Abstract 5658: Immune Reconstitution Prevents Autoimmune Inflammation and Right Ventricular Remodeling in Immunodeficiency-Associated Pulmonary Hypertension
Pulmonary arterial hypertension (PH) is a frequently lethal condition commonly associated with autoimmune conditions. Because autoimmunity is closely linked to immunodeficiency, we utilize athymic (AT) nude rats lacking normal T cells to demonstrate how PH is accentuated by a lack of normal regulatory T cell activity. The purpose of this study was to determine whether immune reconstitution (IR) prevents autoimmune inflammation (AI), right ventricular (RV) remodeling and PH using inbred AT rats reconstituted with euthymic spleen cells.
Methods and Results: Inbred WAG AT nude rats were given a single injection of vascular endothelial growth factor receptor (VEGFR) antagonist SU5416 (20mg/kg sc), AT+SU group. Control AT was treated with vehicle only (DMSO). In adoptive transfer IR experiments, AT rats received unfractionated 20×106 euthymic rat spleen cells, CD4+T cells, CD8+T cells, CD4+CD25+T cells isolated with magnetic cell sorting before or after SU5416 administration. 2D-Echo, pulmonary hemodynamics and RV/LV+S ratio were assessed at 10d and 21d. Echo revealed decreased RV fractional shortening (p<0.05) and PA acceleration time (p<0.005) in AT+SU compared with IR and controls. IR prevented increase of RVSP compared to AT+SU (P<0.05) and of RV/LV+S (P<0.001). RV fetal cardiac gene expression (a-MHC, b-MHC, SERCA, BNP, SkACT, ANP) was consistent with pathologic stress pattern injury pattern and was significantly attenuated by IR. Furthermore, IR reduced expression of Th1, TH2 cytokines and pulmonary infiltration of macrophages, mast cells, B cells, IgG deposition and up-regulated lung BMPR2, FOXP3+, c-kit+, HOX11+ expression with increased c-kit+ and BMPR2 expression being noted in the pulmonary vascular endothelium.
Conclusions: This study demonstrates that T cell deficiency is permissive for PH development and that IR prevents hemodynamic RV remodeling, attenuates AI and limits PH. Interestingly, that PH prevention is associated with increased regenerative HOX11+, C-kit stem cell populations.