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
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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Article

Heterologous immunity provides a potent barrier to transplantation tolerance

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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DSG and costimulation blockade synergistically inhibit memory cells. Bot...
DSG and costimulation blockade synergistically inhibit memory cells. Both alloreactive and virus-specific memory cell responses were analyzed. (a) Skin graft survival of mice that had previously (1 week earlier) received T cells from sensitized congenic mice and were treated with either the tolerance induction protocol alone or in combination with various agents. The combination of DSG and costimulatory blockade promoted tolerance of donor-specific memory cells (n = 5; MST, 100 days; filled squares). The costimulation blockade tolerance regimen given alone (n = 5, open squares) or in combination with other agents, including rapamycin (n = 5, filled triangles), anti-CD25 (n = 5, open triangles), and anti-γc (n = 5, filled diamonds) failed to inhibit memory-dependent rejection. Two additional experiments demonstrated similar results. (b) LCMV-immune mice were rechallenged with LCMV clone 13 and treated with costimulation blockade (costim), DSG, or the combination of costimulation blockade and DSG. Five days after rechallenge, CD8+ (class I restricted NP396-404 and GP276-286) and CD4+ (class II restricted P13 GP60-80) responses were analyzed. The combination of costimulatory blockade and DSG synergistically inhibited LCMV-specific CD8+ memory T cells (*P < 0.01). No tx, no treatment; immune no rechall, immune mouse without viral rechallenge.