Transplantation - Recent Highlights

TNF receptor blockade

We have extended studies implicating TNF, signaling through TNFR2, in tissue repair, a process that in the heart may be mediated by activated resident cardiac stem cells (CSCs) (Stem Cells 2013;31(9):1881-92).

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We have extended studies implicating TNF, signaling through TNFR2, in tissue repair, a process that in the heart may be mediated by activated resident cardiac stem cells (CSCs) (Stem Cells 2013;31(9):1881-92). We have shown that in human cardiac tissue affected by ischemia heart disease (IHD), TNFR2 is expressed on intrinsic CSCs, identified as c-kit(+)/CD45(-)/VEGFR2(-) interstitial round cells, which are activated as determined by entry to cell cycle and expression of Lin-28. In model systems we have shown that hypoxia induces c-kit(+) CSC activation thrpugh TNF/TNFR2/Lin-28 signaling. These observations suggest that TNFR2 signaling in resident c-kit(+) CSCs induces cardiac repair, findings which provide further understanding of the unanticipated harmful effects of TNF blockade in human IHD. This contrasts with our previous observations in renal cancer, where TNF, acting through TNFR2, is an autocrine growth factor for ccRCC acting via Etk-VEGFR2 cross-talk. This latter observation has led to the award of joint Kidney Research UK funding for a project between theme leads within the Transplantation and Regenerative Medicine and Cancer themes (Bradley, Eisen).

March 2014


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Novel immunosuppressive agents

We have shown that baseline serum B-cell activating factor (BAFF) is a biomarker for predicting acute antibody-mediated rejection in patients receiving antibody-incompatible renal transplants (Transplantation 2013;96:413) and are conducting, with GSK, a phase 2 study to evaluate the efficacy and...

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We have shown that baseline serum B-cell activating factor (BAFF) is a biomarker for predicting acute antibody-mediated rejection in patients receiving antibody-incompatible renal transplants (Transplantation 2013;96:413) and are conducting, with GSK, a phase 2 study to evaluate the efficacy and safety of an anti-BAFF mAb (belimumab) in renal transplant recipients. We have also completed participation in a trial of eculizumab (anti-C5 mAb, Alexion Pharma) to determine its efficacy in preventing acute antibody-mediated rejection in sensitised renal transplant recipients. With colleagues in Immunology we have shown that pre-transplant administration of  Rituximab anti-CD20 mAb depletes germinal centre B cells from lymph nodes but Tfh and Tfr cells persist, and these likely contribute to alloimmunity after the B cell pool recovers.


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Improving donor organ function

We remain at the international forefront of initiatives to increase use of organs donated after circulatory death (DCD) (Lancet 2013;381:727, Am J Transpl 2013;13:823).

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We remain at the international forefront of initiatives to increase use of organs donated after circulatory death (DCD) (Lancet 2013;381:727, Am J Transpl 2013;13:823). The use of warm ex-vivo perfusion of human kidneys has been successfully established and we aim to evaluate pharmacological manipulation of marginal kidneys unsuitable for transplantation. Dr Murphy (MRC Mitochondrial Unit) has developed mitochondria-targeted antioxidants (Nature Med 2013; 19:753) and we are collaborating to determine if they protect transplanted kidneys from IR injury. With Dr Robertson (Photonics) we are evaluating of a near IR probe to estimate of fat content of donor livers prior to transplantation. We are close to completing two trials of cold machine perfusion of donor kidneys and are evaluating normothermic in vivo perfusion of DCD donors, working with a Dutch Company to help develop a portable oxygen perfusion system.

March 2014


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MHC class I and class II and their ligands

We are undertaking genetic and molecular studies of MHC gene products and their ligands with a view to translating the findings into new diagnostic and therapeutic approaches.

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Regulation of MHC expression and HLA immunogenicity: We are studying the mechanisms responsible for controlling cell-surface MHC expression, in part to identify novel targets for small molecules. For MHC class I, we have shown that TAPBPR (Tapsin-related protein) is an inducible widely expressed intracellular protein with an important and unique role in antigen presentation. Like tapsin it binds to MHC class I/b2M heterodimers in the ER but, unlike all other known components of the class I presentation pathway, it stays associated with and regulates MHC class I beyond the ER (PNAS 2013; 110: 3465). In the case of MHC class II, we showed previously that Salmonella infection of human dendritic cells (DC) specifically reduced MHC class II at the cell surface by polyubiquitination. We have now demonstrated that reduced surface MHC class II expression occurs by an invariant chain-independent trafficking mechanism, resulting in accumulation of MHC-II in multi-vesicular bodies. We have also shown, for the first time, that Salmonella infection differentially influences presentation of antigen to functionally distinct CD4-T cell subsets, with reduced antigen presentation to Type A CD4-T cells and enhances presentation to Type B CD4-T cells linked to autoimmune disease (EJI 2013;43:897. EJI 2014; ahead of print).

NK receptors and other innate immune receptors: Our aim is to understand the genetic and functional consequences of interactions of NK receptors, particularly KIR, with different MHC class I molecules with a view to manipulating them to promote tolerance to tissue or stem cell transplants whilst initiating anti-leukaemia effects. We are applying a novel high-throughput KIR typing system to assess copy number variation and genotype, not detectable by conventional typing methods, in a variety of settings and shown that KIR haplotypes are more complex and diverse than previously thought (Genome Res 2012;22:1845). We have recently completed a comprehensive high-resolution analysis of the "KIR-ome" at a single cell level to analyse the magnitude of NK adaption to virus infections and shown that CMV, but not other common herpesviruses, leads to stable imprints in the KIR repertoire, suggesting a role for both activating and inhibitory KIRs in immunity to CMV. Our ability to rapidly generate NK cells in vitro with a given specificity opens up new opportunities for adoptive NK cell therapy guided by HLA class I genotype (Blood 2013: 121: 2678). New developments for more rapid, high-throughput KIR typing will include droplet PCR and imputation. We are also using molecular modelling of HLA to predict immunogenicity of mismatched organs with a view to using this to aid allocation of donor kidneys to recipients.


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Pluripotent stem cells as a source of cells and tissues for transplantation, and provide new insights from modelling human disease

Human induced pluripotent stem cells (hIPSCs) offer the prospect of generating unlimited quantities of cells for transplantation, with potential application for a broad range of disorders, and provide a new resource to study human diseases in vitro. Major aims are to understand the molecular...

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Notable achievements are the discovery that the capacity of hiPSCs to differentiate into different lineages is tightly associated with the cell-cycle machinery and varies with progression through the cell cycle. Whereas early G1 is permissive for TGF-b-dependent endoderm differentiation, cyclin D restricts the activity of Smad2/3 in late G1, causing a switch from endoderm to neuroectoderm potential. These findings suggest that manipulating the cell-cycle using small molecules could direct the differentiation of pluripotent stem cells towards specific cell types without a requirement for exogenous growth factors (Cell 2013; 155: 135). Future work aims to validate these findings in adults stem cells and to study the importance of these mechanisms in adult organs regeneration and in disease. We have also identified signalling pathways controlling the differentiation of hPSCs into pancreatic or hepatic progenitors and shown, for the first time, that activin/TGF-b signalling blocks pancreatic specification induced by retinoic acid while promoting hepatic specification in combination with bone morphogenetic protein and fibroblast growth factor (Diabetologia 2012; 55: 3284). Activin/TGF-b signalling achieves this essential function by controlling the levels of transcription factors needed for liver and pancreatic development. The resulting protocol allowed production of near homogeneous pancreatic progenitors which have recently been used to map regulatory regions which are involved in pancreatic agenesis in human (Nature Genetics 2013, 46(1):61-4). This report represent a proof principle that hIPSCs can be used to study the genetic mechanisms controlling pancreatic development and similar studies are now being performed at the Sanger Institute through the Pancreatic genetics program.

March 2014


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