Elevation of Intracellular Cyclic AMP in Alloreactive CD4+ T Cells Induces Alloantigen-Specific Tolerance That Can Prevent GVHD Lethality In Vivo

Matthew J. O'Shaughnessy, Zong Ming Chen, Irene Gramaglia, Patricia A. Taylor, Angela Panoskaltsis-Mortari, Christine Vogtenhuber, Ed Palmer, Thomas Grader-Beck, Vassiliki A. Boussiotis, Bruce R. Blazar

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

Abstract

Cyclic AMP (cAMP) is an important negative regulator of T cell activation, and an increased level of cAMP is associated with T cell hyporesponsiveness in vitro. We sought to determine whether elevating intracellular cAMP levels ex vivo in alloreactive T cells during primary mixed lymphocyte reactions (MLR) is sufficient to induce alloantigen-specific tolerance and prevent graft-versus-host disease (GVHD). Primary MLRs were treated with exogenous 8Br-cAMP and IBMX, a compound that increases intracellular cAMP levels by inhibition of phosphodiesterases. T cell proliferation and IL-2 responsiveness in the treated primary MLR cultures were greatly reduced, and viable T cells recovered on day 8 also had impaired responses to restimulation with alloantigen compared to control-treated cells, but without an impairment to nonspecific mitogens. Labeling experiments showed that cAMP/IBMX inhibited alloreactive T cell proliferation by limiting the number of cell divisions, increasing susceptibility to apoptosis, and rendering nondeleted alloreactive T cells hyporesponsive to alloantigen restimulation. cAMP/IBMX-treated CD4+ T cells had a markedly reduced capacity for GVHD lethality in major histocompatibility complex class II disparate recipients, but maintained the capacity to mediate other CD4+ T cell responses in vivo. Thus, our results provide the first preclinical evidence of using cAMP-elevating pharmaceutical reagents to achieve long-term alloantigen-specific T cell tolerance that is sufficient to prevent GVHD.

Original languageEnglish (US)
Pages (from-to)530-542
Number of pages13
JournalBiology of Blood and Marrow Transplantation
Volume13
Issue number5
DOIs
StatePublished - May 2007

Bibliographical note

Funding Information:
This study was supported by the National Institutes of Health grants AI34495 (BRB), HL56067 (BRB), AOA43552 (VAB) and CA104596 (VAB).

Keywords

  • GVHD
  • Immune response
  • Mice
  • T cells
  • Tolerance
  • Transgenic

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