Retroviral gene therapy of collagen-induced arthritis by local delivery of IL-4.
Rheumatoid arthritis (RA) is an autoimmune arthritis, for which treatment options remain limited. This study investigated the potential role of adoptive cellular gene therapy as a novel means for treating the RA animal model collagen-induced arthritis (CIA). Adoptive transfer of antigen-specific T-cell hybridomas retrovirally transduced to express IL-4 1 day before booster immunization significantly reduced the number of inflamed joints. Cell transfer after clinical onset of disease had no therapeutic effect. Bioluminescence imaging showed that the hybridomas migrated to the inflamed joints, thus delivering the regulatory protein locally at the site of inflammation. The homing was, at least in part, due to chemotaxis in response to proinflammatory chemokines that are expressed in inflamed joints. There were no significant changes in the cytokine milieu of the draining lymph nodes, nor in the systemic levels of anti-collagen antibodies in treated mice. We conclude that the beneficial clinical effects observed in our model were most likely based on the local action(s) of IL-4 in the inflamed joints and that the local delivery (and effects) of regulatory cytokines, like IL-4, constitutes a novel and effective method of preventing organ-specific autoimmune disease and of minimizing systemic adverse effects.
Tarner
Ingo H
IH
Department of Medicine, Division of Immunology and Rheumatology, Stanford University, School of Medicine, Stanford, California 94305, USA.
Nakajima
Atsuo
A
Seroogy
Christine M
CM
Ermann
Joerg
J
Levicnik
Alenka
A
Contag
Christopher H
CH
Fathman
C Garrison
CG
D019264:Adoptive Transfer; D000818:Animals; D001169:Arthritis, Experimental / Q000517:prevention & control / Q000628:therapy*; D002465:Cell Movement; D015316:Genetic Therapy; D006825:Hybridomas; D007249:Inflammation / Q000276:immunology; D015847:Interleukin-4 / Q000378:metabolism / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D019707:Receptors, Chemokine / Q000378:metabolism; D012190:Retroviridae / Q000235:genetics*; D013601:T-Lymphocytes / Q000276:immunology*; D014162:Transfection
D019707:Receptors, Chemokine; D015847:Interleukin-4