Heterologous immunity provides a potent barrier to transplantation tolerance

Andrew B. Adams, Matthew A. Williams, Thomas R. Jones, Nozomu Shirasugi, Megan M. Durham, Susan M. Kaech, E. John Wherry, Thandi Onami, J. Gibson Lanier, Kenneth E. Kokko, Thomas C. Pearson, Rafi Ahmed, Christian P. Larsen

Research output: Contribution to journalArticle

496 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1887-1895
Number of pages9
JournalJournal of Clinical Investigation
Volume111
Issue number12
DOIs
StatePublished - Jun 2003
Externally publishedYes

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    Adams, A. B., Williams, M. A., Jones, T. R., Shirasugi, N., Durham, M. M., Kaech, S. M., Wherry, E. J., Onami, T., Lanier, J. G., Kokko, K. E., Pearson, T. C., Ahmed, R., & Larsen, C. P. (2003). Heterologous immunity provides a potent barrier to transplantation tolerance. Journal of Clinical Investigation, 111(12), 1887-1895. https://doi.org/10.1172/JCI200317477