Summary We have recently described the immunosuppressive properties of AR‐C117977 and AR‐C122982, representatives of a group of compounds identified as inhibitors of lactate transporters (monocarboxylate transporters; MCTs). These compounds demonstrate the potential therapeutic usefulness of inhibiting MCT‐1, but their physical and metabolic properties made them unsuitable for further development. We have therefore tried to find analogues with similar immunosuppressive efficacy and a more suitable profile for oral administration. Five analogues of AR‐C117977 were synthesised and screened for binding to the transporter, for inhibition of proliferation of both human and rat lymphocytes, for in vivo activity in a model of graft‐versus‐host (GvH) response in the rat, and in high‐ and low‐responder cardiac transplant models in the rat. There was a good correlation between levels of binding of the five analogues to MCT and their inhibition of lymphocyte proliferation in human and rat cells. Furthermore, activity in both the GvH response and the cardiac transplant models correlated well with the determined concentrations of test compound in plasma. These findings on new analogues of MCT‐1 inhibitors have taken us further towards defining the pharmacokinetic properties that may help to identify future drug candidates among inhibitors of MCT‐1.

This report describes a MCT-1 specific inhibitor having immunosuppressive activity on alloimmune responses and inducing donor-specific suppression.

There is a need for immunosuppressive protocols in islet transplantation that are neither nephrotoxic nor diabetogenic. We have examined blockade of the CD28‐B7, CD40‐CD40L and ICAM‐LFA‐1 pathways in a model of allogeneic islet transplantation in mice to determine the efficacy of this blockade in prolongation of graft survival. Histological evidences of inflammation and function were evaluated in grafts that had been functioning for 100 days. Treatment with a combination of all three drugs, or with CTLA4Ig and anti‐CD40L, administered four times during the first six postoperative days, resulted in an excellent graft survival. All animals had a graft survival of >100 days (i.e. indefinitely). Mice treated with CTLA4Ig and anti‐CD40L all showed well‐preserved islets without signs of degeneration or destruction. There were no signs of rejection, as evidenced by the absence of infiltrating lymphocytes. This group had the least amount of rejection/inflammation changes according to ranking of all grafts. In conclusion, a short induction treatment with anti‐CD40L and CTLA4Ig totally prevents rejection and preserves the allogeneic islets transplanted to mice. The addition of anti‐LFA‐1 did not confer any benefit.

AR-C117977, a monocarboxylate transporter inhibitor, reduces immune responses both in vitro and in vivo, maintains long-term graft survival, and induces operational tolerance. To evaluate the immunosuppressive limitations of AR-C117977, this study was performed in nonvascularized transplant models noted for their refractive response to standard immunosuppressive agents. Rat skin was transplanted from DA(RT1avl) into PVG(RT1c) and the reverse. Mouse islet allotransplantation was performed with BALB/c H2d donors and C57Bl/6J H2b recipients. In the skin graft model, AR-C117977 monotherapy was associated with long-term skin graft survival in one rat strain combination. AR-C117977 and cyclosporine A (CsA) in combination resulted in significant prolongation of graft survival in both rat strains. CsA monotherapy did not prevent acute rejection in either strain. Islet allograft survival was moderately prolonged with CsA or AR-C117977. AR-C117977 is an efficient immunosuppressive drug in stringent rodent transplant models and further studies are warranted.