Presenting Author:

Eileah Loda

Principal Investigator:

Roumen

Department:

Keywords:

Neuromyelitis, Optica, NMO, Multiple Sclerosis, PLG, nanoparticles, autoimmune, AQP4

Location:

Third Floor, Feinberg Pavilion, Northwestern Memorial Hospital

59 B – Basic Science

Antigen-Coupled PLG Nanoparticle treatment reduces Disease Severity in the Rodent Model of Neuromyelitis Optica

Background: Neuromyelitis Optica (NMO) is an autoimmune disease of the Central Nervous System (CNS) characterized by T cell and antibody responses to the water channel protein Aquaporin 4 (AQP4). NMO patients often suffer from severe disability such as blindness and paralysis due to chronic damage to the optic nerves and spinal cord. Current treatments for NMO are expensive, non-curative and fail to provide durable disease control.

Objectives: Our approach is to use carboxylated biodegradable nanoparticles composed of the FDA-approved biopolymer (polylactide-co-glycolide) (PLG) to induce tolerance both prophylactically and therapeutically in the NMO animal model. Our previous work using PLG to encapsulate proteins or peptides have been shown to induce T cell tolerance for the treatment of animal models of MS, as well as other autoimmune and allergic disease models where the antigen is known.

Methods: Mice were immunized with the pathogenic AQP4201-220 peptide emulsified with Freund’s Complete Adjuvant to induce disease. To increase the severity of the disease we developed an NMO model which is induced using mice disrupted in IFN-gamma or its signaling. PLG nanoparticles were coupled with the AQP4201-220 peptide or OVA323-339 control and administered intravenously to mice 7 days prior to immunization for prophylactic treatment or at the peak of the disease for therapeutic treatment. Clinical scores were recorded daily throughout the disease course. Blood was collected for the analysis of antibodies present in the serum. Spleens and lymph nodes were collected to determine AQP4201-220 peptide-specific T cell cytokine production.

Results: Prophylactic treatment with PLG AQP4 coupled nanoparticles significantly reduced disease incidence and symptom severity in the NMO mouse model. Ex-vivo recall of spleens and lymph nodes showed a significant reduction in T-cell reactivity to the AQP4 peptide compared to the OVA control group with less IL-17, GMCSF, IL-6, IFN-γ, and TNFα. Prophylactic treatment also inhibited clinical disease in the severe NMO model. PLG-AQP4201-220 treatment reduced the clinical score of NMO mice, prevented disease in almost all animals and ex-vivo recall showed reduced secretion of IL-17A from splenocytes and lymph node cells. Therapeutic treatment of PLG-AQP4201-220 significantly ameliorated disease severity compared to PBS and OVA controls in the severe NMO model and reduced GMCSF and IL-17 in ex-vivo recall. Prophylactic particle treatment maintained lower levels of anti-AQP4201-220 antibodies in the serum compared to controls.

Conclusion: PLG nanoparticle treatment for the animal model of NMO shows promising results and significantly reduces disease when administered both prophylactically and therapeutically. This treatment approach is likely to have beneficial and clinically relevant applications in future research. Funds: R21 Grant 12878760