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 ade noviruses represent efficient vectors for gene tranfer in quiescent cells i n vivo. Adenoviral vectors encoding rat IL-10 (AdlL-10), rat IL-4 (AdlL-4) or beta-galactosidase (AdlacZ) or without transgene (Addl324) were injected directly into rat hearts at the time of transplantation in order to lest t heir potential to prolong heart allograft survival. Expression of vectorize d sequences was confirmed in heart biopsies, and kinetic analysis of P-gala ctosidase showed transient expression. Cardiac allograft survival was signi ficantly prolonged after administration of 10(9) p.f.u. of AdlL-10 (16.6 +/ - 3.2 days, P < 0.05), but not AdlL-4 (9.8 +/- 1.6 days), compared with Add l324-treated (9.3 +/- 3.3 days) or untreated groups (7.8 +/- 1.5 days). Imm unohistochemical 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(+) ce lls. importantly, adenovirus-derived IL-la modified the functional status o f leukocytes by inducing a significant decrease in IFN-gamma production but significantly increased transforming-growth factor pi (TGF-PI) expression within the grafts compared with those treated with Addl324. These results s how that expression of IL-10 by rat hearts after gene transfer mediated by an adenoviral vector decreases allogeneic immune responses and allows prolo ngation of allograft survival.