Extracellular Vesicles in Transplantation: Friend or Foe.

The long-term function of transplanted organs, even under immunosuppression, is hindered by rejection, especially chronic rejection. Chronic rejection occurs more frequently after lung transplantation, termed chronic lung allograft dysfunction (CLAD), than after transplantation of other solid organs. Pulmonary infection is a known risk factor for CLAD, as transplanted lungs are constantly exposed to the external environment; however, the mechanisms by which respiratory infections lead to CLAD are poorly understood. The role of extracellular vesicles (EVs) in transplantation remains largely unknown. Current evidence suggests that EVs released from transplanted organs can serve as friend and foe. EVs carry not only major histocompatibility complex antigens but also tissue-restricted self-antigens and various transcription factors, costimulatory molecules, and microRNAs capable of regulating alloimmune responses. EVs play an important role in antigen presentation by direct, indirect, and semidirect pathways in which CD8 and CD4 cells can be activated. During viral infections, exosomes (small EVs <200 nm in diameter) can express viral antigens and regulate immune responses. Circulating exosomes may also be a viable biomarker for other diseases and rejection after organ transplantation. Bioengineering the surface of exosomes has been proposed as a tool for targeted delivery of drugs and personalized medicine. This review focuses on recent studies demonstrating the role of EVs with a focus on exosomes and their dual role (immune activation or tolerance induction) after organ transplantation, more specifically, lung transplantation.

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.

Immune responses of lung transplant recipients against SARS-CoV-2 and common respiratory coronaviruses: Evidence for pre-existing cross-reactive immunity.

Humoral and cellular immune responses to SARS-CoV-2 and other coronaviruses in lung transplant recipients are unknown. We measured antibodies and T cell responses against the SARS-CoV-2 spike S2 and nucleocapsid antigens and spike antigens from common respiratory coronaviruses (229E, NL63, OC43, and HKU1) after vaccination or infection of LTxRs. 148 LTxRs from single center were included in this study: 98 after vaccination and 50 following SARS-CoV-2 infection. Antibodies were quantified by enzyme-linked immunosorbent assay. The frequency of T cells secreting IL2, IL4, IL10, IL17, TNFα, and IFNγ were enumerated by enzyme-linked immunospot assay. Our results have shown the development of antibodies to SARS-CoV-2 spike protein in infected LTxRs (39/50) and vaccinated LTxRs (52/98). Vaccinated LTxRs had higher number of T cells producing TNFα but less cells producing IFNγ than infected LTxRs in response to the nucleocapsid antigen and other coronavirus spike antigens. We didn't find correlation between the development of antibodies and cellular immune responses against the SARS-CoV-2 spike protein after vaccination. Instead, LTxRs have pre-existing cellular immunity to common respiratory coronaviruses, leading to cross-reactive immunity against SARS-CoV-2 which likely will provide protection against SARS-Cov-2 infection.