Tresperimus: a new agent for transplant tolerance induction

Tresperimus is a novel agent that induces allogeneic transplant tolerance. It is structurally related to deoxyspergualin (DSC) but has been modified t o resist rapid hydrolysis in aqueous solution, which simplifies administrat ion. Despite this modification, tresperimus's actions in experimental model s seem almost identical to DSC. Initially, DSG was developed as an antitumo ur agent. Its antitumour efficacy appears limited but DSC and tresperimus h ave favourable effects on transplant rejection. A short course of tresperim us has been shown to have similar or greater quantitative effects to cyclos porin in bone marrow, cardiac and skin transplant models. However, qualitat ively the effects are different. Prevention of rejection is due to inductio n of donor-specific tolerance without affecting immunity to third party ant igens. In addition, CD4+ T-cells from tresperimus-treated animals can trans fer donor specific tolerance to nai:ve animals, an effect not seen with cyc losporin or other traditional immunosuppressive drugs. The mechanism by whi ch tolerance is induced is not clear. Tresperimus (like DSG) binds to Hsc70 , which among other effects inhibits nuclear localisation of NF-kappaB. NF- kappaB nuclear localisation is induced by CD40 ligation in antigen-presenti ng cells, an important early step in T-cell co-stimulation. NF-kappaB is al so required for CD28 ligation signalling, important in late co-stimulation. It also is involved in B-cell activation, via CD40 ligation and kappa ligh t chain production. Hsc70 is also required for efficient cytosolic peptide chaperoning to MHC class molecules. Presumably, it is disruption of T-cell/ dendritic cell interaction that leads to induction of T-cell anergy. Trespe rimus is well-tolerated. The main dose limiting side effects are orthostati c hypotension and peri-oral numbness. These effects are dependant on blood drug levels and, due to its short half-life, correspond to the rate of infu sion. Phase II/III clinical studies are accruing patients and results have not yet been reported. Tresperimus shows promise in the move from immunosup pression to tolerance induction as the way to prevent transplant rejection and graft-versus-host disease (GVHD). However, its role in tolerance induct ion and effect in combination with other tolerance inducing agents e.g., CT LA-4-lg and anti-CD40L antibodies remains unclear.