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Heterologous immunity provides a potent barrier to transplantation tolerance
Andrew B. Adams, … , Rafi Ahmed, Christian P. Larsen
Andrew B. Adams, … , Rafi Ahmed, Christian P. Larsen
Published June 15, 2003
Citation Information: J Clin Invest. 2003;111(12):1887-1895. https://doi.org/10.1172/JCI17477.
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Article

Heterologous immunity provides a potent barrier to transplantation tolerance

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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.

Authors

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

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Figure 5

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Antigen-specific tolerance of memory cells. (a) Congenic mice were eithe...
Antigen-specific tolerance of memory cells. (a) Congenic mice were either infected with LCMV (Thy 1.1) or received a skin allograft (CD45.1). Eight weeks after challenge, T cells were isolated to obtain both allo- and virus-specific memory cells and then transferred into naive B6 mice (CD45.2/Thy1.2). Mice then received the tolerance protocol or the tolerance protocol with DSG. sg, skin graft. (b) When the tolerance protocol alone was administered, both alloreactive and virus-specific memory cell populations were preserved, resulting in allograft rejection. When given in combination with DSG, donor-reactive cells were specifically deleted, and viral memory remained intact upon rechallenge. Unstim, unstimulated. (c) Model for heterologous immunity as a barrier to transplantation tolerance.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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