Aurore Prunevieille

Massachusetts General Hospital

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Gilles Bénichou

Massachusetts General Hospital

Bruno Gonzalez-Nolasco

Massachusetts General Hospital

Saumya Das

Harvard University

Robert R. Kitchen

Novo Nordisk (Finland)

François Cherbonneau

Harvard University

Ibrahim J. Domian

Harvard University

Jérôme Larghero

Inserm

G. Benichou

Massachusetts General Hospital

B.A. Gonzalez-Nolasco

Curtis L. Cetrulo

Cedars-Sinai Medical Center

Cooperative Institutions

Massachusetts General Hospital

Harvard University

Shriners Hospitals for Children - Boston

Université Paris Cité

Inserm

Assistance Publique – Hôpitaux de Paris

Hôpital Saint-Louis

Cedars-Sinai Medical Center

Cardiovascular Research Center

Centre National de la Recherche Scientifique

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TRACE-Seq: A Transgenic System for Unbiased Loading of mRNA into Extracellular Vesicles Allowing Non-Invasive Transcriptome Profiling of Living Cells

SSRN Electronic Journal (2021)

François Cherbonneau Aurore Prunevieille Robert R. Kitchen Gilles Bénichou Jérôme Larghero

Changes in gene expression due to cell heterogeneity and response to stressors in specific microenvironments remains poorly understood. Current methodologies that seek to interrogate gene expression at a molecular level require sampling of cellular transcriptome and therefore lysis of the cell preventing serial analysis of cellular transcriptome. To address this area of unmet need, we have recently developed a new technology allowing transcriptomic analysis over time without cellular destruction. Our novel method, TRACE-seq (TRanscriptomic Analysis Captured in Extracellular vesicles using sequencing), is characterized by a cell-type specific transgene expression. It provides data on a representative part of the cell transcriptome inside extracellular vesicles. Thus, the transcriptome of cells expressing TRACE can be followed over time in a non-destructive manner, which is a powerful tool for many fields of fundamental and translational biology research.

Extracellular Vesicles

Profiling (computer programming)

TRACE (psycholinguistics)

10.2139/ssrn.3782783

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Graft-derived exosomes. When small vesicles play a big role in transplant rejection

American Journal of Transplantation (2018)

Gilles Bénichou Aurore Prunevieille

The article from Sharma et al (page 1626) shows the potential role of extracellular nanovesicles (exosomes) carrying tissue-specific autoantigens in the rejection of cardiac transplants. The article from Sharma et al (page 1626) shows the potential role of extracellular nanovesicles (exosomes) carrying tissue-specific autoantigens in the rejection of cardiac transplants. Recipient proinflammatory T cells recognizing donor major histocompatibility complex (MHC) molecules in a direct fashion trigger early acute rejection of cardiac allografts. In clinical settings, prevention of acute rejection is regularly achieved via continuous suppression of these T cells using immunosuppressive drugs, including calcineurin inhibitors. Nevertheless, within five years posttransplantation, up to 50% of patients suffer late cardiac allograft failure, the major pathological manifestation of which is chronic allograft vasculopathy (CAV). CAV is characterized by intimal thickening, smooth muscle cell proliferation, and accumulation of extracellular matrix, which result in arterial narrowing and eventually graft ischemia and fibrosis. There is a body of evidence showing that CAV is initiated via a process involving cells of both innate and adaptive systems. However, the immunological mechanisms underlying CAV are still largely unknown. Gaining insights into this question is critical to the design of strategies for the prevention and/or treatment of late cardiac allograft failure and CAV. There is a clear association between indirect alloreactivity by CD4+ T cells, the presence of donor-specific antibodies, and chronic allograft rejection. In addition, several studies have documented the presence of T cell autoimmunity and autoantibodies during chronic rejection. Original studies in our laboratory described de novo T and B cell responses to cardiac myosin (CM) in chronic rejection of cardiac allografts in mice and swine.1Benichou G Alessandrini A Charrad RS Wilkes DS Induction of autoimmunity after allotransplantation.Front Biosci. 2007; 12: 4362-4369Crossref PubMed Scopus (20) Google Scholar Subsequently, Kalache et al documented the relevance of anti-CM autoimmunity in patients with CAV.2Kalache S Dinavahi R Pinney S Mehrotra A Cunningham MW Heeger PS Anticardiac myosin immunity and chronic allograft vasculopathy in heart transplant recipients.J Immunol. 2011; 187: 1023-1030Crossref PubMed Scopus (57) Google Scholar Given that immunity to CM is known to cause autoimmune myocarditis, we hypothesized that CAV could be mediated through a process similar to that observed in chronic inflammatory autoimmune diseases. Subsequent reports from M. Rose and Mohanakumar's groups showed the presence of vimentin-specific autoimmunity in graft vasculopathy observed after heart transplantation in mice and patients.3Nath DS Ilias Basha H Tiriveedhi V et al.Characterization of immune responses to cardiac self-antigens myosin and vimentin in human cardiac allograft recipients with antibody-mediated rejection and cardiac allograft vasculopathy.J Heart Lung Transplant. 2010; 29: 1277-1285Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar,4Barber LD Whitelegg A Madrigal JA Banner NR Rose ML Detection of vimentin-specific autoreactive CD8 + T cells in cardiac transplant patients.Transplantation. 2004; 77: 1604-1609Crossref PubMed Scopus (51) Google Scholar Autoimmunity against various self-antigens has now been documented during rejection of lung, kidney, and other organ transplants and therefore represents a general phenomenon in transplantation.1Benichou G Alessandrini A Charrad RS Wilkes DS Induction of autoimmunity after allotransplantation.Front Biosci. 2007; 12: 4362-4369Crossref PubMed Scopus (20) Google Scholar However, whether and how autoimmunity truly contributes to allograft rejection are still unclear. In this issue of the American Journal of Transplantation, M. Sharma and colleagues revisited this issue using a model in which mice transplanted with a syngeneic heart were injected with rabbit anti-CM antibodies.5Sharma M, Liu W, Perincheri S, Gunasekaran M, Mohanakumar T. Exosomes expressing the self-antigens myosin and vimentin play an important role in syngeneic cardiac transplant rejection induced by antibodies to cardiac myosin [published online ahead of print January 9, 2018]. Am J Transplant. doi: 10.1111/ajt.14650Google Scholar First, they observed that administration of anti-CM Abs at the time of transplantation (d0) was sufficient to induce graft rejection. This was associated with increased leukocyte infiltration of cardiac grafts, de novo production of mouse Abs against CM and vimentin (VIM) and expansion/activation of CM/VIM specific autoreactive CD4+ T cells producing inflammatory cytokines (γIFN, TNFα and IL-17). Second, the serum of rejecting mice was shown to contain exosomes carrying CM, VIM and miRNAs involved in inflammation. Finally, administration of these exosomes to a mouse caused rejection of a syngeneic heart transplant. It is noteworthy that autoantibodies and rejectogenic exosomes were not detected in mice with stable graft functions. Another important observation was that administration of mice with anti-CM antibodies performed seven days posttransplantation (instead of d0) failed to induce autoimmunity and graft rejection. This suggests that anti-CM-mediated rejection occurs only in an inflammatory environment caused presumably by ischemia reperfusion injury associated with the surgical procedure. Exosomes are microvesicles (50-100 nm) produced in the endosomes and secreted by a variety of cells during activation. Recent studies showed that exosomes released by allografts contribute to the host's immune response leading to their rejection. Apparently, recipient APCs displaying allogeneic MHC molecules acquired from donor exosomes (MHC cross-dressing) play a key role in the initiation of inflammatory direct alloresponses by T cells leading to acute allograft rejection.6Liu Q Rojas-Canales DM Divito SJ et al.Donor dendritic cell-derived exosomes promote allograft-targeting immune response.J Clin Invest. 2016; 126: 2805-2820Crossref PubMed Scopus (199) Google Scholar,7Marino J Babiker M Crosby Bertorini P et al.Donor exosomes rather than passenger leukocytes initiate alloreactive T cell responses after transplantation.Sci Immunol. 2016; 1: 1-12Crossref Scopus (122) Google Scholar In addition to direct alloreactivity, it is plausible that MHC and other proteins transported by graft-derived exosomes are regularly processed and presented as peptides by self-MHC molecules on recipient APCs thus eliciting indirect T cell alloresponses. Indirect T cell immunity drives alloantibody production and it is believed to be the driving force behind chronic allograft rejection. At the same time, there is accumulating evidence supporting the contribution of autoimmunity to selected graft tissue specific autoantigens in chronic rejection. Finally, recent studies have documented the contribution of exosomes carrying autoantigens in autoimmune diseases. Altogether, this raises the possibility that secondary indirect alloimmunity and autoimmune inflammatory responses may be elicited and perpetuated by graft-derived exosomes continuously released by the allograft. However, it is likely that such a cascade of events may only happen in an inflammatory environment caused by tissue injury or an infection. The results presented in the article by M. Sharma et al support this view. Indeed, in this study, mouse administration of anti-CM antibodies triggered an anti-CM inflammatory T cell response, which spread to VIM and caused the release of exosomes carrying both autoantigens outside the graft; a series of events presumably responsible for rejection of syngeneic heart transplants. Likewise, Dieudé et al described the ability of exosome-like vesicles from endothelial cells to induce anti-perlecan autoantibody production and accelerated rejection of aortic grafts in mice.8Dieude M Bell C Turgeon J et al.The 20S proteasome core, active within apoptotic exosome-like vesicles, induces autoantibody production and accelerates rejection.Sci Transl Med. 2015; 7: 318ra200Crossref PubMed Scopus (125) Google Scholar Further evaluation of the actual role of exosomes carrying self-antigens in allograft rejection will require inhibition of graft exosome secretion in transplanted animals. Autoantibodies are regularly found pretransplantation in patients and could contribute to rejection of allografts in a fashion similar to that described in this article.9Bharat A Kuo E Steward N et al.Immunological link between primary graft dysfunction and chronic lung allograft rejection.Ann Thorac Surg. 2008; 86 (discussion 196-187.): 189-195Abstract Full Text Full Text PDF PubMed Scopus (128) Google Scholar In addition, graft injury caused by T and B cell inflammatory alloimmunity, including alloreactive antibodies, could promote the release of exosomes carrying pathogenic autoantigens by the allograft thus causing late acute or chronic rejection. These hypotheses must be investigated. In conclusion, it is clear that presentation of graft tissue–specific antigens by recipient APCs in an inflammatory environment can trigger T and B cell autoimmune responses leading to chronic rejection. In clinical settings, auto-antibodies may be present in patients pretransplantation or produced as the result of B cell dysregulation due to T cell continuous suppression. At the same time, recent reports from A. Naji, T. Mohanakumar and other laboratories show the relevance of exosomes as biomarkers in chronic allograft rejection.10Vallabhajosyula P Korutla L Habertheuer A et al.Tissue-specific exosome biomarkers for noninvasively monitoring immunologic rejection of transplanted tissue.J Clin Invest. 2017; 127: 1375-1391Crossref PubMed Scopus (96) Google Scholar,11Gunasekaran M Xu Z Nayak DK et al.Donor-derived exosomes with lung self-antigens in human lung allograft rejection.Am J Transplant. 2017; 17: 474-484Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar Together with Sharma's current study, this suggests that autoantibodies could initiate a local immune process, which spreads outside the graft via exosome release thus causing graft rejection. The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation.

Graft rejection

Extracellular Vesicles

10.1111/ajt.14720

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Citations (5)

TRACE-seq: A transgenic system for unbiased and non-invasive transcriptome profiling of living cells

iScience (2022)

François Cherbonneau Guoping Li Priyanka Gokulnath Parul Sahu Aurore Prunevieille

Dynamic profiling of changes in gene expression in response to stressors in specific microenvironments without requiring cellular destruction remains challenging. Current methodologies that seek to interrogate gene expression at a molecular level require sampling of cellular transcriptome and therefore lysis of the cell, preventing serial analysis of cellular transcriptome. To address this area of unmet need, we have recently developed a technology allowing transcriptomic analysis over time without cellular destruction. Our method, TRACE-seq (TRanscriptomic Analysis Captured in Extracellular vesicles using sequencing), is characterized by a cell-type specific transgene expression. It provides data on the transcriptome inside extracellular vesicles that provides an accurate representation of stress-responsive cellular transcriptomic changes. Thus, the transcriptome of cells expressing TRACE can be followed over time without destroying the source cell, which is a powerful tool for many fields of fundamental and translational biology research.

Extracellular Vesicles

10.1016/j.isci.2022.103806

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Citations (4)

Emerging role of exosomes in allorecognition and allograft rejection

Current Opinion in Organ Transplantation (2017)

Bruno Gonzalez-Nolasco Mengchuan Wang Aurore Prunevieille Gilles Bénichou

Purpose of review This article reviews recent literature on the nature of extracellular vesicles released by allogeneic transplants and examine their role in T-cell alloimmunity involved in rejection and tolerance of these grafts. Recent findings Donor cells release extracellular vesicles, including exosomes, after transplantation of allogeneic organs and tissues. Consequently, recipient APCs take up these exosomes and present donor MHC antigens on their surface (allo-MHC cross-dressing) thus, activating some alloreactive T cells via a mechanism called semi-direct pathway of allorecognition. In addition, one study shows that exosomes carrying noninherited maternal antigens are associated with maternal microchimerism and tolerance in offspring. Finally, a few studies describe potential utilization of exosomes as modulators of alloimmunity and biomarkers of rejection in allotransplantation. Summary Extracellular vesicles, including exosomes, released by allografts contribute to recognition of donor antigens by T cells after allotransplantation. This occurs through cross-dressing of recipient APCs with donor MHC antigens and subsequent activation of T cells, a process called semi-direct alloreactivity. The relevance of this phenomenon in rejection and tolerance of allografts and the potential utilization of exosomes as biomarkers in transplantation are discussed.

Alloimmunity

Allorecognition

Allotransplantation

10.1097/mot.0000000000000489

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Citations (49)

ATP-mediated signaling of P2X7 receptors controls donor extracellular vesicle release and MHC cross-decoration after allotransplantation

American Journal of Transplantation (2024)

Bruno Gonzalez-Nolasco Hyshem H. Lancia Natacha Carnel-Amar Xianding Wang Aurore Prunevieille

Alloimmunity

Allotransplantation

Extracellular vesicles

Pyroptosis

10.1016/j.ajt.2024.12.008

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T cell antigenicity and immunogenicity of allogeneic exosomes

American Journal of Transplantation (2021)

Aurore Prunevieille Mohamed H. Babiker-Mohamed Colleen Aslami Bruno Gonzalez-Nolasco Nuala Mooney

Extracellular vesicles, including exosomes, are regularly released by allogeneic cells after transplantation. Recipient antigen-presenting cells (APCs) capture these vesicles and subsequently display donor MHC molecules on their surface. Recent evidence suggests that activation of alloreactive T cells by the so-called cross-dressed APCs plays an important role in initiating the alloresponse associated with allograft rejection. On the other hand, whether allogeneic exosomes can bind to T cells on their own and activate them remains unclear. In this study, we showed that allogeneic exosomes can bind to T cells but do not stimulate them in vitro unless they are cultured with APCs. On the other hand, allogeneic exosomes activate T cells in vivo and sensitize mice to alloantigens but only when delivered in an inflammatory environment.

Extracellular Vesicles

10.1111/ajt.16591

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Citations (33)

Inducing Donor MHC Chimerism with Bone Marrow Derived Exosomes in Non-Human Primates

The Journal of Heart and Lung Transplantation (2020)

Parth Patel B.A. Gonzalez-Nolasco J.A. Morrissette Aurore Prunevieille A.J. Kaitlan

Human bone

10.1016/j.healun.2020.01.1321

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Citations (1)