title: Pharmacological inhibition of VIP signaling enhances antiviral immunity and improves survival in murine cytomegalovirus-infected allogeneic bone marrow transplant recipients.
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.
authors: Department of Hematology/Oncology, Winship Cancer Institute, Emory University, Atlanta, GA 30322, USA.
authors: Jian-Ming
authors: JM
authors: Li
authors: Mohammad S
authors: MS
authors: Hossain
authors: Lauren
authors: L
authors: Southerland
authors: Edmund K
authors: EK
authors: Waller
mesh_terms: D056704:Adaptive Immunity / Q000187:drug effects* / Q000235:genetics; D000818:Animals; D016026:Bone Marrow Transplantation / Q000276:immunology / Q000401:mortality*; D002478:Cells, Cultured; D006086:Graft vs Host Disease / Q000150:complications / Q000188:drug therapy / Q000235:genetics / Q000276:immunology; D006566:Herpesviridae Infections / Q000188:drug therapy / Q000235:genetics / Q000276:immunology* / Q000401:mortality; D016867:Immunocompromised Host / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018146:Muromegalovirus / Q000187:drug effects / Q000276:immunology*; D009496:Neurotensin / Q000494:pharmacology* / Q000627:therapeutic use; D011993:Recombinant Fusion Proteins / Q000494:pharmacology / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects; D016019:Survival Analysis; D014184:Transplantation, Homologous; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology; D014660:Vasoactive Intestinal Peptide / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000494:pharmacology / Q000627:therapeutic use; D019562:Viral Load / Q000187:drug effects
chemical_list: D011993:Recombinant Fusion Proteins; C069189:(VIP-neurotensin) hybrid antagonist; D014660:Vasoactive Intestinal Peptide; D009496:Neurotensin