Prolonged amelioration of acute lung allograft rejection by overexpression of human interleukin-10 under control of a long acting ubiquitin C promoter in rats.
BACKGROUND
The prolonged effect of electroporation-mediated human interleukin-10 (hIL-10) overexpression in skeletal muscle under the control of the constitutional polyubiquitin C promoter (pUb hIL-10) on rat lung allograft rejection was evaluated.


METHODS
Left lung allotransplantation was performed from Brown-Norway to Fischer-F344 rats. Either 2.5 mug pCIK hIL-10 (hIL-10/cytomegalovirus early promoter enhancer) alone (Group I/sacrifice Day 5 and II/sacrifice Day 10) or in combination with 2.5 mug pUb hIL-10 (hIL-10/UbC promoter; Group III/sacrifice Day 10) were injected into the tibialis anterior muscle of the recipient, followed by electroporation 24 hours before transplantation. Animals in Control Groups IV and V without gene transfer were euthanized on Day 5 and 10, respectively. All animals received a daily non-therapeutic dose of cyclosporine A (2.5 mg/kg).


RESULTS
In Control Group IV, complete rejection (median A3B3) was noted on Day 5 with a Pao(2) of 43 +/- 9 mm Hg. In recipients of Control Group V, measurement of gas exchange on Day 10 and rejection grading was impossible because of complete destruction of the allograft. Group I animals on Day 5 (233 +/- 123 mm Hg; p = 0.02 vs Group IV) and Group II animals on Day 10 (150 +/- 139 mm Hg; p = 0.15 vs Group IV) demonstrated improved graft function. Graft function in Group III was further improved on Day 10 (299 +/- 123 mm Hg; p = 0.002 vs Group IV; p = 0.05 vs Group II; p = 0.36 vs Group I). Rejection was significantly reduced in Group III (median, A2B2) compared with Group II (median, A4B3; p < 0.05).


CONCLUSIONS
Interleukin-10 overexpression under control of the constitutive ubiquitin C promoter ameliorates acute rejection and preserves lung graft function for a prolonged time.
Stammberger
Uz
U
Division of General Thoracic Surgery, University Hospital, Bern, Switzerland. uz.stammberger@insel.ch
Bilici
Murat
M
Gugger
Mathias
M
Gazdhar
Amiq
A
Hamacher
Jürg
J
Hyde
Stephen C
SC
Schmid
Ralph A
RA
D000208:Acute Disease; D000818:Animals; D018014:Gene Transfer Techniques; D006084:Graft Rejection / Q000473:pathology*; D006801:Humans; D007150:Immunohistochemistry; D007273:Injections, Intramuscular; D016753:Interleukin-10 / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology; D008168:Lung / Q000503:physiopathology; D016040:Lung Transplantation / Q000009:adverse effects*; D018482:Muscle, Skeletal / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011659:Pulmonary Gas Exchange; D051381:Rats; D011914:Rats, Inbred BN; D011916:Rats, Inbred F344; D013997:Time Factors; D014184:Transplantation, Homologous; D025822:Ubiquitin C / Q000235:genetics*
D025822:Ubiquitin C; D016753:Interleukin-10