Macrophage Accumulation Associated With Rat Cardiac Allograft Rejection Detected by Magnetic Resonance Imaging With Ultrasmall Superparamagnetic Iron Oxide Particles

Abstract

Background-Acute cardiac allograft rejection continues to be the cause of graft loss and contributes to the morbidity and mortality after cardiac transplantation. In this study, we report a new method for detecting organ rejection in transplantation with an MR-based technique using dextran-coated ultrasmall superparamagnetic iron oxide (USPIO) particles. These particles (Ϸ27 nm in diameter) are known to shorten relaxation times in MRI experiments. Methods and Results-A new rat model of heterotopic heart and lung transplantation has been developed for MRI experiments. Allotransplantations (DA3 BN) were performed (nϭ8), with syngeneic transplantations (BN3 BN) serving as controls (nϭ8). MR images were obtained with a gradient echo method. At postoperative day 7, allotransplants developed moderate rejection as determined histopathologically. A significant reduction in MR signal intensity was observed after USPIO injection into rats with allotransplanted hearts. Syngeneic transplants showed no differences in MR signal intensity before and after USPIO injections. After injection of USPIO particles at postoperative day 6, a group of allotransplanted rats was treated with cyclosporin A (3 mg/kg). Animals treated with cyclosporin A for 7 days showed no reduction in MR signal intensity after USPIO reinjection at day 14, whereas animals treated for 4 days showed a significant decrease in MR signal intensity in the transplanted hearts indicative of acute graft rejection. Pathological analysis of these animals revealed that dextran-coated USPIO particles were taken up by the infiltrating macrophages that accumulated within the rejecting cardiac graft. Conclusions-This

Superparamagnetic Iron Oxide Nanoparticle Probes for Molecular Imaging

“…Applications 55 have included identifying sites of transplant rejection 71 and the identification of atherosclerotic plaques. 75,130 Thus far, evidence suggests that macrophage uptake of SPIO at sites of atherosclerosis could indicate disease sites prior to luminal narrowing, leading to earlier diagnosis and treatment.…”

Superparamagnetic Iron Oxide Nanoparticles in Biomedicine: Applications and Developments in Diagnostics and Therapy

“…The increased local presence of macrophages and the associated increased accumulation of SPIO during a rejection and changes in the permeability of transplant vessels were able to be imaged in MRI in an animal model during the rejection of heart [171] and kidney transplants [172].…”

Leukocyte-Targeted Myocardial Contrast Echocardiography Can Assess the Degree of Acute Allograft Rejection in a Rat Cardiac Transplantation Model

“…10,15 Agents that affect primarily T cells, 12 including CsA, 16,17 can also limit monocyte/macrophage infiltration. 10,16 Indeed, the extent of macrophage infiltration as assessed by MRI with a magnetic contrast agent targeted to those cells was shown to allow detection of acute cardiac rejection in rats. 10 Some microbubble agents initially introduced as blood flow tracers for myocardial contrast echocardiography (MCE) are adhesive to and phagocytosed by leukocytes, including macrophages.…”

“…10,16 Indeed, the extent of macrophage infiltration as assessed by MRI with a magnetic contrast agent targeted to those cells was shown to allow detection of acute cardiac rejection in rats. 10 Some microbubble agents initially introduced as blood flow tracers for myocardial contrast echocardiography (MCE) are adhesive to and phagocytosed by leukocytes, including macrophages. 18,19 The microbubbles interacting with leukocytes remain acoustically active and provide for ultrasound imaging of inflammation.…”