Pr Eric E. GabisonOphtalmologie · Cornée & réfractive · Paris
Home › Pro area › Editorial — graft rejection › Pharmacological inflections
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

Pharmacological inflections

Early pharmacological inflections

Early pharmacological inflections

Several avenues reflect a more refined understanding of corneal alloreactivity. One approach is to block co-stimulation: interrupting the CD40–CD154 axis with a monoclonal antibody prolongs graft survival in mice and shifts the balance of effector T cells from Th1 toward regulatory cells [8]. Another is to target (lymph)angiogenesis, by jointly blocking VEGFR-2 and VEGFR-3 or by modulating the endogenous regulators of hem- and lymphangiogenesis; vascularization of the recipient bed decreases, and with it the risk of rejection, provided intervention occurs within a certain time window [9,10]. Galenic formulation, finally, opens a third avenue: immunosuppressant nanoparticles, anti-angiogenic nanowafers, and thermosensitive hydrogels maintain, in relevant preclinical models, the survival of a high-risk graft for several months after a single subconjunctival injection, with the combination of an immunosuppressive nanoparticle and an anti-VEGF vector bringing survival above 85% [11,12]. These approaches improve delivery and adherence, and some could change practice in the short term. They remain, however, in the same register: they restrain the immune response more than they restore tolerance.

Antisense and targeted biotherapies

Antisense and targeted biotherapies

Several targeted agents are already at an advanced clinical or preclinical stage. The most advanced is aganirsen (GS-101), an antisense oligonucleotide directed against IRS-1 (insulin receptor substrate-1), a protein overexpressed by endothelial cells in an angiogenic context. As eye drops, it inhibits corneal neovascularization and causes it to regress [13]. The phase III I-CAN trial showed a reduction in neovascular surface area and in the need for grafting [14], and the FDA granted it orphan drug designation for the prevention of corneal rejection [15]. By acting on neovascularization, the best-established risk factor for rejection, it intervenes upstream of allorecognition.

Humoral immunity has also been targeted. Rituximab (anti-CD20) depletes B lymphocytes; it is used in organ transplantation to desensitize recipients carrying anti-donor antibodies or in ABO incompatibility. Its application to the cornea remains indirect and calls for caution. In a highly sensitized recipient, B-cell depletion can in fact worsen the anti-donor T-cell response, because it also removes a population of interleukin-10-producing regulatory B cells [16]. This finding extends beyond this particular case: non-selective depletion can remove the very regulatory circuits one is trying to preserve.

Two other approaches point in the same direction. Blocking CD28–CD80/86 co-stimulation with anti-CD80/86 antibodies prolongs graft survival in a high-risk murine model, by restraining T-cell proliferation and interferon-γ production [17]. Mesenchymal stem cells, through their immunomodulatory effect, likewise prolong allograft survival and promote Treg expansion; at low dose and via the subconjunctival route, they prove safer and more effective than by the systemic route [18].