Research Article Trends in Transplantation Trends in Transplant, 2017 doi: 10.15761/TiT.1000241 Volume 10(4): 1-6 ISSN: 1887-455X Te efect of Monocarboxylate Transporter (MCT1) inhibitor, AR-C117977 on accelerated rejection of cardiac grafts in pre-sensitised rats and concordant xenotransplantation Clara Paul 1# , Robert Bundick 2 , Robert Craggs 2 , David Donald 3 , Susan Edwards 2 , Elain Holness 2 , Agneta Montgomery 1 *, Zhongquan Qi 4 , Henrik Ekberg 1 and Clare Murray 2 1 Department of Surgery, University Hospital, Malmo, Sweden 2 Department of Discovery BioScience, AstraZeneca R&D Charnwood, Bakewell Road, Loughborough, Leicestershire LE11 5RH, UK 3 Department of Medicinal Chemistry AstraZeneca, Charnwood, Loughborough, Leicestershire, UK 4 Organ Transplantation Institute of Xiamen University, P.R China # These authors contributed equally to this work Abstract Previous studies have demonstrated the immunosuppressive properties of the monocarboxylate transporter MCT1 inhibitor, AR-C117977. Te objective of this study was to evaluate the possible limitations in immunosuppressive efcacy of AR-C117977 in models of hyper acute rejection of cardiac transplants in pre-sensitised rats and in concordant cardiac xenotransplantation. Methods: A primary graft was given without treatment in order to induce sensitisation. At 10 days, a second cardiac transplant was performed, and doses of the test compound were given and compared to or combined with cyclosporin (CsA). Serum samples were retrieved for fow cytometry and measurements of antibody from the presensitised recipients before and after the second transplantation. Results: Survival was signifcantly prolonged with AR-C117977 in combination with CsA (median 12.5 days) compared with single treatment. AR-C117977 had a better efect on antibody formation and binding to B-cells than CsA, but a similar efect on T-cells. Acute rejection could not be prevented in any of the treatment groups in the xenotransplant model. Conclusion: A short course of the MCT1 inhibitor AR-C117977, in combination with CsA, prevented accelerated acute rejection in presensitised rats, but no long- term graft survival was achieved. Rejection in xenotransplantation was not prevented. Correspondence to: Clara Paul, Agneta Montgomery, Department of Surgery, Institution of Surgical Science, Malmö, Lund University, Sweden, Email: helenclarapaul@gmail.com Key words: immunosuppression, monocarboxylate transporter, allograf, antibody, xenotransplantation, presensitised Received: November 03, 2017; Accepted: November 27, 2017; Published: November 30, 2017 Introduction For many years, the importance of antibody formation in chronic rejection and how to prevent chronic rejection has been discussed widely [1-3]. Half a century ago, acute rejection was the main problem in transplantation and there were only a few immunosuppressive therapies available. As a result, many patients lost their grafs. Today, the main problem is to detect and prevent chronic rejection. Recipients with donor specifc antibodies are in need of high immunosuppressive regimes to prevent graf loss. Te calcineurin inhibitors (CNI), such as CsA and tacrolimus, are nephrotoxic and in high doses detrimental to kidneys. However, combinations of diferent drugs in moderate doses would theoretically potentiate the immunosuppressive efect by blocking multiple pathways. Most centres worldwide use a cocktail of diferent drugs at lower doses to minimize side-efects of the immunosuppressive drugs but with sufcient efcacy to prevent acute rejection. But there is still no drug on the market efcient enough to solve chronic rejection and formation of antibodies. In the situation of hyper acute rejection, there are both a massive cellular and a humoral component. To combine diferent immunosuppressive drugs with diferent immunomodulatory mechanisms could be one way of blocking diferent immunological pathways and reducing loss of grafs in chronic rejection. In transplantation, a major issue is to prevent acute and chronic rejection without the need for immunosuppressive agents with toxic side-efects. Monocarboxylate transporters (MCTs) are interesting targets for inhibition of the immune system. Te MCTs have numerous physiological functions as they are expressed in a wide range of tissues. Mainly, they control the transport of monocarboxylates such as lactate across the cell membrane. Tey play a functional role in T-cell