VIP 信号的药理学抑制增强了抗病毒免疫并改善了巨细胞病毒感染的同种异体骨髓移植受者的存活率。
Pharmacological inhibition of VIP signaling enhances antiviral immunity and improves survival in murine cytomegalovirus-infected allogeneic bone marrow transplant recipients.
机构信息
Department of Hematology/Oncology, Winship Cancer Institute, Emory University, Atlanta, GA 30322, USA.
出版信息
Blood. 2013 Mar 21;121(12):2347-51. doi: 10.1182/blood-2012-06-437640. Epub 2013 Jan 16.
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.
摘要
巨细胞病毒（CMV）感染在异基因骨髓移植（allo-BMT）后受到供体源性细胞免疫的控制。血管活性肠肽（VIP）抑制 Th1 免疫。我们假设阻断 VIP 信号会增强 allo-BMT 小鼠受者的抗 CMV 免疫。受者接受来自主要组织相容性复合体（MHC）错配 VIP 敲除（KO）或野生型供体的骨髓（BM）和 T 细胞移植，并接受 7 天的皮下 VIPhyb（肽 VIP 拮抗剂）或磷酸盐缓冲盐水（PBS）治疗。VIP 信号的遗传和药理学阻断可保护 allo-BMT 受者免受致命性小鼠 CMV（mCMV）感染，提高存活率而不增加移植物抗宿主病。用 VIPhyb 治疗或移植 VIP-KO 同种异体移植物的小鼠的病毒载量显著降低，mCMV-M45-肽-MHC-四聚体（+）CD8（+）T 细胞数量增加，PD-1 表达降低，在 mCMV 感染后增强了原发性和继发性细胞免疫反应，而 PBS 治疗的小鼠则没有。这些结果表明，allo-BMT 后给予 VIP 拮抗剂是一种有前途的安全治疗方法，可增强抗病毒细胞免疫。
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