Systemic administration of anti-interleukin-10 antibody prolongs organ allograft survival in normal and presensitized recipients

Background. Systemic administration of cellular interleukin (IL)-10 at a do se of 100 mu g/day for 1 week after transplantation accelerates mouse cardi ac allograft rejection across MHC barriers. This effect is associated with enhancement of donor-specific cytotoxic T lymphocyte and alloantibody (allo Ab) titers. To further evaluate the in vivo role of IL-10, we tested the in fluence of a neutralizing anti-IL-10 monoclonal antibody (mAb) in both norm al and donor (skin) presensitized mouse organ allograft recipients. Methods. Heart or liver transplants were performed from B10 (H2(b)) donors to C3H (H2(k)) recipients. Anti-IL-10 mAb (SXC.I) was administered intraven ously in a single injection or repeated once daily injections. Cytotoxic ac tivity of graft-infiltrating cells was determined by Cr-51-release assay. C irculating alloAb levels were quantified by complement-dependent cytotoxici ty and flow cytometry. Results. Survival of vascularized B10 cardiac allografts in normal recipien ts was prolonged significantly in the mAb-treated groups. A single injectio n of 1 mg of anti-IL-10 mAb immediately after heart transplantation gave a similar graft median survival time to repeated injections of lower dose mAb (0.5 mg/day for 6 days after transplantation) (Ig isotype control 11 days; single mAb injection 18 days; multiple injection 20 days). In presensitize d recipients, anti-IL-10 mAb from days 0 to 6 significantly prolonged survi val of both cardiac and orthotopic liver grafts. Graft median survival time was extended from 5 to 10 days and from 4 to 11 days, respectively. Prolon gation of liver allograft survival in presensitized recipients was associat ed with suppression of circulating alloAb levels and with significant reduc tions in the incidence of B220(+) cells in both grafts and recipient spleen s. Conclusions. The data support an adverse role of anti-IL-10 in allograft re jection; it seems that by reducing alloAb responses, anti-IL-10 mAb may hav e potential for use as a therapeutic immunosuppressant, particularly in pre sensitized organ allograft recipients.