Donor-specific hypo-responsiveness occurs in simultaneous liver-kidney transplant recipients after the first year

Taner, Timuçin; Gustafson, Michael P.; Hansen, Michael J.; Park, Walter D.; Bornschlegl, Svetlana; Dietz, Allan B.; Stegall, Mark D.

doi:10.1016/j.kint.2018.01.022

Cited by 47 publications

(45 citation statements)

References 34 publications

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“…In a previous study in which liver allograft perfusate fluid was used to generate and culture MSCs, the authors had speculated that these cells mobilize from the liver in the recipient and may play a role in modulation of the alloimmune responses . Although neither their nor our results investigate or demonstrate this possibility directly, the increased expression of adhesion molecules that would help home the L‐MSCs to other sites of inflammation, such as the simultaneously transplanted kidney allograft, is a plausible mechanism of how the liver allograft reduces the alloimmune responses in the host . It is noteworthy that the genes and gene sets that are related to tissue integrity and homeostasis, which are shared by L‐MSCs, are up‐regulated in the kidney allografts of the simultaneous liver‐kidney transplant recipients compared with the kidney allografts of solitary kidney transplant recipients .…”

Section: Discussioncontrasting

confidence: 56%

“…First, transcriptional analysis of kidney allografts in recipients of simultaneous liver‐kidney transplants demonstrates that inflammatory pathways are down‐regulated when compared with solitary kidney allografts . Second, the alloreactivity of circulating T cells after liver or simultaneous liver‐kidney transplantation is diminished and is much lower than that observed after kidney transplantation . Thus, it appears that the tolerogenic microenvironment is not restricted to the liver but rather that it impacts overall host alloimmune responses.…”

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confidence: 99%

“…(8) Second, the alloreactivity of circulating T cells after liver or simultaneous liver-kidney transplantation is diminished and is much lower than that observed after kidney transplantation. (9) Thus, it appears that the tolerogenic microenvironment is not restricted to the liver but rather that it impacts overall host alloimmune responses. The mechanism through which systemic immune tolerance emerges remains to be resolved, but it likely involves many liver-resident cells.…”

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confidence: 99%

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Phenotypic, Transcriptional, and Functional Analysis of Liver Mesenchymal Stromal Cells and Their Immunomodulatory Properties

et al. 2020

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The liver is an immunologically active organ with a tolerogenic microenvironment at a quiescent state. The immunoregulatory properties of the liver appear to be retained after transplantation because liver allografts can reduce alloresponses against other organs that are simultaneously transplanted. Mechanisms of this phenomenon remain unknown. Given the known immunomodulatory properties of mesenchymal stromal cells (MSCs), we hypothesized that liver mesenchymal stromal cells (L‐MSCs) are superior immunomodulators and contribute to liver‐mediated tolerance. L‐MSCs, generated from human liver allograft biopsies, were compared with adipose mesenchymal stromal cells (A‐MSCs) and bone marrow mesenchymal stromal cells (BM‐MSCs). Trilineage differentiation of L‐MSCs was confirmed by immunohistochemistry. Comparative phenotypic analyses were done by flow cytometry and transcriptome analyses by RNA sequencing in unaltered cell cultures. The in vitro functional analyses were performed using alloreactive T cell proliferation assays. The transcriptome analysis showed that the L‐MSCs are different than the A‐MSCs and BM‐MSCs, with significant enrichment of genes and gene sets associated with immunoregulation. Compared with the others, L‐MSCs were found to express higher cell surface levels of several select immunomodulatory molecules. L‐MSCs (versus A‐MSCs/BM‐MSCs) inhibited alloreactive T cell proliferation (22.7% versus 56.4%/58.7%, respectively; P < 0.05) and reduced the frequency of interferon ɤ–producing T cells better than other MSCs (52.8% versus 94.4%/155.4%; P < 0.05). The antiproliferative impact of L‐MSCs was not dependent on cell‐to‐cell contact, could be reversed incompletely by blocking programmed death ligand 1, and required a higher concentration of the competitive inhibitor of indoleamine 2,3‐dioxygenase for complete reversal. In conclusion, L‐MSCs appear to be uniquely well‐equipped immunomodulatory cells, and they are more potent than A‐MSCs and BM‐MSCs in that capacity, which suggests that they may contribute to liver‐induced systemic tolerance.

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Section: Discussioncontrasting

confidence: 56%

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confidence: 99%

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confidence: 99%

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Phenotypic, Transcriptional, and Functional Analysis of Liver Mesenchymal Stromal Cells and Their Immunomodulatory Properties

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“…Accordingly, alloreactive CD4 + and CD8 + circulating blood cells in the SLKT were less frequent. ( 43 ) These studies demonstrated that the immunomodulatory capacity of the liver can be extended beyond the local microenvironment and that it is allospecific. Furthermore, partial auxiliary LT has been performed as a strategy to avoid kidney graft loss in 7 hyperimmunized patients with promising results.…”

Section: Discussionmentioning

confidence: 99%

“…( 39‐41 ) In this sense, 2 recently remarkable studies of Taner et al enlightened the mechanism of tolerance in SLKT. ( 42,43 ) At 1‐year surveillance biopsies of kidney grafts, KT recipients with positive XM, but not SLKT with positive XM, had increased expression of genes associated with donor‐specific antigens, inflammation, and endothelial cell activation. Moreover, overall SLKT recipients had a marked increased expression of genes associated with tissue integrity/metabolism, regardless of the XM status.…”

Section: Discussionmentioning

confidence: 99%

Kidney Graft Outcomes in High Immunological Risk Simultaneous Liver‐Kidney Transplants

et al. 2020

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Recipients of simultaneous liver‐kidney transplantations (SLKTs) have a lower risk of rejection compared with recipients of kidney transplants alone. However, there is disagreement about the impact of pretransplant anti–human leukocyte antigen sensitization on patient and kidney graft survival in the long term. The aim of the study was to evaluate the impact of the recipient immunological risk and comorbidities in renal graft outcomes on SLKT. We reviewed the SLKTs performed in our center from May 1993 until September 2017. Patient and graft survival were analyzed according to the immunological risk, comorbidities, liver and kidney rejection episodes, immunosuppression, and infections. A total of 20 recipients of SLKT were considered in the high immunological risk (HIR) group, and 68 recipients were included in the low immunological risk (LIR) control group. The prevalence of hepatitis C virus infection, second renal transplant, and time on dialysis prior to transplantation were significantly higher in the HIR group. The incidence of acute kidney rejection was higher in the HIR group (P<0.01). However, death‐censored kidney graft survival as well as the estimated glomerular filtration rate at follow‐up were not different between the 2 groups. Comorbidities, but not the immunological risk, impact negatively on patient survival. Despite the higher incidence of rejection in the HIR SLKT group, longterm renal function and graft survival were similar to the LIR group.

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Does the Liver Provide Immunosuppressive Advantage?

Levitsky

2019

Clinical Liver Disease

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Donor-specific hypo-responsiveness occurs in simultaneous liver-kidney transplant recipients after the first year

Cited by 47 publications

References 34 publications

Phenotypic, Transcriptional, and Functional Analysis of Liver Mesenchymal Stromal Cells and Their Immunomodulatory Properties

Phenotypic, Transcriptional, and Functional Analysis of Liver Mesenchymal Stromal Cells and Their Immunomodulatory Properties

Kidney Graft Outcomes in High Immunological Risk Simultaneous Liver‐Kidney Transplants

Does the Liver Provide Immunosuppressive Advantage?

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