TY - JOUR
T1 - Elevation of Intracellular Cyclic AMP in Alloreactive CD4+ T Cells Induces Alloantigen-Specific Tolerance That Can Prevent GVHD Lethality In Vivo
AU - O'Shaughnessy, Matthew J.
AU - Chen, Zong Ming
AU - Gramaglia, Irene
AU - Taylor, Patricia A.
AU - Panoskaltsis-Mortari, Angela
AU - Vogtenhuber, Christine
AU - Palmer, Ed
AU - Grader-Beck, Thomas
AU - Boussiotis, Vassiliki A.
AU - Blazar, Bruce R.
N1 - Funding Information:
This study was supported by the National Institutes of Health grants AI34495 (BRB), HL56067 (BRB), AOA43552 (VAB) and CA104596 (VAB).
PY - 2007/5
Y1 - 2007/5
N2 - 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.
AB - 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.
KW - GVHD
KW - Immune response
KW - Mice
KW - T cells
KW - Tolerance
KW - Transgenic
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U2 - 10.1016/j.bbmt.2007.01.071
DO - 10.1016/j.bbmt.2007.01.071
M3 - Article
C2 - 17448912
AN - SCOPUS:34247122701
SN - 1083-8791
VL - 13
SP - 530
EP - 542
JO - Biology of Blood and Marrow Transplantation
JF - Biology of Blood and Marrow Transplantation
IS - 5
ER -