Rapamycin prolongs susceptibility of responding T cells to tolerance induction by CD8+ veto cells.
BACKGROUND
CD8 veto cells are an antigen-specific immunoregulatory cell type that induces tolerance by causing apoptosis in T cells that recognize antigens on the veto cell. However, responding T cells are only susceptible to veto based deletion for a 48-hour window, which represents a severe limitation to the use of veto cells as a cellular therapeutic. Several immunosuppresant drugs inhibit T cell differentiation at distinct points. We hypothesized that immunosuppresants, which arrest T cell differentiation, would maintain responding T cells in a vetoable state.


METHODS
CD8 veto cells were generated from BALB/c (H-2) mice. The 2C transgenic mouse, which expresses a T cell receptor specific for L was used to visualize responding cells. Veto activity was measured by both visualizing apoptosis of the responding 2C T cells and by measuring a decrease in lysis of H-2 targets. Several immunosuppressant drugs were tested for their effect on veto cell activity.


RESULTS
BALB/c veto cells exhibited a potent and antigen-specific deletion of 2C responder cells, but not mature 2C effectors. The addition of rapamycin significantly extended the window of opportunity to veto based deletion by preventing the responding 2C T cells from differentiating out of a vetoable state.


CONCLUSIONS
These findings demonstrate that by utilizing rapamycin, the window of opportunity for veto-based induction of tolerance to transplantation antigens is significantly extended. This approach circumvents a serious obstacle in the development of veto cells as an efficacious cellular therapy to induce allospecific tolerance to transplantation antigens.
Anderson
Kimberly M
KM
Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA.
Zimring
James C
JC
D000818:Animals; D000906:Antibodies / Q000276:immunology; D017209:Apoptosis; D016827:CD8 Antigens / Q000378:metabolism*; D002460:Cell Line; D016572:Cyclosporine / Q000494:pharmacology; D005260:Female; D007108:Immune Tolerance / Q000187:drug effects* / Q000276:immunology; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008212:Lymphocyte Depletion; D051379:Mice; D008807:Mice, Inbred BALB C; D020123:Sirolimus / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism; D013997:Time Factors; D019014:fas Receptor / Q000378:metabolism
D000906:Antibodies; D016827:CD8 Antigens; D007166:Immunosuppressive Agents; D019014:fas Receptor; D016572:Cyclosporine; D020123:Sirolimus