In vivo delivery of lentiviral vectors expressing vasoactive intestinal peptide complementary DNA as gene therapy for collagen-induced arthritis.
OBJECTIVE
Vasoactive intestinal peptide (VIP) has been shown to exert potent immunomodulatory activity, and the use of lentiviral vectors has been found to be an effective means of gene delivery. The present study was therefore undertaken to investigate the feasibility and efficiency of gene therapy using lentiviral vectors expressing VIP (LentiVIP) for the treatment of rheumatoid arthritis (RA).


METHODS
We evaluated the therapeutic potential of the gene therapy strategy in the collagen-induced arthritis (CIA) mouse model, administering the vectors at different phases of the disease. The inflammatory response was determined by measuring the levels of various inflammatory cytokines and chemokines in the joints and serum. The Th1-mediated response was evaluated by determining the proliferative response and cytokine profile of T cells stimulated with autoantigen.


RESULTS
A single intraperitoneal injection of LentiVIP was highly effective in treating CIA. Mice with established, severe arthritis showed complete regression of the disease. The therapeutic effect of LentiVIP was associated with widespread biodistribution of the vector and increased VIP levels, especially in joints and lymphoid organs, and was mediated through a striking reduction of the 2 deleterious components of the disease, i.e., the autoimmune response (self-reactive Th1 cell activity and autoantibody production) and the inflammatory response. LentiVIP treatment also induced the generation and/or activation of CD4+,CD25+,FoxP3+ Treg cells in arthritic mice.


CONCLUSIONS
Our findings show that in vivo administration of lentiviral vector expressing VIP produces one of the most potent therapeutic effects described so far in any animal model of RA. We propose that VIP gene transfer should be further investigated as a potential novel, effective treatment of RA and other chronic autoimmune disorders.
Delgado
Mario
M
Immunology and Cell Biology Department, Instituto de Parasitología y Biomedicina López Neyra, CSIC, Granada, Spain.
Toscano
Miguel G
MG
Benabdellah
Karim
K
Cobo
Marien
M
O'Valle
Francisco
F
Gonzalez-Rey
Elena
E
Martín
Francisco
F
D000818:Animals; D001169:Arthritis, Experimental / Q000235:genetics* / Q000378:metabolism / Q000628:therapy*; D018076:DNA, Complementary / Q000627:therapeutic use*; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000627:therapeutic use; D007249:Inflammation / Q000628:therapy; D016086:Lentivirus / Q000235:genetics; D051379:Mice; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology; D014660:Vasoactive Intestinal Peptide / Q000235:genetics* / Q000627:therapeutic use
D018076:DNA, Complementary; D014660:Vasoactive Intestinal Peptide