Extracellular Vesicles Mediate Immune Responses to Tissue-Associated Self-Antigens: Role in Solid Organ Transplantations

Abstract

Transplantation is a treatment option for patients diagnosed with end-stage organ diseases; however, long-term graft survival is affected by rejection of the transplanted organ by immune and nonimmune responses. Several studies have demonstrated that both acute and chronic rejection can occur after transplantation of kidney, heart, and lungs. A strong correlation has been reported between de novo synthesis of donor-specific antibodies (HLA-DSAs) and development of both acute and chronic rejection; however, some transplant recipients with chronic rejection do not have detectable HLA-DSAs. Studies of sera from such patients demonstrate that immune responses to tissue-associated antigens (TaAgs) may also play an important role in the development of chronic rejection, either alone or in combination with HLA-DSAs. The synergistic effect between HLA-DSAs and antibodies to TaAgs is being established, but the underlying mechanism is yet to be defined. We hypothesize that HLA-DSAs damage the transplanted donor organ resulting in stress and leading to the release of extracellular vesicles, which contribute to chronic rejection. These vesicles express both donor human leukocyte antigen (HLA) and non-HLA TaAgs, which can activate antigen-presenting cells and lead to immune responses and development of antibodies to both donor HLA and non-HLA tissue-associated Ags. Extracellular vesicles (EVs) are released by cells under many circumstances due to both physiological and pathological conditions. Primarily employing clinical specimens obtained from human lung transplant recipients undergoing acute or chronic rejection, our group has demonstrated that circulating extracellular vesicles display both mismatched donor HLA molecules and lung-associated Ags (collagen-V and K-alpha 1 tubulin). This review focuses on recent studies demonstrating an important role of antibodies to tissue-associated Ags in the rejection of transplanted organs, particularly chronic rejection. We will also discuss the important role of extracellular vesicles released from transplanted organs in cross-talk between alloimmunity and autoimmunity to tissue-associated Ags after solid organ transplantation.

Extracellular Vesicles in Transplantation: Friend or Foe

“…Our group has recently identified exosomes in circulation that carry donor HLAs and lung-associated SAgs (Col-V and Kα1T) after LTx, 11,46 and furthermore, that levels of exosomes with SAgs increased in circulation before clinical evidence of rejection. 10 Several studies have demonstrated that exosomes play a crucial role in carrying and presenting functional major histocompatibility peptide complexes to modulate antigen-specific T-cell responses 11,46,75,76 and that exosome-mediated allorecognition can involve both innate and adaptive immunity. Finally, antigen-carrying exosomes found in circulation after transplantation may also be useful as an early biomarker of rejection.…”

“…EVs possess both physiological and pathological roles, and emerging evidence suggests that EVs can induce rejection of solid organ transplants by a semidirect pathway and can also participate in the induction of tolerance. 76,131,132 An earlier study found that EVs with HLA G and Fas ligand were involved in maternal immune tolerance. Recent data demonstrate that placenta-derived EVs significantly modulate immune responses leading to maternal immune tolerance during pregnancy.…”

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

“…The origin of EVs can be ectosomal or endosomal. They are divided on the basis of size: (a) microvesicles (100-1,000 nm); (b) apoptotic bodies (1,000-5,000 nm); (c) exosomes/small EVs <200 nm (71,72) (Figure 1). There are multiple terms associated with the nomenclature of EVs and exosomes as per Minimal Information for Studies of Extracellular Vesicles (MISEV) guidelines.…”

“… Diagrammatic reprentation of extracellular vesicle carrying CD9, CD63, CD81, TSG101, ALIX, tissue-specific markers (collagen V and K alpha1 tubulin in lung transplant; cardiac myosin and vimentin in cardiac transplant; fibronectin, collagen IV and perlecan in kidney transplant) ( 73 ). Images created using BioRENDER.…”

Transcriptomic Landscape of Circulating Extracellular Vesicles in Heart Transplant Ischemia–Reperfusion

“…EVs play a role in cell-to-cell communication in various physiological processes as they carry, e.g., proteins, carbohydrates, lipids, messenger RNAs (mRNAs), and microRNAs that can interact with target cells [3]. In the regulation of inflammation, they have now been recognized as potential biomarkers and immune mediators in organ transplantation [4].…”