Heterologous immunity provides a potent barrier to transplantation tolerance.
Many strategies have been proposed to induce tolerance to transplanted tissue in rodents; however, few if any have shown equal efficacy when tested in nonhuman primate transplant models. We hypothesized that a critical distinction between specific pathogen-free mice and nonhuman primates or human patients is their acquired immune history. Here, we show that a heterologous immune response--specifically, virally induced alloreactive memory--is a potent barrier to tolerance induction. A critical threshold of memory T cells is needed to promote rejection, and CD8(+) "central" memory T cells are primarily responsible. Finally, treatment with deoxyspergualin, an inhibitor of NF-kappa B translocation, together with costimulation blockade, synergistically impairs memory T cell activation and promotes antigen-specific tolerance of memory. These data offer a potential explanation for the difficulty encountered when inducing tolerance in nonhuman primates and human patients and provide insight into the signaling pathways essential for memory T cell activation and function.
Adams
Andrew B
AB
Emory Transplant Center and Department of Surgery, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
Williams
Matthew A
MA
Jones
Thomas R
TR
Shirasugi
Nozomu
N
Durham
Megan M
MM
Kaech
Susan M
SM
Wherry
E John
EJ
Onami
Thandi
T
Lanier
J Gibson
JG
Kokko
Kenneth E
KE
Pearson
Thomas C
TC
Ahmed
Rafi
R
Larsen
Christian P
CP
D000818:Animals; D000941:Antigens; D016026:Bone Marrow Transplantation / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D003429:Cross Reactions; D006084:Graft Rejection; D006146:Guanidines / Q000494:pharmacology; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects; D007156:Immunologic Memory; D007166:Immunosuppressive Agents / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018448:Models, Immunological; D011323:Primates; D013045:Species Specificity; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D014181:Transplantation Immunology; D014184:Transplantation, Homologous; D014777:Virus Diseases / Q000276:immunology
D000941:Antigens; D006146:Guanidines; D007166:Immunosuppressive Agents; C037258:gusperimus