Antisense deoxyoligonucleotides or antibodies to murine MD-1 inhibit rejection of allogeneic and xenogeneic skin grafts in C3H mice.
BACKGROUND
Altered expression of murine MD-1, a molecule controlling expression of members of the interleukin (IL)-1 receptor family of signaling proteins, regulates antigen-presenting cell-induced alloreactions. We investigated the effect of treatment with antisense deoxyoligonucleotides or antibodies to MD-1 in vivo on allogeneic and xenogeneic skin graft survival and the immune responses in transplanted mice.


METHODS
C3H mice received C57BL/6 or Lewis rat skin grafts, followed by i.v. injections of anti-MD-1 antibody or antisense oligonucleotides or control reagents at 48-hr intervals. Survival was monitored. In separate studies, mice were sacrificed at 5-day intervals. Serum was analyzed for circulating MD-1 antigen, and peritoneal cells for surface expression of MD-1. The proliferative and cytolytic response of lymphocytes harvested from treated animals and restimulated in vitro with allo- or xenogeneic cells, and the cytokines produced, was measured. Graft histology was assessed at 11 days after transplantation.


RESULTS
Treatment with anti-MD-1 oligonucleotides or antibodies suppressed rejection of both xeno- and allogeneic grafts, decreased induction of graft-specific cytotoxic T cells, increased production of type-2 cytokines (IL-4 and IL-10), and decreased production of type-1 cytokines (IL-2 and interferon-gamma). Serum levels of MD-1 were suppressed, as was expression of MD-1 on the surface of antigen-presenting cells. Grafts from MD-1-treated mice showed little lymphocyte infiltration, and no signs of graft necrosis.


CONCLUSIONS
Our data suggest a critical in vivo role for MD-1 expression in regulating graft rejection, as well as in the concomitant sensitization of T cells and their cytokine production profile, which parallels the rejection response.
Hadidi
Sima
S
Toronto General Hospital, Transplant Research Division, 200 Elizabeth Street, Toronto, M5G 2C4 Ontario, Canada.
Chen
Zhiqi
Z
Phillips
Jim
J
Yu
Kai
K
Gorczynski
Reginald M
RM
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000954:Antigens, Surface / Q000097:blood / Q000235:genetics* / Q000276:immunology*; D002455:Cell Division / Q000276:immunology; D015870:Gene Expression / Q000276:immunology; D006084:Graft Rejection / Q000276:immunology* / Q000517:prevention & control* / Q000628:therapy; D006085:Graft Survival / Q000276:immunology; D007371:Interferon-gamma / Q000096:biosynthesis; D015847:Interleukin-4 / Q000096:biosynthesis; D017737:Macrophages, Peritoneal / Q000276:immunology; D008297:Male; D008562:Membrane Glycoproteins; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D016038:Skin Transplantation / Q000276:immunology*; D013154:Spleen / Q000166:cytology; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D014183:Transplantation, Heterologous; D014184:Transplantation, Homologous
D000911:Antibodies, Monoclonal; D000954:Antigens, Surface; C113553:Ly86 protein, mouse; D008562:Membrane Glycoproteins; D020319:Oligodeoxyribonucleotides, Antisense; D012333:RNA, Messenger; D015847:Interleukin-4; D007371:Interferon-gamma