Heterologous immunity provides a potent barrier to transplantation tolerance

TLDR

Many tolerance strategies effective in rodents fail in nonhuman primates, highlighting a species gap in transplant tolerance. The study tests whether heterologous, virally induced alloreactive memory—stemming from acquired immune history—constitutes a barrier to transplantation tolerance. Treatment with deoxyspergualin, an NF‑κB translocation inhibitor, combined with costimulation blockade, synergistically impairs memory T‑cell activation and promotes antigen‑specific tolerance. The data reveal that a threshold of CD8⁺ central memory T cells drives rejection, explaining the difficulty of inducing tolerance in primates and humans and illuminating key signaling pathways for memory T‑cell activation.

Abstract

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.