Adenovirus-mediated interleukin-13 gene therapy attenuates acute kidney allograft injury.
BACKGROUND
Kidney transplantation is possible by virtue of systemic immunosuppression, which is in turn accompanied by serious side effects. The search for novel therapeutic agents and strategies is ongoing. Here we investigate the effects of adenovirus-mediated gene therapy with interleukin (IL)-13, which is a cytokine with strong immunomodulatory properties, on acute renal allograft injury. In addition, we compare the effects of local (intrarenal) and systemic (intramuscular) IL-13 gene therapy in kidney transplantation.


METHODS
The experiments were performed in a rat Fisher to Lewis acute rejection model of kidney transplantation. An adenovirus-IL-13 or adenovirus-luciferase was injected either into the donor kidney before transplantation (local treatment) or into the hind leg muscle of recipient rats (systemic treatment). A group with no treatment served as control. No additional immunosuppressive therapy was applied. The rats were sacrificed after 8 days and inflammatory markers and renal pre-fibrosis were assessed.


RESULTS
Efficient gene transfer was confirmed by ELISA, immunohistochemistry and real-time PCR. IL-13 gene therapy diminished graft infiltration with macrophages and cytotoxic T cells and limited up-regulation of mRNA levels of the adhesion molecule E-selectin and pro-inflammatory cytokines TNF-alpha and IFN-gamma. Moreover, reduced renal interstitial pre-fibrosis was found in the rats receiving IL-13 gene therapy. The effects of local and systemic therapy were similar.


CONCLUSIONS
This study demonstrates that IL-13 gene therapy in the graft significantly attenuates acute renal allograft damage, suggesting local therapy with IL-13 as a strategy to reduce the need for systemic immunosuppressive medication and thereby its side effects.
Sandovici
Maria
M
Department of Clinical Pharmacology, Faculty of Medical Sciences, University Medical Center Groningen, University of Groningen, The Netherlands. m.sandovici@med.umcg.nl
Deelman
Leo E
LE
van Goor
Harry
H
Helfrich
Wijnand
W
de Zeeuw
Dick
D
Henning
Robert H
RH
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D003404:Creatinine / Q000097:blood; D017931:DNA Primers; D015536:Down-Regulation; D019040:E-Selectin / Q000235:genetics; D004797:Enzyme-Linked Immunosorbent Assay; D015316:Genetic Therapy; D005822:Genetic Vectors; D006084:Graft Rejection / Q000276:immunology / Q000517:prevention & control*; D007150:Immunohistochemistry; D007371:Interferon-gamma / Q000235:genetics; D018793:Interleukin-13 / Q000097:blood / Q000235:genetics*; D016030:Kidney Transplantation; D008264:Macrophages / Q000276:immunology; D008297:Male; D016133:Polymerase Chain Reaction; D051381:Rats; D011916:Rats, Inbred F344; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
D017931:DNA Primers; D019040:E-Selectin; D018793:Interleukin-13; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D003404:Creatinine