Abstract
PURPOSE: Age-related macular degeneration (AMD), the leading cause of blindness in western populations, is associated with an overactive complement system, and an increase in circulating antibodies against certain epitopes, including elastin. As loss of the elastin layer of Bruch's membrane (BrM) has been reported in aging and AMD, we previously showed that immunization with elastin peptide oxidatively modified by cigarette smoke (ox-elastin), exacerbated ocular pathology in the smoke-induced ocular pathology (SIOP) model. Here we asked whether ox-elastin peptide-based immunotherapy (PIT) ameliorates damage.
METHODS: C57BL/6J mice were injected with ox-elastin peptide at two doses via weekly subcutaneous administration, while exposed to cigarette smoke for 6 months. FcγR-/- and uninjected C57BL/6J mice served as controls. Retinal morphology was assessed by electron microscopy, and complement activation, antibody deposition and mechanisms of immunological tolerance were assessed by Western blotting and ELISA.
RESULTS: Elimination of Fcγ receptors, preventing antigen/antibody-dependent cytotoxicity, protected against SIOP. Mice receiving PIT with low dose ox-elastin (LD-PIT) exhibited reduced humoral immunity, reduced complement activation and IgG/IgM deposition in the RPE/choroid, and largely a preserved BrM. While there is no direct evidence of ox-elastin pathogenicity, LD-PIT reduced IFNγ and increased IL-4 within RPE/choroid. High dose PIT was not protective.
CONCLUSIONS: These data further support ox-elastin role in ocular damage in part via elastin-specific antibodies, and support the corollary that PIT with ox-elastin attenuates ocular pathology. Overall, damage is associated with complement activation, antibody-dependent cell-mediated cytotoxicity, and altered cytokine signature.
| Original language | English |
|---|---|
| Article number | 108755 |
| Pages (from-to) | 108755 |
| Journal | Experimental Eye Research |
| Volume | 212 |
| Early online date | 4 Sept 2021 |
| DOIs | |
| Publication status | Published - Nov 2021 |
Bibliographical note
Funding Information:Funding for this project was provided in part by the National Institutes of Health (NIH) R01EY019320 ( BR ), R01EY015128 ( BWJ ), R01EY028927 ( BWJ ) and P30EY014800 ( BWJ ), the Department of Veterans Affairs RX000444 and BX003050 (BR), the South Carolina SmartState Endowment (BR), and an Unrestricted Research Grant from Research to Prevent Blindness , New York, NY to the Department of Ophthalmology & Visual Sciences, University of Utah. ADD is supported in part through the National Institute for Health Research (NIHR) Biomedical Research Centre at Moorfields Eye Hospital and University College London Institute of Ophthalmology. We would like to thank Carl Atkinson (Medical University of South Carolina) for the room air and smoke-exposed FcγR −/− mice.
Funding Information:
ADD acts as a consultant for Novartis, Affybody, UCB, Hubble Tx and receives research grants from Janssen Pharmaceuticals and Meira GTX. All other authors have no financial conflicts of interest.
Publisher Copyright:
© 2021