A role for persisting antigen, antigen presentation, and ICAM-1 in increased renal graft survival after oral or portal vein donor-specific immunization.
BACKGROUND
We studied the mechanism behind increased renal allotransplant survival when C3H mice received donor-specific portal vein or oral immunization with C57BL/6 cells. Both regimens lead to donor-specific increased graft survival, in association with decreased production of cytotoxic T lymphocytes and altered cytokine production from host lymphocytes (decreased interleukin [IL]-2 production; increased IL-4, IL-10, and transforming growth factor-beta).


METHODS
We examined a role for persistent donor-derived antigen, in association with host dendritic cells, as well as a role for intercellular adhesion molecule-1 (ICAM-1), in the maintenance of unresponsiveness in host C3H spleen cells to donor antigen. We investigated whether there was a cooperative interaction between donor dendritic cells (DC) and host hepatic mononuclear cells in the induction of immunoregulation in C3H cells.


RESULTS
In mice with surviving renal grafts, donor antigen, in association with host DC, induced the recall of cytotoxicity from C57BL/6 immune C3H spleen cells and IL-4 but not IL-2 production, despite the decreased cytotoxicity seen in the renal transplant recipients themselves. Fresh donor DC induced IL-2 but not IL-4 production. Blocking expression of ICAM-1 on donor grafts, either with anti-ICAM-1 monoclonal antibodies after renal grafting or using grafts from ICAM-1 "knockout" mice, led to further increased survival. Cultured C3H responder spleen cells, incubated with C57BL/6 DC and C3H hepatic cells, transferred hyporesponsiveness to C57BL/6 cells in vitro and in vivo (as assayed by survival of C57BL/6 renal allografts).


CONCLUSIONS
Our data suggest a role for ICAM-1, persistent donor antigen (on host DC), and accessory hepatic monocytes in the induction and maintenance of tolerance after portal vein immunization.
Transplant Research Division, The Toronto Hospital, Ontario, Canada.
R M
RM
Gorczynski
Z
Z
Chen
H
H
Zeng
X M
XM
Fu
D000284:Administration, Oral; D000818:Animals; D017951:Antigen Presentation / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology; D005260:Female; D006084:Graft Rejection / Q000276:immunology / Q000517:prevention & control; D006085:Graft Survival / Q000276:immunology*; D007108:Immune Tolerance / Q000276:immunology; D007116:Immunization, Passive; D018799:Intercellular Adhesion Molecule-1 / Q000502:physiology*; D016753:Interleukin-10 / Q000097:blood; D007376:Interleukin-2 / Q000097:blood; D015847:Interleukin-4 / Q000097:blood; D007519:Isoantigens / Q000276:immunology*; D016030:Kidney Transplantation / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D011169:Portal Vein; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000097:blood
D007376:Interleukin-2; D007519:Isoantigens; D016212:Transforming Growth Factor beta; D018799:Intercellular Adhesion Molecule-1; D016753:Interleukin-10; D015847:Interleukin-4