Silencing of HLA class I on primary human hepatocytes as a novel strategy for reduction in alloreactivity

Figueiredo, Constança; Oldhafer, Felix; Wittauer, Eva-Maria; Carvalho‐Oliveira, Marco; Akhdar, A.; Beetz, Oliver; Chen‐Wacker, Chen; Yuzefovych, Yuliia; Falk, Christine S.; Blasczyk, Rainer; Vondran, Florian W. R.

doi:10.1111/jcmm.14484

Cited by 12 publications

(14 citation statements)

References 33 publications

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“…Researchers have access to several molecular tools to disrupt β2M expression, and the choice depends on the outcome needed. Post-transcriptional manipulation by RNA interference (RNAi), either using small interfering RNA (siRNA) or short hairpin RNA (shRNA), stably downregulated or silenced the expression of HLA proteins in B-lymphocyte cell lines ( 58 ) in conjunction with human ESCs ( 59 ), iPSCs ( 60 ), primary human hepatocytes ( 61 ), endothelial cells ( 62 , 63 ) and in a perfusion system at the whole organ level in rat kidney ( 64 ). Silencing with RNAi proved to be stable even after the iPSCs were differentiated to megakaryocytes and even platelets ( 60 ).…”

Section: Hla Depletionmentioning

confidence: 99%

Fit-For-All iPSC-Derived Cell Therapies and Their Evaluation in Humanized Mice With NK Cell Immunity

et al. 2021

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Human induced pluripotent stem cells (iPSCs) can be limitlessly expanded and differentiated into almost all cell types. Moreover, they are amenable to gene manipulation and, because they are established from somatic cells, can be established from essentially any person. Based on these characteristics, iPSCs have been extensively studied as cell sources for tissue grafts, blood transfusions and cancer immunotherapies, and related clinical trials have started. From an immune-matching perspective, autologous iPSCs are perfectly compatible in principle, but also require a prolonged time for reaching the final products, have high cost, and person-to-person variation hindering their common use. Therefore, certified iPSCs with reduced immunogenicity are expected to become off-the-shelf sources, such as those made from human leukocyte antigen (HLA)-homozygous individuals or genetically modified for HLA depletion. Preclinical tests using immunodeficient mice reconstituted with a human immune system (HIS) serve as an important tool to assess the human alloresponse against iPSC-derived cells. Especially, HIS mice reconstituted with not only human T cells but also human natural killer (NK) cells are considered crucial. NK cells attack so-called “missing self” cells that do not express self HLA class I, which include HLA-homozygous cells that express only one allele type and HLA-depleted cells. However, conventional HIS mice lack enough reconstituted human NK cells for these tests. Several measures have been developed to overcome this issue including the administration of cytokines that enhance NK cell expansion, such as IL-2 and IL-15, the administration of vectors that express those cytokines, and genetic manipulation to express the cytokines or to enhance the reconstitution of human myeloid cells that express IL15R-alpha. Using such HIS mice with enhanced human NK cell reconstitution, alloresponses against HLA-homozygous and HLA-depleted cells have been studied. However, most studies used HLA-downregulated tumor cells as the target cells and tested in vitro after purifying human cells from HIS mice. In this review, we give an overview of the current state of iPSCs in cell therapies, strategies to lessen their immunogenic potential, and then expound on the development of HIS mice with reconstituted NK cells, followed by their utilization in evaluating future universal HLA-engineered iPSC-derived cells.

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Section: Hla Depletionmentioning

confidence: 99%

Fit-For-All iPSC-Derived Cell Therapies and Their Evaluation in Humanized Mice With NK Cell Immunity

et al. 2021

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“…In vitro study shows that targeting primary human hepatocytes by silencing their HLA class I expression can alleviate alloreactive T cell proliferation without impairing metabolic function (164). In contrast to this human finding, adeno-associated viral vector transfer of donor MHC-I molecule to recipient hepatocytes can induce allospecific CD8 + Treg expansion, and promote allogeneic pancreatic islet graft tolerance (165).…”

Section: Ongoing and Novel Therapeutic Approaches To Promote Liver Trmentioning

confidence: 99%

Transplant Tolerance Induction: Insights From the Liver

2020

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A comparison of pre-clinical transplant models and of solid organs transplanted in routine clinical practice demonstrates that the liver is most amenable to the development of immunological tolerance. This phenomenon arises in the absence of stringent conditioning regimens that accompany published tolerizing protocols for other organs, particularly the kidney. The unique immunologic properties of the liver have assisted our understanding of the alloimmune response and how it can be manipulated to improve graft function and survival. This review will address important findings following liver transplantation in both animals and humans, and how these have driven the understanding and development of therapeutic immunosuppressive options. We will discuss the liver's unique system of immune and non-immune cells that regulate immunity, yet maintain effective responses to pathogens, as well as mechanisms of liver transplant tolerance in pre-clinical models and humans, including current immunosuppressive drug withdrawal trials and biomarkers of tolerance. In addition, we will address innovative therapeutic strategies, including mesenchymal stem cell, regulatory T cell, and regulatory dendritic cell therapy to promote liver allograft tolerance or minimization of immunosuppression in the clinic.

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“…Alternatively, gene transfer of alloantigen to hepatocytes induces the expansion of CD8 Tregs, which further prevent the allograft rejection in mice pancreatic islets transplantation. These gene-modified hepatocytes may also provide some possible tolerance induction strategy in the future (128, 129).…”

Section: Therapeutic Targets For Liver Transplant Tolerance Inductionmentioning

confidence: 99%

Mechanisms of Immune Tolerance in Liver Transplantation-Crosstalk Between Alloreactive T Cells and Liver Cells With Therapeutic Prospects

et al. 2019

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Liver transplantation (LTx) is currently the most powerful treatment for end-stage liver disease. Although liver allograft is more tolerogenic compared to other solid organs, the majority of LTx recipients still require long-term immune suppression (IS) to control the undesired alloimmune responses, which can lead to severe side effects. Thus, understanding the mechanism of liver transplant tolerance and crosstalk between immune cells, especially alloreactive T cells and liver cells, can shed light on more specific tolerance induction strategies for future clinical translation. In this review, we focus on alloreactive T cell mediated immune responses and their crosstalk with liver sinusoidal endothelial cells (LSECs), hepatocytes, hepatic stellate cells (HSCs), and cholangiocytes in transplant setting. Liver cells mainly serve as antigen presenting cells (APCs) to T cells, but with low expression of co-stimulatory molecules. Crosstalk between them largely depends on the different expression of adhesion molecules and chemokine receptors. Inflammatory cytokines secreted by immune cells further elaborate this crosstalk and regulate the fate of naïve T cells differentiation within the liver graft. On the other hand, regulatory T cells (Tregs) play an essential role in inducing and keeping immune tolerance in LTx. Tregs based adoptive cell therapy provides an excellent therapeutic option for clinical transplant tolerance induction. However, many questions regarding cell therapy still need to be solved. Here we also address the current clinical trials of adoptive Tregs therapy and other tolerance induction strategies in LTx, together with future challenges for clinical translation from bench to bedside.

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Silencing of HLA class I on primary human hepatocytes as a novel strategy for reduction in alloreactivity

Cited by 12 publications

References 33 publications

Fit-For-All iPSC-Derived Cell Therapies and Their Evaluation in Humanized Mice With NK Cell Immunity

Fit-For-All iPSC-Derived Cell Therapies and Their Evaluation in Humanized Mice With NK Cell Immunity

Transplant Tolerance Induction: Insights From the Liver

Mechanisms of Immune Tolerance in Liver Transplantation-Crosstalk Between Alloreactive T Cells and Liver Cells With Therapeutic Prospects

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