Impact of donor extracellular vesicle release on recipient cell “cross-dressing” following clinical liver and kidney transplantation

Mastoridis, Sotiris; Londoño, María-Carlota; Kurt, Ada; Kodela, Elisavet; Crespo, Elena; Mason, John; Bestard, Oriol; Martínez‐Llordella, Marc; Sánchez‐Fueyo, Alberto

doi:10.1111/ajt.16123

Cited by 31 publications

(43 citation statements)

References 33 publications

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“…These cross-dressed recipient DCs marked inhibited anti-donor T cell proliferation ex vivo . Our observations in patients also resemble the identification of circulating host APCs cross-dressed with donor MHC Ag in human liver allograft recipients early and transiently after transplantation ( 114 ). In our studies, between the time of donor DCreg infusion and liver transplantation, memory CD8 + T cells expressing high levels of the transcription factors T-bet and Eomesodermin (T-bet hi Eomes hi ) decreased, whereas regulatory (CD25 hi CD127 - Foxp3 + ):T-bet hi Eomes hi CD8 + T cell ratios increased.…”

Section: Liver Transplant Tolerancesupporting

confidence: 79%

Dendritic Cell-Mediated Regulation of Liver Ischemia-Reperfusion Injury and Liver Transplant Rejection

et al. 2021

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Liver allograft recipients are more likely to develop transplantation tolerance than those that receive other types of organ graft. Experimental studies suggest that immune cells and other non-parenchymal cells in the unique liver microenvironment play critical roles in promoting liver tolerogenicity. Of these, liver interstitial dendritic cells (DCs) are heterogeneous, innate immune cells that appear to play pivotal roles in the instigation, integration and regulation of inflammatory responses after liver transplantation. Interstitial liver DCs (recruited in situ or derived from circulating precursors) have been implicated in regulation of both ischemia/reperfusion injury (IRI) and anti-donor immunity. Thus, livers transplanted from mice constitutively lacking DCs into syngeneic, wild-type recipients, display increased tissue injury, indicating a protective role of liver-resident donor DCs against transplant IRI. Also, donor DC depletion before transplant prevents mouse spontaneous liver allograft tolerance across major histocompatibility complex (MHC) barriers. On the other hand, mouse liver graft-infiltrating host DCs that acquire donor MHC antigen via “cross-dressing”, regulate anti-donor T cell reactivity in association with exhaustion of graft-infiltrating T cells and promote allograft tolerance. In an early phase clinical trial, infusion of donor-derived regulatory DCs (DCreg) before living donor liver transplantation can induce alterations in host T cell populations that may be conducive to attenuation of anti-donor immune reactivity. We discuss the role of DCs in regulation of warm and liver transplant IRI and the induction of liver allograft tolerance. We also address design of cell therapies using DCreg to reduce the immunosuppressive drug burden and promote clinical liver allograft tolerance.

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Section: Liver Transplant Tolerancesupporting

confidence: 79%

Dendritic Cell-Mediated Regulation of Liver Ischemia-Reperfusion Injury and Liver Transplant Rejection

et al. 2021

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“…Two papers in recent issues of AJT , from the laboratories of Sanchez‐Fuyeo 1 and Thomson 2 address the profound interest of transplanters in “cross‐dressed” (XD) leukocytes. These words indicate host cells that have acquired membrane proteins from the transplant donor.…”

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confidence: 99%

“…The main strength of both these new papers lies in describing the XD phenomenon in human subjects. The analysis of two different types of human liver transplants [deceased donor 1 and live donor 2 ] reveals that the XD process arises in the early (0–10 days) period after either (a) the liver transplant, or after (b) “DC‐reg” infusion prior to adult LD‐liver transplantation. For comparison, kidney transplants were also studied for XD cells in circulation.…”

mentioning

confidence: 99%

“…These authors clearly demonstrated that DC‐reg infusion, not only altered host APCs by cross‐dressing, but also downregulated memory CD8 + T cells and increased the Treg population in the circulation following liver transplantation. Furthermore, both papers note that while the “cross dressing of circulating APCs following liver transplantation that peaks on day 1,” is transient, “the continued presence of the donor liver” provides an intragraft environment in which “cross‐dressing might persist for prolonged periods” 1,2 …”

mentioning

confidence: 99%

“…This transient phenomenon was found only in liver, but not in kidney transplantation. The absence of any circulating XD‐DC or XD‐monocytes, even during a late rejection episode 1 after 7 years is puzzling, given the extensive work in rodent models showing widespread distribution of exosomes and XD host DCs during acute rejection events in skin, heart, and kidney grafts 3,4 . This claim, that host circulating DC cross‐dressing is seen only at very early (days 1–4) time points, and is a transient phenomenon, only seen in human liver transplantation, is based on relatively few subjects.…”

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confidence: 99%

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Semi-direct alloantigen presentation detected in human liver but not kidney transplant recipients: Implications for the future

Burlingham

Chapman

2021

American Journal of Transplantation

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Circulating host dendrictic cells (DCs) acquire donor MHC antigens either immediately after liver transplantation (Mastoridis et al., page 2387) or after host pretreatment with 'immature' donor‐derived DCs (Macedo et al., page 2372), resulting in a unique tolerogenic signal, although, in the latter, host DCs acquire both donor MHC and PD‐L1, triggering downregulation of host alloreactive T cells.

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Normothermic liver perfusion derived extracellular vesicles have concentration‐dependent immunoregulatory properties

Jennings,

McMorrow,

Chlebeck

et al. 2024

J of Extracellular Vesicle

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Extracellular vesicles (EVs) are major contributors to immunological responses following solid organ transplantation. Donor derived EVs are best known for their role in transplant rejection through transferring donor major histocompatibility complex proteins to recipient antigen presenting cells, a phenomenon known as ‛cross‐decoration’. In contrast, donor liver‐derived EVs are associated with organ tolerance in small animal models. Therefore, the cellular source of EVs and their cargo could influence their downstream immunological effects. To investigate the immunological effects of EVs released by the liver in a physiological and transplant‐relevant model, we isolated EVs being produced during normothermic ex vivo liver perfusion (NEVLP), a novel method of liver storage prior to transplantation. We found EVs were produced by the liver during NEVLP, and these EVs contained multiple anti‐inflammatory miRNA species. In terms of function, liver‐derived EVs were able to cross‐decorate allogeneic cells and suppress the immune response in allogeneic mixed lymphocyte reactions in a concentration‐dependent fashion. In terms of cytokine response, the addition of 1 × 109 EVs to the mixed lymphocyte reactions significantly decreased the production of the inflammatory cytokines TNF‐α, IL‐10 and IFN‐γ. In conclusion, we determined physiologically produced liver‐derived EVs are immunologically regulatory, which has implications for their role and potential modification in solid organ transplantation.

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Impact of donor extracellular vesicle release on recipient cell “cross-dressing” following clinical liver and kidney transplantation

Abstract: This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 31 publications

References 33 publications

Dendritic Cell-Mediated Regulation of Liver Ischemia-Reperfusion Injury and Liver Transplant Rejection

Dendritic Cell-Mediated Regulation of Liver Ischemia-Reperfusion Injury and Liver Transplant Rejection

Semi-direct alloantigen presentation detected in human liver but not kidney transplant recipients: Implications for the future

Normothermic liver perfusion derived extracellular vesicles have concentration‐dependent immunoregulatory properties

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