TY - JOUR
T1 - Regulation of human T cell responses by dNP2-ctCTLA-4 inhibits human skin and microvessel graft rejection
AU - Lim, Sangho
AU - Kirkiles-Smith, Nancy C.
AU - Pober, Jordan S.
AU - Bothwell, Alfred L.M.
AU - Choi, Je Min
N1 - Funding Information:
This research was supported by the Bio & Medical Technology Development Program ( NRF-2017M3A9C8027972 ) of the National Research Foundation (NRF) funded by the Korean government to J.-M. Choi; and the NIH grant R01-HL051014 to J.S. Pober.
Funding Information:
This research was supported by the Bio & Medical Technology Development Program (NRF-2017M3A9C8027972) of the National Research Foundation (NRF) funded by the Korean government to J.-M. Choi; and the NIH grant R01-HL051014 to J.S. Pober.
Publisher Copyright:
© 2018 Elsevier Ltd
PY - 2018/11
Y1 - 2018/11
N2 - Manipulation of human T cell functioning by delivery of macromolecules such as DNA, RNA, or protein is limited, unless the human T cells have been stimulated or electropermeabilized. To achieve successful adaptation and survival of a grafted organ, the alloreactive T cells that induce graft rejection must be regulated. Corticosteroids, calcineurin inhibitors, and mTOR inhibitors, which are systemic immunosuppressants, are currently used for transplantation, with significant side effects. In this study, we demonstrated that a cell-permeable peptide (CPP), dNP2, could efficiently deliver proteins into human CD4 and CD8 T cells. We confirmed regulatory functioning of the cytoplasmic domain of CTLA-4 conjugated with dNP2 (dNP2-ctCTLA-4) in human T cell activation, proliferation, and chemokine receptor expression. We utilized a human skin allograft system in SCID/beige mice to examine whether dNP2-ctCTLA-4 could inhibit allograft rejection by controlling T cell responses. The grafted skin tissue inflammation, allogeneic T cell infiltration, and blood cytokine level was markedly reduced by dNP2-ctCTLA-4, resulting in successful transplantation. In addition, it also inhibited T cell alloresponses against microvessels formed form Bcl-2-transduced human umbilical vein endothelial cells implanted into Balb/c Rag1 −/− /IL-2Rγ −/- double knockout (DKO) mice, assessed as reduced T cell infiltration and granzyme B expression. These results collectively suggest that dNP2 peptide conjugation offers a valuable tool for delivering macromolecules like proteins into human T cells, and dNP2-ctCTLA-4 is a novel agent that shows potential in controlling human T cell responses to allow successful adaptation of grafted tissues.
AB - Manipulation of human T cell functioning by delivery of macromolecules such as DNA, RNA, or protein is limited, unless the human T cells have been stimulated or electropermeabilized. To achieve successful adaptation and survival of a grafted organ, the alloreactive T cells that induce graft rejection must be regulated. Corticosteroids, calcineurin inhibitors, and mTOR inhibitors, which are systemic immunosuppressants, are currently used for transplantation, with significant side effects. In this study, we demonstrated that a cell-permeable peptide (CPP), dNP2, could efficiently deliver proteins into human CD4 and CD8 T cells. We confirmed regulatory functioning of the cytoplasmic domain of CTLA-4 conjugated with dNP2 (dNP2-ctCTLA-4) in human T cell activation, proliferation, and chemokine receptor expression. We utilized a human skin allograft system in SCID/beige mice to examine whether dNP2-ctCTLA-4 could inhibit allograft rejection by controlling T cell responses. The grafted skin tissue inflammation, allogeneic T cell infiltration, and blood cytokine level was markedly reduced by dNP2-ctCTLA-4, resulting in successful transplantation. In addition, it also inhibited T cell alloresponses against microvessels formed form Bcl-2-transduced human umbilical vein endothelial cells implanted into Balb/c Rag1 −/− /IL-2Rγ −/- double knockout (DKO) mice, assessed as reduced T cell infiltration and granzyme B expression. These results collectively suggest that dNP2 peptide conjugation offers a valuable tool for delivering macromolecules like proteins into human T cells, and dNP2-ctCTLA-4 is a novel agent that shows potential in controlling human T cell responses to allow successful adaptation of grafted tissues.
KW - Alloresponse
KW - Graft rejection
KW - Human T cell
KW - Transplantation
KW - ctCTLA-4
KW - dNP2
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U2 - 10.1016/j.biomaterials.2018.08.049
DO - 10.1016/j.biomaterials.2018.08.049
M3 - Article
C2 - 30165256
AN - SCOPUS:85053111040
VL - 183
SP - 128
EP - 138
JO - Biomaterials
JF - Biomaterials
SN - 0142-9612
ER -