L’induction de tolérance aux allogreffes: quelles perspectives pour les applications cliniques?

Summary

In the 1980s, chemical and biological agents with a selective action on T lymphocytes, such as polyclonal antibodies and cyclosporin, became available for use in clinical transplantation. The advent of monoclonal antibodies specifically targeting functionally distinct T-lymphocyte subsets represented a major breakthrough. However, despite the availability of these refined therapeutic tools, the trend in clinical practice has been to combine the various drugs available rather than to exploit this significantly improved selectivity.

The experimental use of biological agents in general, and of monoclonal antibodies in particular, has shown that, in contrast to conventional chemical immunosuppressants, they may promote immune tolerance. The operational definition of immune tolerance is “an acquired antigen-specific state of immunological unresponsiveness that is durable in the absence of generalised immunosuppression”. The immune tolerance induced by treatment with alloantigen under cover of biological agents is peripheral in nature, as can be demonstrated by experiments with thymectomised animals.

However, one essential question remains unanswered: how to extend to the clinical setting the advantages of the unique tolerogenic properties demonstrated by these biological agents in the long term allograft survival data reproducibly observed in experimental models, including those involving non-human primates. A better knowledge of the molecular mechanisms involved in the induction of immune tolerance by monoclonal antibodies will allow the development of small molecule agonists or antagonists of the relevant targets.