Interleukin-10 produced by recombinant adenovirus prolongs survival of cardiac allografts in rats.
Interleukin-10 (IL-10) and interleukin-4 (IL-4), two Th2-derived cytokines, are molecules with anti-inflammatory and immunodeviating properties whose direct expression in allografts may prolong graft survival. Recombinant adenoviruses represent efficient vectors for gene transfer in quiescent cells in vivo. Adenoviral vectors encoding rat IL-10 (AdIL-10), rat IL-4 (AdIL-4) or beta-galactosidase (AdlacZ) or without transgene (Addl324) were injected directly into rat hearts at the time of transplantation in order to test their potential to prolong heart allograft survival. Expression of vectorized sequences was confirmed in heart biopsies, and kinetic analysis of beta-galactosidase showed transient expression. Cardiac allograft survival was significantly prolonged after administration of 10(9) p.f.u. of AdIL-10 (16.6 +/- 3.2 days, P < 0.05), but not AdIL-4 (9.8 +/- 1.6 days), compared with Addl324-treated (9.3 +/- 3.3 days) or untreated groups (7.8 +/- 1.5 days). Immunohistochemical analysis of allografts after gene transfer of IL-10 showed that leukocyte infiltration was quantitatively equivalent to that seen in control groups but with a strong tendency towards lower levels of CD8+ cells. Importantly, adenovirus-derived IL-10 modified the functional status of leukocytes by inducing a significant decrease in IFN-gamma production but significantly increased transforming-growth factor beta 1 (TGF-beta 1) expression within the grafts compared with those treated with Addl324. These results show that expression of IL-10 by rat hearts after gene transfer mediated by an adenoviral vector decreases allogeneic immune responses and allows prolongation of allograft survival.
David
A
A
Institut National de la Santé Et de la Recherche Médicale (INSERM) U437, Nantes, France.
Chétritt
J
J
Guillot
C
C
Tesson
L
L
Heslan
J M
JM
Cuturi
M C
MC
Soulillou
J P
JP
Anegon
I
I
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D015870:Gene Expression; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage*; D006084:Graft Rejection / Q000276:immunology / Q000517:prevention & control*; D016027:Heart Transplantation / Q000276:immunology*; D007150:Immunohistochemistry; D007167:Immunotherapy / Q000379:methods; D016753:Interleukin-10 / Q000235:genetics* / Q000627:therapeutic use; D015847:Interleukin-4 / Q000235:genetics; D051381:Rats; D014184:Transplantation, Homologous; D001616:beta-Galactosidase / Q000235:genetics
D016753:Interleukin-10; D015847:Interleukin-4; D001616:beta-Galactosidase