Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 111, Issue 12, Pages 1887-1895Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI200317477
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Funding
- NCI NIH HHS [R01 CA074364, CA74364-03] Funding Source: Medline
- NIAID NIH HHS [U19 AI044644, R01 AI040519, P01 AI044644, R37 AI040519, AI44644] Funding Source: Medline
- NIDDK NIH HHS [DK/AI40519] Funding Source: Medline
- NIGMS NIH HHS [T32 GM008169] Funding Source: Medline
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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, vitally 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-kappaB 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.
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