Pr Eric E. GabisonOphtalmologie · Cornée & réfractive · Paris
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Editorial contents ▾
  1. Introduction
  2. A proven but ageing therapeutic arsenal
  3. Where the current arsenal falls short: high-risk keratoplasty
  4. Early pharmacological inflections
  5. Antisense and targeted biotherapies
  6. Harnessing endogenous tolerogenic pathways: PD-L1 and HLA-G
  7. The paradigm shift: from suppression to tolerance
  8. Regulatory T cells in keratoplasty
  9. Treg and CAR-Treg therapies: M. Miyara's program
  10. The acellular horizon: from cell therapy to vesicle therapy
  11. Summary table of anti-rejection strategies
  12. Conclusion
  13. References

Tolerogenic pathways & paradigm shift

Harnessing endogenous tolerogenic pathway

Harnessing endogenous tolerogenic pathways: PD-L1 and HLA-G

The cornea has its own tolerogenic mechanisms, which can be reinforced rather than bypassed. The main one is PD-L1 (B7-H1), a programmed death ligand constitutively expressed by the corneal epithelium and endothelium. When it engages its receptor PD-1 on infiltrating T lymphocytes, it blocks their proliferation, shuts down their interferon-γ production, and drives them to apoptosis, favoring graft acceptance [19]. Neutralizing PD-L1, or grafting a donor cornea that lacks it, accelerates and worsens rejection, indicating that this pathway is not redundant [20]. Fas ligand (CD95L), also present on the endothelium, operates through the same apoptotic mechanism of effector deletion [21].

The other key player is HLA-G, a non-classical class I HLA molecule with immunoregulatory activity. It is found in the human cornea, where it inhibits both immune cells and neovascularization [22]. Its tolerogenic power, well known in organ transplantation and during pregnancy, makes it a direct therapeutic target. A viral vector (AAV) carrying HLA-G, injected intrastromally, reduces vascularization, T-lymphocyte infiltration and fibrosis in animal models; a chimeric form reproducing the secreted dimer, the single-chain immunomodulator, prevents rejection in a high-risk graft model treated with ex vivo gene therapy [23]. This approach relies on ocular AAV vectorology and aims for local, sustained tolerance.

The paradigm shift: from suppression to

The paradigm shift: from suppression to tolerance

Another approach is, rather than compensating for defective tolerance with drugs, to restore the physiological mechanisms of peripheral tolerance. The 2025 Nobel Prize in Physiology or Medicine, awarded to Mary E. Brunkow, Fred Ramsdell and Shimon Sakaguchi for their work on this peripheral tolerance, recently underscored its importance [24,25]. As early as 1995, Sakaguchi had identified regulatory T cells (Treg) through the CD25 marker [26]; Brunkow and Ramsdell showed that mutation of FOXP3 causes the devastating autoimmunity of IPEX syndrome, establishing FOXP3 as the master gene of this lineage. CD4+CD25+FOXP3+ Treg actively maintain self-tolerance and shut down immune responses once they have run their course, with direct implications for transplantation [25].