The objective of this document is to provide recommendations to CF and lung transplant clinicians for the management of perioperative and underlying comorbidities of CFLTRs and the impact of transplantation on these comorbidities. The Cystic Fibrosis Foundation (CFF) organized a multidisciplinary committee to develop CF Lung Transplant Clinical Care Recommendations. Three workgroups were formed to develop focused questions. Following a literature search, consensus recommendations were developed by the committee members based on literature review, committee experience and iterative revisions, and in response to public comment. The committee formulated 32 recommendation statements in the topics related to infectious disease, endocrine, gastroenterology, pharmacology, mental health and family planning. Broadly, the committee recommends close coordination of care between the lung transplant team, the cystic fibrosis care center, and specialists in other disciplines with experience in the care of CF and lung transplant recipients. These consensus statements will help lung transplant providers care for CFLTRs in order to improve post-transplant outcomes in this population

Role of defensins in the pathogenesis of chronic lung allograft rejection

Chronic rejection predominantly manifested as bronchiolitis obliterans syndrome (BOS), still remains a major problem affecting long-term outcomes in human lung transplantation (LTx). Donor specific antibodies (DSA) and infiltration of neutrophils in the graft have been associated with the development of BOS. This study determines the role of defensins, produced by neutrophils, and its interaction with α-1-antitrypsin (AAT) towards induction of airway inflammation and fibrosis which are characteristic hallmarks of BOS. Bronchoalveolar lavage (BAL) and serum from LTx recipients, BOS+ (n=28), BOS− (n=26) and normal healthy controls (n=24) were analyzed. Our results show that BOS+ LTx recipients had higher α-defensins (HNP1–3) and β-defensin2 HBD2 concentration in BAL and serum compared to BOS-DSA-recipients and normal controls (p=0.03). BOS+ patients had significantly lower serum AAT along with higher circulating concentration of HNP–AAT complexes in BAL (p=0.05). Stimulation of primary small airway epithelial cells (SAECs) with HNPs induced expression of HBD2, adhesion molecules (ICAM and VCAM), cytokines (IL-6, IL-1β, IL-13, IL-8 and MCP-1) and growth-factor (VEGF and EGF). In contrast, anti-inflammatory cytokine, IL-10 expression decreased 2-fold (p=0.002). HNPs mediated SAEC activation was completely abrogated by AAT. In conclusion, our results demonstrates that neutrophil secretory product, α-defensins, stimulate β-defensin production by SAECs causing upregulation of pro-inflammatory and pro-fibrotic signaling molecules. Hence, chronic stimulation of airway epithelial cells by defensins can lead to inflammation and fibrosis the central events in the development of BOS following LTx

Extracellular vesicles: a potential new player in antibody-mediated rejection in lung allograft recipients

Identification of recipients with pre-existing antibodies and cross-matching of recipient sera with donor lymphocytes have reduced the incidence of antibody-mediated rejection (AMR) after human lung transplantation. However, AMR is still common and requires not only immediate intervention but also has long-term consequences including an increased risk of chronic lung allograft dysfunction (CLAD). The mechanisms resulting in AMR remain largely unknown due to the variation in clinical and histopathological features among lung transplant recipients; however, several reports have demonstrated a strong association between the development of antibodies against mismatched donor human leucocyte antigens [donor-specific antibodies (DSAs)] and AMR. In addition, the development of antibodies against lung self-antigens (K alpha1 tubulin and collagen V) also plays a vital role in AMR pathogenesis, either alone or in combination with DSAs. In the current article, we will review the existing literature regarding the association of DSAs with AMR, along with clinical diagnostic features and current treatment options for AMR. We will also discuss the role of extracellular vesicles (EVs) in the immune-related pathogenesis of AMR, which can lead to CLAD