An immunoadhesin incorporating the molecule OX-2 is a potent immunosuppressant that prolongs allo- and xenograft survival.
We have established that, in mice receiving donor-specific immunization by the portal vein, the increased graft survival seen is associated with the increased expression of a molecule (OX-2) on a subpopulation of dendritic cells (DC), and polarization of cytokine production to type 2 cytokines on Ag-specific restimulation of cells from these mice. Furthermore, infusion of a mAb to OX-2 blocks both the increased graft survival and the altered cytokine production seen. We have constructed an immunoadhesin in which the extracellular domain of OX-2 is linked to the murine IgG2a Fc region, and we have expressed this molecule (OX-2:Fc) in a eukaryotic (baculovirus) expression system. Incubation of lymphocytes with 50 ng/ml OX-2:Fc inhibits a primary mixed lymphocyte reaction in vitro, as assayed by proliferation and induction of cytotoxic T cells, and also alters cytokine production with decreased IL-2 (IFN-gamma) production and increased IL-4 (IL-10) production. Similarly, in vivo infusion of OX-2:Fc promotes increased allo- and xenograft (both skin and renal grafts) survival and decreases the Ab response to sheep erythrocytes. Our data suggest this molecule might have clinical importance in allo- and xenotransplantation.
Gorczynski
R M
RM
Transplant Research Division, The Toronto Hospital, Canada. rgorczynski@transplantunit.org
Cattral
M S
MS
Chen
Z
Z
Hu
J
J
Lei
J
J
Min
W P
WP
Yu
G
G
Ni
J
J
D000818:Animals; D000910:Antibodies, Heterophile / Q000096:biosynthesis; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D015703:Antigens, CD / Q000008:administration & dosage / Q000276:immunology; D000954:Antigens, Surface / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D018122:B7-1 Antigen / Q000008:administration & dosage / Q000276:immunology; D051940:B7-2 Antigen; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D002478:Cells, Cultured; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D006085:Graft Survival / Q000235:genetics / Q000276:immunology*; D006131:Growth Inhibitors / Q000494:pharmacology; D007106:Immune Sera / Q000494:pharmacology; D007108:Immune Tolerance / Q000235:genetics / Q000276:immunology; D007141:Immunoglobulin Fc Fragments / Q000008:administration & dosage / Q000235:genetics / Q000494:pharmacology; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000378:metabolism* / Q000494:pharmacology; D007262:Infusions, Intravenous; D016030:Kidney Transplantation / Q000276:immunology; D007700:Kinetics; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D007959:Lymphocyte Culture Test, Mixed; D008297:Male; D008562:Membrane Glycoproteins / Q000008:administration & dosage / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D051381:Rats; D011917:Rats, Inbred Lew; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology; D012756:Sheep; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014183:Transplantation, Heterologous; D014184:Transplantation, Homologous
D000910:Antibodies, Heterophile; D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000954:Antigens, Surface; D018122:B7-1 Antigen; D051940:B7-2 Antigen; C497965:Cd86 protein, mouse; C497966:Cd86 protein, rat; D015815:Cell Adhesion Molecules; D016207:Cytokines; D006131:Growth Inhibitors; D007106:Immune Sera; D007141:Immunoglobulin Fc Fragments; D007166:Immunosuppressive Agents; D008562:Membrane Glycoproteins; D011993:Recombinant Fusion Proteins; C042739:antigens, CD200