June 2023
Volume 64, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2023
Evidence of potential early-stage ocular tertiary lymphoid tissue formation following high dose retinal AAV8 gene therapy
Author Affiliations & Notes
  • Kirsten Bucher
    Eberhard Karls Universitat Tubingen, Tubingen, Baden-Württemberg, Germany
  • Daniela Süsskind
    Eberhard Karls Universitat Tubingen, Tubingen, Baden-Württemberg, Germany
  • Martin Biel
    Ludwig-Maximilians-Universitat Munchen, Munchen, Bayern, Germany
  • Stylianos Michalakis
    Ludwig-Maximilians-Universitat Munchen, Munchen, Bayern, Germany
  • Karl-Ulrich Bartz-Schmidt
    Eberhard Karls Universitat Tubingen, Tubingen, Baden-Württemberg, Germany
  • Tobias Peters
    Eberhard Karls Universitat Tubingen, Tubingen, Baden-Württemberg, Germany
  • M Dominik Fischer
    Eberhard Karls Universitat Tubingen, Tubingen, Baden-Württemberg, Germany
    University of Oxford, Oxford, Oxfordshire, United Kingdom
  • Simon J Clark
    Eberhard Karls Universitat Tubingen, Tubingen, Baden-Württemberg, Germany
    The University of Manchester, Manchester, Manchester, United Kingdom
  • Footnotes
    Commercial Relationships   Kirsten Bucher None; Daniela Süsskind None; Martin Biel ViGeneron, Code O (Owner); Stylianos Michalakis ViGeneron, Code O (Owner); Karl-Ulrich Bartz-Schmidt None; Tobias Peters None; M Dominik Fischer None; Simon Clark None
  • Footnotes
    Support  PRO-RETINA Grant
Investigative Ophthalmology & Visual Science June 2023, Vol.64, 3911. doi:
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      Kirsten Bucher, Daniela Süsskind, Martin Biel, Stylianos Michalakis, Karl-Ulrich Bartz-Schmidt, Tobias Peters, M Dominik Fischer, Simon J Clark; Evidence of potential early-stage ocular tertiary lymphoid tissue formation following high dose retinal AAV8 gene therapy. Invest. Ophthalmol. Vis. Sci. 2023;64(8):3911.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : Retinal gene therapies with recombinant adeno-associated virus (rAAV) vectors are innovative approaches for the treatment of various retinal dystrophies. However, high vector doses can induce ocular immune activation and the accumulation of lymphoid cells in retina and choroid. Tertiary lymphoid tissues (TLT) are organized lymphoid aggregates with signs of proliferation forming in non-lymphoid organs during chronic inflammation. They can present transiently with their cellular organization varying from simple clusters of lymphocytes to structures reminiscent of secondary lymphoid organs. Data suggest that TLT serve as local sites of antigen presentation and lymphocyte activation. Here, we investigated potential TLT formation in eyes of non-human primates treated with high-dose retinal gene therapy with rAAV8.

Methods : TLT formation was investigated by immune-histological analysis of eye sections from a toxicology study of a clinical grade rAAV8 vector performed in Macaca fascicularis. Animals had been subretinally injected with either a lower dose of 1×10e11 vector genomes (vg), a higher dose of 1×10e12 vg or a sham injection. After three months the animals were sacrificed and their eyes processed for histology.

Results : Lymphoid aggregates were detectable in both retina and choroid in 5 out of 8 animals receiving the 1×10e12 vg dose, but none were observed in either the lower dose group nor the sham treated. All lymphoid aggregates contained large numbers of CD3+ T cells and CD20+ B cells. In all aggregates the cell membranes of CD3+ T cells formed close contacts with HLA-DR+ antigen presenting cells and both B cells and T cells showed evidence of proliferation as determined by co-staining with the proliferation marker ki67. The observed lymphoid aggregates are likely to represent early stage TLT as they did not stain positive for Lyve-1+ lymphatic vessels nor PNAd+ high endothelial venules, both markers of late-stage TLT formation.

Conclusions : High-dose retinal gene therapy with rAAV8 vectors can induce lymphoid aggregate formation featuring characteristics of early stage TLT. This implies a tolerable dosing limit of subretinal rAAV8 before the formation of early-stage TLT. However, the long-term effect of these structures, and whether they are beneficial or detrimental in the longer term, remains to be elucidated.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.

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