Research Summary for “Indices of Renal Tolerance”



Open evening to share a series of informative and accessible presentations from lead researchers from the DECISIONS / GAMBIT studies sharing outcomes of the research.

GAMBIT study:
Over the last 5 years we have been collecting blood and urine samples, from patients such as yourself. These samples were frozen by our laboratory staff on the day of collection or within 24 hours of your donation. We have been running a number of laboratory tests on these samples. We finalised the process of sample collection in December 2014 and we have been running the laboratory tests and analysing the data during all this time.

As we indicated we were testing for a group of markers that may help us to predict which patients will do well when their immunosuppression regime is decreased. In the process of analysing the data we found out that the expression of these markers was clearly influenced by the immunosuppressive drugs you were taking. This was an important effect to avoid. Therefore we have been able to devise a way to avoid measurement errors due to this effect with a new set of markers. This new set of markers measured in this particular way, is what we hope will allow us to detect which patients may do well when their regime is decreased in the future. The publication from this part can be found in this link: http://www.ncbi.nlm.nih.gov/pubmed/27328267

We are not yet in a position to suggest to any particular patient that it maybe possible to modify your treatment according to the results of these tests. A pilot trial needs to be run and results analysed.

We have also been studying a particular set of white blood cells (B lymphocytes). Prior to our initial study their role in maintaining good graft function was not very well known. We have been able to demonstrate that these cells are capable of producing certain substances when activated in a particular manner. Patients who have been able to maintain their graft in the absence of immunosuppression have B lymphocytes that respond differently. This information may help us to understand better what happens in these patients. The publications from this part can be found in the following links:
http://www.ncbi.nlm.nih.gov/pubmed/26795594 ; (another link will be added later on)









DECISIONS study
Between 2013 and 2014 we asked a group of you who had stable transplant function to take part in a further study given the acronym DECISIONS. This study was designed to take into account what patients felt about the medical risks associated with using the group of markers under investigation to change treatment.
The study had two parts. The first involved filling in a questionnaire about any symptoms you were experiencing and doing a task to find out what level of risk you might be prepared to take to reduce your immunosuppressive drugs if you were found to express the group of markers.

The second involved some of you talking about your kidney transplant(s) and why you had chosen the particular level of risk during the task.

The second part of the study is still being analysed, but the interviews were written as a report that identifies a range of factors and influences that some of you take into account when choosing your level of risk. This includes, amongst other things, the impact of dialysis or family responsibilities and perhaps financial commitments. For some of you having no adverse drug symptoms meant you were not prepared to risk your graft, whereas for some others a desire to 'give back' to medical research and society led to a willingness to take a higher level of risk -even up to 50%. Other factors included your experience as a patient and the level of trust in the medical profession. It was also important what your partner's or family's views and opinions were on the matter.

The implication is that various factors, including emotion, influence the level of risk that patients may take when enrolling in clinical trials and there is a need for the medical profession to be aware of this and take it into account when discussing new treatment protocols. The Publication for this paper can be found at the following link http://www.ncbi.nlm.nih.gov/pubmed/26986241.

We hope this information is of interest to you. If you would like more specific information please don't hesitate to ask in our information day or e-mail:
maria.hernandez@kcl.ac.uk
Please bear in mind that it may take a while to answer some of your queries.


Transplant Inflammation and Repair



The theme of Professor Anthony Dorling's research programme is "vascular inflammation". In the last 5 years, his focus has been the cellular and molecular mechanisms involved in vascular rejection of transplanted organs, with an interest in both humoral and cellular processes. His pure laboratory work is focussed mainly on the role that coagulation proteases play in inflammatory vascular disease. He has shown in animal models that inhibiting coagulation protease activation within transplanted organs has a significant impact on preventing rejection, completely inhibiting humoral processes. In part this is through inhibition of thrombosis, but significantly, it also involves preventing thrombin-mediated signalling through protease activated receptors, which is a critical step in establishing tissue chemokine gradients to initiate leukocyte recruitment into organs. This is expected to have direct translational impact with the advent of pharmaceutical protease activated receptors antagonists in the next few years. It also forms the basis of the work within the MRC centre to develop cell-tethered protein therapeutics designed to inhibit thrombin or thrombin generation. In collaboration with the University of Pittsburgh, he has recently made some significant contributions to understanding why thrombosis is such a problem in pig-to-primate xenotransplantation. His animal work also includes models of intimal hyperplasia, including transplant arteriosclerosis, and he has demonstrated the importance of protease activated receptor signalling on mobilized CD34+ cells in these types of chronic vascular inflammation. This has led to a pilot observational study in humans, to identify the circulating cell types associated with intimal hyperplasia, which has just started recruiting.

Clinically, his research is focussed in two main areas. The first has been in antibody-incompatible transplants. He has been attempting to understand accommodation. Working in an early desensitisation programme established at the Hammersmith Hospital, his group was the first to define an accommodated phenotype in highly sensitised patients who developed a positive cross match in the post-operative period, without clinical problems. He also showed that low titres of HLA Abs could induce a cytoprotective phenotype in endothelial cells consistent with that seen in the transplanted organs. Following on from this, he showed that this phenotype was adenosine and adenosine-receptor dependent and that this pathway was also involved in the development of cytoprotection after exposure to xenoantibodies. This area of work continues at Guy's, in collaboration with Mr NIzam Mamode and the Purine Research laboratory. The second area has been in chronic rejection. Using an observational study and latterly a randomised controlled clinical trial to target B cells (RituxiCAN-C4 trial), he has been collecting cohorts of patients in different stages of chronic antibody-mediated rejection (CAMR). The outcomes of all this clinically based work are expected to be in the public domain by 2012. The main findings are; a) Donor-specific T cell IFN-gamma production in patients with CAMR is B cell dependent; b) In early CAMR, the presence of detectable (B cell-dependent) allospecific T cell responses from peripheral blood leukocytes correlates with early progression towards graft deterioration; c) In late CAMR, the presence of detectable (B cell-dependent) allospecific T cell responses from peripheral blood leukocytes identifies a subgroup of patients who respond to enhanced levels of oral immunotherapy. These studies form the basis of the research that will underpin the work in the new 'Optimising Transplant Survival' clinic to be established in 2012.

Lymph tissue and lymph flow after organ transplantation



Lymphatic vessels in the human body facilitate the trafficking of antigen presenting cells to draining lymph nodes where they trigger an immune response. Donor lymphatic vessels are not connected to that of recipient's during organ transplantation. The results of this disruption to the body have received little research attention but a recent paper by Dr Wilson Wong sheds some new light on this process.

Traditionally, the main site of allosensitization is thought to be in the spleen of the recipient as a result of migration of donor passenger leukocytes via blood. Using Single Photon Emission Computed Tomography/Computerized Tomography (SPECT/CT) lymphoscintigraphy, Dr Wong's group have identified mediastinal lymph nodes as the draining nodes for the donor graft. Staining with HY tetramer after transplantation of HY mismatched heart grafts and ELISPOT following allogeneic grafts to detect donor specific T cells revealed them as important sites for allosensitization. Our data indicates that mediastinal lymph nodes play a crucial role in the alloimmune response, and should be used for ex vivo and adoptive transfer studies after transplantation in addition to the spleen.

In transplantation, there is a dynamic immune response within the donor graft. As a result tertiary lymphoid organs can be found, which contribute to the rejection response. However, lymphoid organs are also important in transplant tolerance. We therefore investigated whether tertiary lymphoid organs may also form during transplantation tolerance. We found that in a kidney allograft tolerance model, grafts that are accepted displayed a higher amount of tertiary lymphoid tissue, leading us to conclude that tertiary lymphoid organ act to amplify the prevailing immune response, be it a tolerant and beneficial immune response or the previously described destructive alloimmunity.

PROTEIN THERAPEUTICS



The protein therapeutics laboratory (PTL) was established at the MRC Centre for Transplantation in 2007.

Directed by Dr Richard Smith the team looks at using therapeutic agents to reduce the risk of an organ being damaged in the hours and days following a transplant.

CELL THERAPEUTICS



The theme of Professor Giovanna Lombardi’s research programme is “transplant tolerance”. The laboratory is co-directed by Professor Robert Lechler. In the last ten years, the focus of the laboratory has been on the mechanisms of transplant rejection and tolerance. The laboratory has developed many projects aimed at understanding the contribution of different cells of the immune system to graft rejection. In particular, their mechanisms of action are under investigation, and this is underpinned by a longstanding interest in the pathways and mechanisms whereby recipient T cells recognise and respond to allogeneic MHC molecules. A current focus is on a third pathway of allorecognition that we proposed (called semidirect) and its contribution to transplant rejection. However the major interest of the laboratory has been on the phenotypic and functional characterisation of naturally occurring regulatory CD4+CD25+ T cells (Tregs) in health and disease both in murine systems and in man. New populations of Tregs circulating in healthy blood have been identified in the laboratory and the question of their stability is under investigation; this issue is critical for the laboratory’s clinical strategy.

One of the approaches that is under investigation in the laboratory is that of manipulating Tregs in vitro prior to use in immunotherapy in transplanted patients. The work has led to important discoveries that led to the idea that adoptive cell therapy using alloantigen-specific, instead of polyclonal Tregs, offers an advantage for preventing allograft rejection. Very encouraging results have been obtained in the murine system, and these have recently been extended into a humanised mouse model of human graft rejection, mediated by human effector cells. This model is being used to address further key questions regarding stability, specificity, and trafficking that will inform the design of clinical trialing of these cells to promote clinical transplant tolerance. In parallel with these experimental studies, a new protocol of expansion of polyclonal Tregs for use in transplant recipients has been established. This work is part of a large EU cell therapy consortium aimed at adoptive Treg therapy in renal transplant recipients and an application is nearly ready to be submitted to the MRC for a similar clinical trial using Tregs to prevent liver transplant rejection. Linked to the pursuit of transplantation tolerance three other types of immune cells (dendritic cells, B cells and Mesenchymal cells) are under investigation to understand their basic mechanisms of action but also whether they can be used to induce transplantation tolerance.

Featured Research

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Research Summary for “Indices of Renal Tolerance”


The theme of Professor Anthony Dorling's research programme is "vascular inflammation"


This research is led by Dr Wilson Wong


The protein therapeutics laboratory (PTL) was established at the MRC Centre for Transplantation in 2007.


The theme of Professor Giovanna Lombardi’s research programme is “transplant tolerance”