Tresperimus: a new agent for transplant tolerance induction.
Tresperimus is a novel agent that induces allogeneic transplant tolerance. It is structurally related to deoxyspergualin (DSG) but has been modified to resist rapid hydrolysis in aqueous solution, which simplifies administration. Despite this modification, tresperimus's actions in experimental models seem almost identical to DSG. Initially, DSG was developed as an antitumour agent. Its antitumour efficacy appears limited but DSG and tresperimus have favourable effects on transplant rejection. A short course of tresperimus has been shown to have similar or greater quantitative effects to cyclosporin in bone marrow, cardiac and skin transplant models. However, qualitatively the effects are different. Prevention of rejection is due to induction of donor-specific tolerance without affecting immunity to third party antigens. In addition, CD4+ T-cells from tresperimus-treated animals can transfer donor specific tolerance to naïve animals, an effect not seen with cyclosporin or other traditional immunosuppressive drugs. The mechanism by which tolerance is induced is not clear. Tresperimus (like DSG) binds to Hsc70, which among other effects inhibits nuclear localisation of NF-kappa B. NF-kappa B nuclear localisation is induced by CD40 ligation in antigen-presenting cells, an important early step in T-cell co-stimulation. NF-kappa B is also required for CD28 ligation signalling, important in late co-stimulation. It also is involved in B-cell activation, via CD40 ligation and kappa light chain production. Hsc70 is also required for efficient cytosolic peptide chaperoning to MHC class I molecules. Presumably, it is disruption of T-cell/dendritic cell interaction that leads to induction of T-cell anergy. Tresperimus is well-tolerated. The main dose limiting side effects are orthostatic 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 infusion. Phase II/III clinical studies are accruing patients and results have not yet been reported. Tresperimus shows promise in the move from immunosuppression to tolerance induction as the way to prevent transplant rejection and graft versus host disease (G v HD). However, its role in tolerance induction and effect in combination with other tolerance inducing agents e.g., CTLA-4-Ig and anti-CD40L antibodies remains unclear.
Simpson
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North Shore Hospital, Private Bag 93-503, Takapuna, Auckland, New Zealand. david.simpson@whl.co.nz
D000818:Animals; D002219:Carbamates / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D006086:Graft vs Host Disease / Q000517:prevention & control*; D006207:Half-Life; D006801:Humans; D007166:Immunosuppressive Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D020714:Maximum Tolerated Dose; D023001:Transplantation Tolerance / Q000187:drug effects*
D002219:Carbamates; D007166:Immunosuppressive Agents; C092303:tresperimus