Abstract
Cytomegalovirus (CMV) infection following allogeneic bone marrow transplant (allo-BMT) is controlled by donor-derived cellular immunity. Vasoactive intestinal peptide (VIP) suppresses Th1 immunity. We hypothesized that blocking VIP-signaling would enhance anti-CMV immunity in murine recipients of allo-BMT. Recipients were transplanted with bone marrow (BM) and T-cells from major histocompatibility complex (MHC)-mismatched VIP-knockout (KO) or wild-type donors, and treated with 7 daily subcutaneous injections of VIPhyb (peptidic VIP-antagonist) or phosphate-buffered saline (PBS). Genetic and pharmacological blockade of VIP-signaling protected allo-BMT recipients from lethal murine CMV (mCMV) infection, improving survival without increasing graft-versus-host disease. Mice treated with VIPhyb or transplanted with VIP-KO allografts had significantly lower viral loads, increased numbers of mCMV-M45-peptide-MHC-tetramer(+) CD8(+) T-cells, with lower PD-1 expression, and enhanced primary and secondary cellular immune responses after mCMV infection than did PBS-treated mice. These results demonstrate that administration of a VIP antagonist after allo-BMT is a promising safely therapeutic approach to enhance antiviral cellular immunity.
Publication types
-
Evaluation Study
-
Research Support, N.I.H., Extramural
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Adaptive Immunity / drug effects*
-
Adaptive Immunity / genetics
-
Animals
-
Bone Marrow Transplantation / immunology
-
Bone Marrow Transplantation / mortality*
-
Cells, Cultured
-
Graft vs Host Disease / complications
-
Graft vs Host Disease / drug therapy
-
Graft vs Host Disease / genetics
-
Graft vs Host Disease / immunology
-
Herpesviridae Infections / drug therapy
-
Herpesviridae Infections / genetics
-
Herpesviridae Infections / immunology*
-
Herpesviridae Infections / mortality
-
Immunocompromised Host / drug effects
-
Immunocompromised Host / immunology
-
Mice
-
Mice, Inbred C57BL
-
Mice, Knockout
-
Muromegalovirus / drug effects
-
Muromegalovirus / immunology*
-
Neurotensin / pharmacology*
-
Neurotensin / therapeutic use
-
Recombinant Fusion Proteins / pharmacology
-
Recombinant Fusion Proteins / therapeutic use
-
Signal Transduction / drug effects
-
Survival Analysis
-
Transplantation, Homologous
-
Up-Regulation / drug effects
-
Up-Regulation / immunology
-
Vasoactive Intestinal Peptide / antagonists & inhibitors*
-
Vasoactive Intestinal Peptide / genetics
-
Vasoactive Intestinal Peptide / pharmacology
-
Vasoactive Intestinal Peptide / therapeutic use
-
Viral Load / drug effects
Substances
-
Recombinant Fusion Proteins
-
(VIP-neurotensin) hybrid antagonist
-
Vasoactive Intestinal Peptide
-
Neurotensin