title: Systemic immunotherapy delays photoreceptor cell loss and prevents vascular pathology in Royal College of Surgeons rats.
abstract: OBJECTIVE
  Degenerative retinopathies, including retinitis pigmentosa, age-related retinal degeneration, autoimmune retinopathy, and related diseases affect millions of people around the world. Currently, there is no effective treatment for most of those diseases. We investigated systemic recombinant T-cell receptor ligand (RTL) immunotherapy for preventing retinal degeneration and vascular damage in the Royal College of Surgeons (RCS) rat model of retinal degeneration.
  
  
  METHODS
  RCS rats were treated with RTL220 tethered to interphotoreceptor retinoid binding protein (IRBP) peptide or control RTL101 without peptide by subcutaneous administration starting at the onset of photoreceptor degeneration or after the degenerative process began daily or every other day and performed for a 13-week period. The retinal cross sections and whole mounts were prepared to determine histopathology, leaking vessels, and formation of vascular complexes. Immunofluorescent studies evaluated microglia and monocyte chemoattractant protein-1 chemokine in treated retinas. Optokinetic studies were performed to determine visual acuity.
  
  
  RESULTS
  Systemic treatment with RTL220 prevented decreases in outer nuclear layer (ONL) thickness and showed a significantly higher number of nuclei than control rats treated with RTL101 or vehicle. RTL220 was also effective in protecting retinal vasculature from leakage and the formation of abnormal vascular complexes even when the treatment was administered after the degenerative process was initiated. Visual acuity measurement showed that rats treated with RTL220 performed significantly better than those with RTL101 and untreated age-matched controls at P60 and P90. Biodistribution studies showed that RTL220 cleared slowly from the administration site. Moreover, RTL220-treated retinas had a significantly reduced number of activated microglia in the subretinal space, decreased monocyte chemoattractant protein-1 production in the retina, inhibited T-cell responses, and reduced anti-interphotoreceptor retinoid binding protein autoantibody titers. Treatment with the control RTL101 (without a specific peptide tethered) or vehicle alone did not inhibit microglia activation or protect photoreceptors or vasculature.
  
  
  CONCLUSIONS
  RTL therapy augmented photoreceptor cell survival, protected vasculature, and increased visual function in the RTL rat. Targeting chronic autoimmunity with RTLs can be an effective therapeutic alternative in delaying retinal degeneration. Subcutaneous delivery of RTLs alone or combined with other drugs could be an attractive option for long-term therapy for retinal degenerative diseases.
authors.affiliation: Ocular Immunology Laboratory, Casey Eye Institute, Oregon Health & Science University, Portland, OR 97239, USA. adamusg@ohsu.edu
authors.forename: Grazyna
authors.initials: G
authors.lastname: Adamus
authors.forename: Shaomei
authors.initials: S
authors.lastname: Wang
authors.forename: Madison
authors.initials: M
authors.lastname: Kyger
authors.forename: Aneta
authors.initials: A
authors.lastname: Worley
authors.forename: Bin
authors.initials: B
authors.lastname: Lu
authors.forename: Gregory G
authors.initials: GG
authors.lastname: Burrows
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001323:Autoantibodies / Q000097:blood; D015551:Autoimmunity / Q000187:drug effects; D001808:Blood Vessels / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D018932:Chemokine CCL2 / Q000096:biosynthesis; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D005260:Female; D007167:Immunotherapy; D007279:Injections, Subcutaneous; D008024:Ligands; D008297:Male; D017628:Microglia / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D008969:Molecular Sequence Data; D010786:Photoreceptor Cells / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology* / Q000493:pharmacokinetics; D012162:Retinal Degeneration / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D012177:Retinol-Binding Proteins / Q000235:genetics / Q000276:immunology*; D014792:Visual Acuity / Q000187:drug effects / Q000276:immunology; D000099214:Retinol-Binding Proteins, Interstitial
chemical_list: D001323:Autoantibodies; D018932:Chemokine CCL2; D008024:Ligands; D011993:Recombinant Fusion Proteins; D012177:Retinol-Binding Proteins; C491766:Ccl2 protein, rat; C552936:RTL220 protein; C487847:Rbp3 protein, rat; D000099214:Retinol-Binding Proteins, Interstitial