Liposome-bound APO2L/TRAIL is an effective treatment in a rabbit model of rheumatoid arthritis.
OBJECTIVE
We previously observed that T lymphocytes present in synovial fluid (SF) from patients with rheumatoid arthritis (RA) were sensitive to APO2L/TRAIL. In addition, there was a drastic decrease in the amount of bioactive APO2L/TRAIL associated with exosomes in SF from RA patients. This study was undertaken to evaluate the effectiveness of bioactive APO2L/TRAIL conjugated with artificial lipid vesicles resembling natural exosomes as a treatment in a rabbit model of antigen-induced arthritis (AIA).


METHODS
We used a novel Ni(2+)-(N-5-amino-1-carboxypentyl)-iminodiacetic acid)-containing liposomal system. APO2L/TRAIL bound to liposomes was intraarticularly injected into the knees of animals with AIA. One week after treatment, rabbits were killed, and arthritic synovial tissue was analyzed.


RESULTS
Tethering APO2L/TRAIL to the liposome membrane increased its bioactivity and resulted in more effective treatment of AIA compared with soluble, unconjugated APO2L/TRAIL, with substantially reduced synovial hyperplasia and inflammation in rabbit knee joints. The results of biophysical studies suggested that the increased bioactivity of APO2L/TRAIL associated with liposomes was due to the increase in the local concentration of the recombinant protein, augmenting its receptor crosslinking potential, and not to conformational changes in the protein. In spite of this increase in bioactivity, the treatment lacked systemic toxicity and was not hepatotoxic.


CONCLUSIONS
Our findings indicate that binding APO2L/TRAIL to the liposome membrane increases its bioactivity and results in effective treatment of AIA.
Martinez-Lostao
Luis
L
Departamento de Bioquímica, Biología Molecular y Celular, Facultad de Ciencias, Universidad de Zaragoza, C/Pedro Cerbuna 12, Zaragoza 50009, Spain. lumartin@unizar.es
García-Alvarez
Felícito
F
Basáñez
Gorka
G
Alegre-Aguarón
Elena
E
Desportes
Paula
P
Larrad
Luis
L
Naval
Javier
J
Martínez-Lorenzo
María José
MJ
Anel
Alberto
A
D000818:Animals; D001169:Arthritis, Experimental / Q000378:metabolism / Q000628:therapy*; D001172:Arthritis, Rheumatoid / Q000378:metabolism / Q000628:therapy*; D005434:Flow Cytometry; D006965:Hyperplasia / Q000378:metabolism / Q000628:therapy; D007249:Inflammation / Q000378:metabolism / Q000628:therapy; D008081:Liposomes / Q000627:therapeutic use; D011817:Rabbits; D013583:Synovial Membrane / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000627:therapeutic use*; D016896:Treatment Outcome
D008081:Liposomes; D053221:TNF-Related Apoptosis-Inducing Ligand