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 dose of 100 microg/day for 1 week after transplantation accelerates mouse cardiac allograft rejection across MHC barriers. This effect is associated with enhancement of donor-specific cytotoxic T lymphocyte and alloantibody (alloAb) titers. To further evaluate the in vivo role of IL-10, we tested the influence of a neutralizing anti-IL-10 monoclonal antibody (mAb) in both normal and donor (skin) presensitized mouse organ allograft recipients.


METHODS
Heart or liver transplants were performed from B10 (H2b) donors to C3H (H2k) recipients. Anti-IL-10 mAb (SXC.I) was administered intravenously in a single injection or repeated once daily injections. Cytotoxic activity of graft-infiltrating cells was determined by 51Cr-release assay. Circulating alloAb levels were quantified by complement-dependent cytotoxicity and flow cytometry.


RESULTS
Survival of vascularized B10 cardiac allografts in normal recipients was prolonged significantly in the mAb-treated groups. A single injection 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 presensitized recipients, anti-IL-10 mAb from days 0 to 6 significantly prolonged survival 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. Prolongation of liver allograft survival in presensitized recipients was associated with suppression of circulating alloAb levels and with significant reductions in the incidence of B220+ cells in both grafts and recipient spleens.


CONCLUSIONS
The data support an adverse role of anti-IL-10 in allograft rejection; it seems that by reducing alloAb responses, anti-IL-10 mAb may have potential for use as a therapeutic immunosuppressant, particularly in presensitized organ allograft recipients.
Li
W
W
Thomas E. Starzl Transplantation Institute and Department of Surgery, University of Pittsburgh Medical Center, Pennsylvania 15213, USA.
Fu
F
F
Lu
L
L
Narula
S K
SK
Fung
J J
JJ
Thomson
A W
AW
Qian
S
S
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D006085:Graft Survival; D016027:Heart Transplantation / Q000276:immunology; D007114:Immunization; D007074:Immunoglobulin G / Q000097:blood; D007075:Immunoglobulin M / Q000097:blood; D016753:Interleukin-10 / Q000502:physiology*; D007518:Isoantibodies / Q000097:blood; D016031:Liver Transplantation / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014184:Transplantation, Homologous
D000911:Antibodies, Monoclonal; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D007518:Isoantibodies; D016753:Interleukin-10