Heterologous immunity provides a potent barrier to transplantation tolerance

J Clin Invest. 2003 Jun;111(12):1887-95. doi: 10.1172/JCI17477.


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-kappa B 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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Antigens
  • Bone Marrow Transplantation / immunology
  • CD8-Positive T-Lymphocytes / immunology
  • Cross Reactions
  • Graft Rejection
  • Guanidines / pharmacology
  • Humans
  • Immune Tolerance* / drug effects
  • Immunologic Memory
  • Immunosuppressive Agents / pharmacology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Models, Immunological
  • Primates
  • Species Specificity
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / immunology
  • Transplantation Immunology*
  • Transplantation, Homologous
  • Virus Diseases / immunology


  • Antigens
  • Guanidines
  • Immunosuppressive Agents
  • gusperimus