Graft versus Host Disease and Donor T cell Activation Is Limited by Vasoactive Intestinal Peptide Synthesis by Host Non-hempatopoietic Cells 公开
Yiwen LI (Spring 2018)
Abstract
Vasoactive Intestinal peptide (VIP) is a neuropeptide expressed by both neural and lymphoid cells with pleiotropic effects on brain, immune, pulmonary, GI and cardiovascular systems. The potent immunomodulatory and anti-inflammatory activity of VIP make it an attractive therapeutic target to suppresses immune responses in conditions of deleterious inflammation. In allogeneic bone marrow transplantation (allo-BMT), graft-versus-host disease is mediated by activated allo-reactive T cells that also upregulate a variety of co-inhibitory pathway molecules, including up-regulation of VIP expression on T cells and dendritic cells. It is unclear whether VIP production by host cells in the transplant recipient influence the incidence or severity of GvHD and donor T cell activation. We examined the effect of endogenous VIP signaling in host tissues and organs in modulating the severity of GvHD in a murine allo-ˇBMT model. We examined the effect of endogenous VIP signaling in host tissues and organs in modulating GvHD in a murine allo-ˇBMT model in which VIP-knock-out C57BL/6 mice, genetically deficient for VIP and the related peptide histidine isoleucine (PHI), were transplanted with bone marrow and splenocytes from MHC mis-matched B10.BR donors and compared to wild-type C57BL/6 transplant recipients. Compared with WT recipient mice, VIP-KO recipients transplanted with allogeneic bone marrow and splenocytes had decreased survival, reduced co-inhibitory pathway molecule expression on T cells, and elevated Th1 and Th17 cytokine production. WT and VIP-ˇKO mice treated with lethal doses of irradiation but not followed with allo-ˇBMT showed no survival difference, suggesting VIP-KO mice are not intrinsically more susceptible to irradiation. Transplant experiments using radiation chimeric mice recipients in which either the hematopoietic or non-hematopoietic compartment lacked expression of VIP further demonstrated that VIP production in non-hematopoietic cells is the key factor in limiting the GvHD activity of donor T cells. Finally, immunofluorescent imaging of transgenic mice in which GFP is regulated by the VIP promoter showed VIP production is highly expressed in efferent neurons innervating the lungs, and that host expression of VIP in lung tissues continues for at least 15 days post-transplant. Taken together, these data suggest that local production of VIP in the lung may be a key factor in the control of allo-reactive donor T cells and subsequent GVHD in epithelial target organs. Furthermore, local production of VIP by host neurons surrounding lung alveoli suggests a novel pathway for pharmacological modulation of allo-reactive T cells and control of GVHD.
Table of Contents
Table of Contents
Introduction & Background 10
VIP Signaling and Immunosuppressive Property……...…………………...……...11
Allogeneic Stem Cell transplantation and GvHD……...…………………...……...12
GvHD pathogenesis ……...…………………...……................................................12
Cytokine Production and aGvHD……...………………..........................................15
Co-ˇinhibitory Pathway ………………………………...…………………...……...17
Experimental Hypothesis……….……………………………………...…………...17
Materials and Methods 18
Mice…………………………...……………………………………….….............19
Transplant Model………………………….………………………………….…...19
Irradiation Sensitivity Experiment…..…………………………………….…..…..19
Flow Cytometry………..…………….....…………………………………….…...20
Confocal Imaging………………………………………….……………....……...20
Histology...……………….……………………….……………………........…...20
Statistical Analysis………...…………………..……………………..………......21
Results ....................................................................................................................22
VIP-ˇKO recipients had more GvHD-ˇinduced death after allogeneic BMT than wild-ˇtype
mice. …………….…...……………………………………...…………………...23
WT and VIP-ˇKO recipients had equivalent radiation sensitivity………….....…...25
VIP-ˇKO recipients had elevated cytokine and lower co-ˇinhibitory molecule production
post-ˇBMT……………………………………………………………………...…...26
VIP Production in Non-ˇHematopoietic Compartment post allo-ˇBMT limits GvHD
………………………………………………………………………………….......32
Detection of VIP production in hematopoietic and non-ˇhematopoietic cells up to D15 post
allo-ˇBMT …………………………………………………………………....34
Discussion …………………………………………………………………....39
References …………………………………………………………………....44
Table of Figures
Figure 1.…………………………...………………………………………….…....……...14
Figure 2.…………………………...…………………………………………….....……...24
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Figure 4.…………………………...…………………………………………….....……...27
Figure 5.…………………………...…………………………………………….....……...28
Figure 6.…………………………...…………………………………………….....……...29
Figure 7.…………………………...…………………………………………….....……...31
Figure 8.…………………………...…………………………………………….....……...33
Figure 9.…………………………...…………………………………………….....……...36
Figure 10.…………………………...…………………………………………….....……...37
Figure 11.…………………………...…………………………………………….....……...38
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