Abstract
PurposeTo investigate multiparametric functional MRI to characterize acute rejection in a murine allogeneic renal transplant model and evaluate the effect of novel therapeutics.Material and MethodsWe performed allogeneic and syngeneic orthotopic transplantations (Balb/c to C57Bl/6 and C57Bl/6 to C57Bl/6). Allogeneic Groups (n = 5) were either treated with the anti-CCL2-Spiegelmer (mNOX-E36) in monotherapy or in combination with low doses of Ciclosporin-A (10mg/kgBW/d) for 10 days. Controls received equivalent doses of a non-functional spiegelmer (revmNOX-E36) or low dose Ciclosporin-A. Diffusion-weighted (DWI) and Dynamic-contrast-enhanced (DCE-) MRI-scans were performed using a clinical 3T-scanner. DWI analysis (b-values from 0–800 s/mm2) was performed mono- and biexponentially, while DCE-MRI was assessed with deconvolution analysis. Therapy effects were assessed ex vivo with histopathology, immunohistochemistry and RT-PCR. Statistical analysis was performed with unpaired t-tests and Spearman´s correlation coefficient.ResultsDWI showed a significant diffusion restriction in allogeneic compared to syngeneic transplants (ADC: 0.63±0.08 vs. 1.29±0.12 mm2/s*103) with decreasing diffusion restriction under therapy. DCE-MRI showed restored organ perfusion under Ciclosporin A alone and combination therapy (Plasma Flow: 43.43±12.49; 38.75±7.53ml/100ml/min) compared to syngeneic controls (51.03±12.49ml/100ml/min). Ex vivo analysis showed reduced monocytic infiltrates, attenuated levels of inflammatory cytokines under mNOX-E36 monotherapy with an additive effect of low dose Ciclosporin A. There was a significant (p<0.05) negative correlation between ADC and interstitial inflammation (r = -0.73) or macrophage infiltration (r = -0.81) and between organ perfusion and intimal arteritis (r = -0.63).ConclusionMultiparametric functional MRI is suited to detect renal allograft rejection in an experimental murine model and allows to characterize effects of immunosuppressive therapy alleviating acute rejection processes in allogeneic transplantation.
Highlights
Kidney transplantation renders formidable short term results with one-year graft survival rates of greater than 90% [1]
Diffusion weighted Imaging (DWI) showed a significant diffusion restriction in allogeneic compared to syngeneic transplants (ADC: 0.63±0.08 vs. 1.29±0.12 mm2/s*103) with decreasing diffusion restriction under therapy
Microcirculation can be assessed by an advanced biexponential analysis of the DWI-data applying the intravoxel incoherent motion (IVIM) model or with dynamic contrast enhanced (DCE-)Magnetic Resonance Imaging (MRI)
Summary
Kidney transplantation renders formidable short term results with one-year graft survival rates of greater than 90% [1]. Improvements of long term graft survival have been moderate over the course of the last two decades [2]. This holds true for renal but for all other solid organ transplants as well [3]. The assessment of treatment effects of immunosuppressive agents as well as the diagnosis of allograft rejection itself is a major problem in transplant medicine. Functional Magnetic Resonance Imaging (MRI) may serve as an alternative diagnostic noninvasive method [6] Diffusion weighted Imaging (DWI) allows to assess acute allograft rejection by probing molecular water diffusion. As of yet, treatment effects have not been evaluated and a direct correlation of MR to histopathological changes has not been performed in the context of renal allograft rejection
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