Nouvelles strategies thérapeutiques en immunosuppression

Summary

There is a compelling need to discover clinically relevant pharmacological strategies to broaden the narrow therapeutic index of cyclosporin, or to develop a new method for nontoxic and gene-targeted immunosuppression that induces donor-specific transplantation tolerance.

We examined the effects of anti-intercellular adhesion molecule-1 (ICAM-1) antisense oligonucléotides, which act synergistically with cyclosporin because their mechanism of action and metabolism are both distinct from those of cyclosporin.

To attempt to induce donor-specific transplant tolerance without relying on nonspecific immunosuppressants, we administered allochimeric major histocompatibility complex (MHC) class I molecules genetically engineered to bear donor-type antigenic determinants on host-type backbones. Two cryptic tolerogenic amino acid epitopes were localised in the a α₁ helical region of the rat RT1.A^u class I MHC alloantigen. We substituted nucleotide sequences encoding all 9 (α_1h ^u62–77-RT1.A^a), the first 4 (α_1h ^u62–69-RT1.A^a) or the last 4 (α_1h ^u70–77-RT1.A^a) α₁ helical RT1.A^u polymorphic amino acids in RT1.A^a cDNA.

Untreated ACI (RT1.A^a) recipients reject Wistar Furth (WF; RT1.A^u) heart allografts at a mean survival time of 8.9 ± 1.0 days. A single injection via the portal vein of 10µg of α_1h ^u62–77-RT1.A^a protein alone was ineffective, but α_1h ^u62–69-RT1.A^a protein alone prolonged the survival of WF heart allografts to 14.0 ± 0.8 days. Administration of 10µg of α_1h ^u70–77-RT1.A^a protein induced tolerance towards WF grafts (>180 days), but not towards third-party Brown Norway (BN; RT1.Aⁿ) heart allografts. When α_1h ^u62–69-RT1.A^a protein was combined with oral cyclosporin 4 mg/kg/day on days 0 to 6, ACI recipients accepted WF heart allografts (>180 days); cyclosporin alone only extended graft survival to 14.3 ± 3.0 days. The effect was alloantigen-specific, because the same combination protocol did not affect the survival of third-party BN heart allografts. Tolerant ACI recipients bearing WF heart allografts for > 100 days subsequently accepted second WF heart allografts (>50 days) but rejected BN heart allografts. Thus, selected donor α₁ helical amino acids superimposed on the host’s class I MHC sequence induce donor-specific tolerance.