Cell labeling for magnetic resonance imaging with the T1 agent manganese chloride

There is growing interest in using MRI to track cellular migration. To date, most work in this area has been performed using ultra‐small particles of iron oxide. Immune cells are difficult to label with iron oxide particles. The ability of adoptively infused tumor specific T cells and N cells to traffic to the tumor microenvironment may be a critical determinant of their therapeutic efficacy. We tested the hypothesis that lymphocytes and B cells would label with MnCl2 to a level that would allow their detection by T1‐weighted MRI. Significant signal enhancement was observed in human lymphocytes after a 1 h incubation with 0.05–1.0 mM MnCl2. A flow cytometry‐based evaluation using propidium iodide and Annexin V staining showed that lymphocytes did not undergo apoptosis or necrosis immediately after and 24 h following a 1 h incubation with up to 1.0 mM MnCl2. Importantly, NK cells and cytotoxic T cells maintained their in vitro killing capacity after being incubated with up to 0.5 mM MnCl2. This is the first report to describe the use of MnCl2 to label lymphocytes. Our data suggests MnCl2 might be an alternative to iron oxide cell labeling for MRI‐based cell migration studies. Copyright © 2006 John Wiley & Sons, Ltd.

[1]  S. Heiland,et al.  MR contrast agents in acute experimental cerebral ischemia: Potential adverse impacts on neurologic outcome and infarction size , 2000, Journal of magnetic resonance imaging : JMRI.

[2]  Eric T Ahrens,et al.  In vivo imaging platform for tracking immunotherapeutic cells , 2005, Nature Biotechnology.

[3]  J. P. McCoy,et al.  In vitro and in vivo evidence of PNH cell sensitivity to immune attack after nonmyeloablative allogeneic hematopoietic cell transplantation. , 2004, Blood.

[4]  Alan P Koretsky,et al.  MRI detection of single particles for cellular imaging. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[5]  J. Bulte,et al.  Preparation of magnetically labeled cells for cell tracking by magnetic resonance imaging. , 2004, Methods in enzymology.

[6]  P. Antich,et al.  Perfluorocarbon imaging in vivo: a 19F MRI study in tumor-bearing mice. , 1989, Magnetic resonance imaging.

[7]  Scott E. Fraser,et al.  Tracking Transplanted Stem Cell Migration Using Bifunctional, Contrast Agent-Enhanced, Magnetic Resonance Imaging , 2002, NeuroImage.

[8]  Ichio Aoki,et al.  In vivo detection of neuroarchitecture in the rodent brain using manganese-enhanced MRI , 2004, NeuroImage.

[9]  Hiroshi Kita,et al.  Mn and Mg influxes through Ca channels of motor nerve terminals are prevented by verapamil in frogs , 1990, Brain Research.

[10]  Jeff W M Bulte,et al.  Monitoring cell therapy using iron oxide MR contrast agents. , 2004, Current pharmaceutical biotechnology.

[11]  A. Koretsky,et al.  Manganese‐enhanced MRI of mouse heart during changes in inotropy † , 2001, Magnetic resonance in medicine.

[12]  H. Eriksson,et al.  Receptor‐Mediated Endocytosis of a Manganese Complex of Transferrin into Neuroblastoma (SHSY5Y) Cells in Culture , 1993, Journal of neurochemistry.

[13]  R. Plemper,et al.  The medial-Golgi ion pump Pmr1 supplies the yeast secretory pathway with Ca2+ and Mn2+ required for glycosylation, sorting, and endoplasmic reticulum-associated protein degradation. , 1998, Molecular biology of the cell.

[14]  J. Bulte,et al.  Magnetic Nanoparticles as Contrast Agents for MR Imaging , 1997 .

[15]  Kathryn Sharer,et al.  In vivo detection of single cells by MRI , 2006, Magnetic resonance in medicine.

[16]  R Weissleder,et al.  Normal T-cell response and in vivo magnetic resonance imaging of T cells loaded with HIV transactivator-peptide-derived superparamagnetic nanoparticles. , 2001, Journal of immunological methods.

[17]  Roland Martin,et al.  Magnetic resonance imaging of labeled T‐cells in a mouse model of multiple sclerosis , 2004, Annals of neurology.

[18]  P. Jynge,et al.  Myocardial manganese elevation and proton relaxivity enhancement with manganese dipyridoxyl diphosphate. Ex vivo assessments in normally perfused and ischemic guinea pig hearts , 1999, NMR in biomedicine.

[19]  J. P. McCoy,et al.  Enhanced cytotoxicity of allogeneic NK cells with killer immunoglobulin-like receptor ligand incompatibility against melanoma and renal cell carcinoma cells. , 2004, Blood.

[20]  L. Sciola,et al.  Enhancing Effect of Manganese on L‐DOPA‐Induced Apoptosis in PC12 Cells , 1999, Journal of neurochemistry.

[21]  R. Weissleder,et al.  MRI of insulitis in autoimmune diabetes , 2002, Magnetic resonance in medicine.

[22]  Chien Ho,et al.  Intracellular labeling of T‐cells with superparamagnetic contrast agents , 1993, Magnetic resonance in medicine.

[23]  Donald S. Williams,et al.  Detection of single mammalian cells by high-resolution magnetic resonance imaging. , 1999, Biophysical journal.

[24]  R Weissleder,et al.  Magnetically labeled cells can be detected by MR imaging , 1997, Journal of magnetic resonance imaging : JMRI.

[25]  M. Fukunaga,et al.  Dynamic activity‐induced manganese‐dependent contrast magnetic resonance imaging (DAIM MRI) , 2002, Magnetic resonance in medicine.

[26]  A. Khanolkar,et al.  CD4+ T Cell-Induced Differentiation of EBV-Transformed Lymphoblastoid Cells Is Associated with Diminished Recognition by EBV-Specific CD8+ Cytotoxic T Cells 1 , 2003, The Journal of Immunology.

[27]  A. Barbeau,et al.  Manganese and extrapyramidal disorders (a critical review and tribute to Dr. George C. Cotzias). , 1984, Neurotoxicology.

[28]  Claudio Luchinat,et al.  Mechanistic studies of a calcium-dependent MRI contrast agent. , 2002, Inorganic chemistry.

[29]  L. Sciola,et al.  Manganese and 1-methyl-4-(2′-ethylphenyl)-1,2,3,6-tetrahydropyridine induce apoptosis in PC12 cells , 1996, Neuroscience Letters.

[30]  H. Rahamimoff,et al.  The inhibitory effect of Mn2+ on the ATP-dependent Ca2+ pump in rat brain synaptic plasma membrane vesicles. , 1991, Biochemical pharmacology.

[31]  B. Griffith,et al.  A novel approach with magnetic resonance imaging used for the detection of lung allograft rejection. , 2000, The Journal of thoracic and cardiovascular surgery.

[32]  R Weissleder,et al.  Superparamagnetic iron oxide: pharmacokinetics and toxicity. , 1989, AJR. American journal of roentgenology.

[33]  Functional Assessment of Tissues with Magnetic Resonance Imaging , 2002, Annals of the New York Academy of Sciences.

[34]  Kevin M. Johnson,et al.  Gadolinium‐bearing red cells as blood pool MRI contrast agents , 1998, Magnetic resonance in medicine.

[35]  Alan P Koretsky,et al.  Highly efficient endosomal labeling of progenitor and stem cells with large magnetic particles allows magnetic resonance imaging of single cells. , 2003, Blood.

[36]  A. Koretsky,et al.  Manganese ion enhances T1‐weighted MRI during brain activation: An approach to direct imaging of brain function , 1997, Magnetic resonance in medicine.

[37]  Afonso C. Silva,et al.  Manganese‐enhanced magnetic resonance imaging (MEMRI) , 2004, NMR in biomedicine.

[38]  E T Ahrens,et al.  Receptor‐mediated endocytosis of iron‐oxide particles provides efficient labeling of dendritic cells for in vivo MR imaging , 2003, Magnetic resonance in medicine.

[39]  W. M. Linehan,et al.  A progress report on the treatment of 157 patients with advanced cancer using lymphokine-activated killer cells and interleukin-2 or high-dose interleukin-2 alone. , 1987, The New England journal of medicine.

[40]  M. Verhoye,et al.  In vivo manganese-enhanced magnetic resonance imaging reveals connections and functional properties of the songbird vocal control system , 2002, Neuroscience.

[41]  T. Hitchens,et al.  A non-invasive approach to detecting organ rejection by MRI: monitoring the accumulation of immune cells at the transplanted organ. , 2004, Current pharmaceutical biotechnology.

[42]  Afonso C. Silva,et al.  In vivo neuronal tract tracing using manganese‐enhanced magnetic resonance imaging , 1998, Magnetic resonance in medicine.