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Dynamic Evolution of Chronic Lung Allograft Rejection in the Mouse.
Tijdschriftbijdrage - Tijdschriftartikel
PURPOSE: Orthotopic left lung transplantation (LTx) in mice is an accepted technique to model human post-LTx complications. However, in depth characterization and proper tools to assess chronic rejection (CR) in this model are lacking. Therefore, we developed a multimodal approach to monitor and characterize CR in murine LTx using a major genetic mismatch of donor and recipient under daily immunosuppression (Cyclosporine A (CsA) + Methylprednisolone (MP)). METHODS: 24 mice underwent LTx and were divided in 3 groups (n=8/group): isograft (BL6>BL6; 10mg CsA+1.0mg MP); allograft with a low dose of steroids (Balb/c>BL6, 10mg CsA+1.0mg MP) and allograft with a high dose of steroids (Balb/c>BL6; 10mg CsA+1.6mg MP). Follow-up included monitoring of immune activation by immunoglobulin (Igs) typing (IgM, IgA, IgE, IgG1, IgG2b, IgG2c and IgG3) and in vivo µCT imaging (lung volume and density) at week 1, 5 and 10 to assess structural changes. Additionally, end-point histopathology was evaluated. RESULTS: Lung volume changed significantly within 10 weeks (p=0.026) and was different between groups (p=0.0002). Lung density was significantly different between groups (p<0.0001). Serum levels of IgA (p=0.015), IgM (p=0.016), IgG2b (p=0.005) and IgG2c (p=0.0002) increased within 10 weeks in all groups, no changes were detected for IgE, IgG1 and IgG3. Histopathology of isografts showed no infiltrations or alterations in lung structure. Low dose 1.0mg MP allografts demonstrated predominantly fibrotic/necrotic lungs with no preserved alveolar structures. Allografts with 1.6mg MP had a heterogeneous histopathology of active cellular and humoral immune organization (broncho-vascular axis) and central/pleural fibrosis mixed with preserved parenchymal structures. CONCLUSION: Multimodal follow-up of transplanted animals using blood Igs and in vivo µCT imaging combined with histopathology are useful to monitor CR after LTx. Immunosuppression has a major influence on the outcome and has to be considered when modelling post LTx complications.
Tijdschrift: Journal of Heart & Lung Transplantation
Jaar van publicatie:2020