[HTML][HTML] Heterologous immunity provides a potent barrier to transplantation tolerance

AB Adams, MA Williams, TR Jones… - The Journal of …, 2003 - Am Soc Clin Investig
AB Adams, MA Williams, TR Jones, N Shirasugi, MM Durham, SM Kaech, EJ Wherry
The Journal of clinical investigation, 2003Am Soc Clin Investig
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 …
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-κB 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.
The Journal of Clinical Investigation