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

Summary, conclusion & references

Summary table of anti-rejection strategies

Summary table of anti-rejection strategies

The table below brings together these approaches, from non-specific immunosuppression to tolerance-restoration strategies, with their target, mechanism, route of administration and level of evidence. Levels of evidence are deliberately noted: most of these strategies remain preclinical.

Anti-rejection strategies: target, mechanism, route and level of evidence
Target / classRepresentative agent(s)MechanismRouteLevel of evidence
CorticosteroidsDexamethasone, prednisolone, loteprednolNon-specific immunosuppressionTopical (± systemic)Standard of care
Calcineurin inhibitorsCiclosporine 2 % (CICLOGRAFT), tacrolimusInhibition of T-lymphocyte activationTopicalCommon use (high risk)
Co-stimulation blockadeAnti-CD40/CD154; anti-CD80/86 (CTLA-4-Ig)Blockade of the second T-cell activation signalSystemic/localPreclinical (murine models)
Anti-angiogenic / anti-lymphangiogenicAnti-VEGF; VEGFR-2/3 blockadeReduction of neovascularization (afferent pathway)Topical/subconjunctivalPreclinical to clinical
Anti-IRS-1 antisenseAganirsen (GS-101)Inhibition of IRS-1-dependent angiogenesisTopical (eye drops)Phase III (I-CAN); FDA orphan drug designation
B-lymphocyte depletionRituximab (anti-CD20)B-cell depletion; humoral desensitizationSystemicIndirect; caution (Breg depletion)
Sustained releaseNanoparticles, nanowafers, hydrogelsSustained delivery of immunosuppressant / anti-VEGFSubconjunctivalPreclinical
Endogenous tolerogenic checkpointsPD-L1 (B7-H1), FasL (CD95L)Apoptosis of effector T lymphocytes; inhibition of IFN-γEndogenous (to be reinforced)Established mechanism (immune privilege)
Tolerogenic HLA moleculeHLA-G (AAV-HLA-G gene therapy)Immunoregulation + inhibition of neovascularizationIntrastromal (AAV)Preclinical
Cellular immunomodulationMesenchymal stem cells (MSCs)Treg induction; immunomodulationSystemic/subconjunctivalPreclinical
Regulatory cell therapyTreg, CAR-TregActive restoration of toleranceSystemic/localClinical (other organs); preclinical for the cornea
Acellular approachTreg extracellular vesicles (Treg-EV)Contact-independent, stable toleranceTopical/subconjunctival (projected)Preclinical (transplantation)
Conclusion

Conclusion

Keratoplasty has profoundly renewed its surgery; its rejection pharmacology, by contrast, has changed little. The current arsenal retains its value in routine grafting, where outcomes are high. It shows its limits, however, precisely where the need is greatest, in high-risk grafting; the recent industrialization of 2% ciclosporin into room-temperature-stable single-dose units improves its quality and ease of use, without changing its nature. Pharmacological inflections and targeted biotherapies — co-stimulation blockade, control of (lymph)angiogenesis, anti-IRS-1 antisense, lymphocyte depletion, sustained release — refine immunosuppression and some may reach practice faster than tolerance therapies. The underlying prospect, to which the 2025 Nobel Prize has given new visibility, is nonetheless to restore peripheral tolerance: either by reinforcing the cornea’s own tolerogenic mechanisms, PD-L1 and HLA-G, or through regulatory T cells and their acellular extension, extracellular vesicles, particularly well suited to the ocular surface. These avenues remain, to date, largely preclinical, and it would be premature to announce their clinical translation. It is up to the corneal community to design the models and trials that will determine whether tolerance can complement, or even take over from, suppression in preventing rejection.

References

References

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