AMI  Vol.1 No.3 , October 2011
Imaging of Insulitis in NOD Mice with IL-2-Gd-DTPA and 1.5 T MRI
Abstract: To explore the possibility to use 1.5 T MRI in imaging of accumulating gadolinium (Gd) into inflamed en- docrine pancreas (insulitis), we compared intravenously delivered IL-2-Gd-DTPA and Gd-DTPA (Magne- vist®) in phenotypically healthy 12 weeks old female non-obese diabetic (NOD) mice. At 1 to 48 h after the injection mice were sacrificed and the pancreas-to-background ratio was determined using MRI. In addition Gd concentration of the pancreas and plasma were measured. The pancreas-to-plasma ratio of Gd was 25-fold 24 h after the i.v. injection of IL-2-Gd-DTPA. At the same time the pancreas-to-background ratio measured with 1.5T MRI was 1.5-times higher in the NOD mice receiving IL-2-Gd-DTPA than Magnevist® (271 ± 37 vs. 183 ± 0,1, P = 0.04) indicating that sufficient differences may exist between IL-2-Gd-DTPA accumulating in the pancreas and in the surrounding tissues to support the use of MRI for imaging of pan- creatic insulitis.
Cite this paper: nullT. Kalliokoski, E. Svedström, J. Saunavaara, A. Roivainen, M. Kankaanpää, H. Oivanen, P. Nuutila and O. Simell, "Imaging of Insulitis in NOD Mice with IL-2-Gd-DTPA and 1.5 T MRI," Advances in Molecular Imaging, Vol. 1 No. 3, 2011, pp. 43-49. doi: 10.4236/ami.2011.13006.

[1]   P. Pozzilli, A. Signore, A. J. Williams and P. E. Beales, “NOD Mouse Colonies around the World—Recent Facts and Figures,” Immunology Today, Vol. 14, No. 5, 1993, pp. 193-196. doi:10.1016/0167-5699(93)90160-M

[2]   E. F. Lampeter, A. Signore, E. A. Gale and P. Pozzilli, “Lessons from the NOD Mouse for the Pathogenesis and Immunotherapy of Human Type 1 (Insulin-Dependent) Diabetes Mellitus,” Diabetologia, Vol. 32, No. 10, 1989, pp. 703-708. doi:10.1007/BF00274528

[3]   Y. Koide, T. Kaidoh, M. Nakamura and T. O. Yoshida, “Molecular Analysis of the Pathogenesis of Autoimmune Insulitis in NOD Mice,” The Tohoku Journal of Experi-mental Medicine, Vol. 173, No. 1, 1994, pp. 157-170. doi:10.1620/tjem.173.157

[4]   G. S. Eisenbarth, “Type I Diabetes Mellitus. A Chronic Autoimmune Disease,” The New England Journal Medi-cine, Vol. 314, No. 21, 1986, pp. 1360-1368.

[5]   A. Signore, E. Procaccini, A. M. Toscano, E. Ferretti, A. J. Williams, P. E. Beales, P. Cugini and P. Pozzilli, “His-tological Study of Pancreatic Beta-Cell Loss in Relation to the Insulitis Process in the Non-Obese Diabetic Mouse,” Histochemistry, Vol. 101, No. 4, 1994, pp. 263- 269. doi:10.1007/BF00315913

[6]   S. Makino, K. Kunimoto, Y. Muraoka, Y. Mizushima, K. Katagiri and Y. Tochino, “Breeding of a Non-Obese, Di-abetic Strain of Mice,” Experimental Animals, Vol. 29, No. 1, 1980, pp. 1-13.

[7]   N. Hatamori, K. Yokono, M. Nagata, K. Doi and S. Baba, “Interleukin 2/Interleukin 2 Receptor System in Type 1 Diabetes,” Diabetes Research and Clinical Practice, Vol. 7, Supplement 1, 1989, pp. S67-S72. doi:10.1016/0168-8227(89)90090-9

[8]   P. Bedossa, A. Bendelac, J. F. Bach and C. Carnaud, “Syngeneic T Cell Transfer of Diabetes into NOD New-born Mice: In Situ Studies of the Autoimmune Steps Leading to Insulin-Producing Cell Destruction,” European Journal of Immunology, Vol. 19, No. 10, 1989, pp. 1947-1951. doi:10.1002/eji.1830191028

[9]   A. Signore, M. Chianelli, A. Toscano, L. Monetini, G. Ronga, C. C. Nimmon, K. E. Britton, P. Pozzilli and M. Negri, “A Radiopharmaceutical for Imaging Areas of Lymphocytic Infiltration: 123I-Interleukin-2. Labelling Procedure and Animal Studies,” Nuclear Medicine Communications, Vol. 13, No. 10, 1992, pp. 713-722.

[10]   O. Rolandsson, T. Stigbrand, K. Riklundahlstrom, J. Eary and C. Greenbaum, “Accumulation of(125)Iodine Labeled Interleukin-2 in the Pancreas of NOD Mice,” Journal of Autoimmunity, Vol. 17, No. 4, 2001, pp. 281- 287. doi:10.1006/jaut.2001.0555

[11]   J. Virostko, E. D. Jansen and A. C. Powers, “Current Status of Imaging Pancreatic Islets,” Current Diabetes Reports, Vol. 6, No. 4, 2006, pp. 328-332. doi:10.1007/s11892-006-0069-9

[12]   A. Moore, J. Grimm, B. Han and P. Santamaria, “Tracking the Recruitment of Diabetogenic CD8+ T-cells to the Pancreas in Real Time,” Diabetes, Vol. 53, No. 6, 2004, pp. 1459-1466. doi:10.2337/diabetes.53.6.1459

[13]   M. Srinivas, P. A. Morel, L. A. Ernst, D. H. Laidlaw and E. T. Ahrens, “Fluorine-19 MRI for Visualization and Quantification of Cell Migration in a Diabetes Model,” Magnetic Resonance Medicine, Vol. 58, No. 4, 2007, pp. 725-734. doi:10.1002/mrm.21352

[14]   M. C. Denis, U. Mahmood, C. Benoist, D. Mathis and R. Weissleder, “Imaging Inflammation of the Pancreatic Islets in Type 1 Diabetes,” Proceeding of the National Academy Sciences of the United States of American, Vol. 101, No. 34, 2004, pp. 12634-12639.

[15]   A. Khurana, J. F. Greene, Jr. and W. A. High, “Quantifi-cation of Gadolinium in Nephrogenic Systemic Fibrosis: Re-examination of a Reported Cohort with Analysis of Clinical Factors,” Journal of the American Academy of Dermatology, Vol. 59, No. 2, 2008, pp. 218-224. doi:10.1016/j.jaad.2008.04.010

[16]   H. J. Weinmann, R. C. Brasch, W. R. Press and G. E. Wesbey, “Characteristics of Gadolinium-DTPA Complex: A Potential NMR Contrast Agent,” American Journal of Roentgenology, Vol. 142, No. 3, 1984, pp. 619-624.

[17]   J. Brailsford, J. Ward, A. G. Chalmers, J. Ridgway and P. J. Robinson, “Dynamic MRI of the Pancreas—Ga- doli-nium Enhancement in Normal Tissue,” Clinical radiology, Vol. 49, No. 2, 1994, pp. 104-108. doi:10.1016/S0009-9260(05)83450-6

[18]   R. Weissleder, A. Moore, U. Mahmood, R. Bhorade, H. Benveniste, E. A. Chiocca and J. P. Basilion, “In Vivo Magnetic Resonance Imaging of Transgene Expression,” Nature Medicine, Vol. 6, No. 3, 2000, pp. 351-355. doi:10.1038/73219

[19]   J. L. Gaglia, A. R. Guimaraes, M. Harisinghani, S. E. Turvey, R. Jackson, C. Benoist, D. Mathis and R. Weis-sleder, “Noninvasive Imaging of Pancreatic Islet Inflam-mation in Type 1A Diabetes Patients,” The Journal of Clinical Investigation, Vol. 121, No. 1, 2011, pp. 442- 445. doi:10.1172/JCI44339

[20]   T. Vial and J. Descotes, “Clinical Toxicity of Interleu-kin-2,” Drug Safety, Vol. 7, No. 6, 1992, pp. 417-433. doi:10.2165/00002018-199207060-00004

[21]   P. Marckmann, L. Skov, K. Rossen, J. G. Heaf and H. S. Thomsen, “Case-Control Study of Gadodiamide-Related Nephrogenic Systemic Fibrosis,” Nephrology Dialysis Transplantation, Vol. 22, No. 11, 2007, pp. 3174-3178. doi:10.1093/ndt/gfm261

[22]   H. S. Thomsen and P. Marckmann, “Extracellular Gd-CA: Differences in Prevalence of NSF,” European Journal of Radiology, Vol. 66, No. 2, 2008, pp. 180-183. doi:10.1016/j.ejrad.2008.01.024

[23]   M. W. Konrad, G. Hemstreet, E. M. Hersh, P. W. Mansell, R. Mertelsmann, J. E. Kolitz and E. C. Bradley, “Pharmacokinetics of Recombinant Interleukin 2 in Hu-mans,” Cancer Research, Vol. 50, No. 7, 1990, pp. 2009- 2017.

[24]   J. H. Donohue and S. A. Rosenberg, “The Fate of Inter-Leukin-2 after in Vivo Administration,” The Journal of Immunology, Vol. 130, No. 5, 1983, pp. 2203-2208.

[25]   A. Signore, A. Picarelli, A. Annovazzi, K. E. Britton, A. B. Grossman, E. Bonanno, B. Maras, D. Barra and P. Pozzilli, “123I-Interleukin-2: Biochemical Characterization and in Vivo Use for Imaging Autoimmune Diseases,” Nuclear Medicine Communications, Vol. 24, No. 3, 2003, pp. 305-316. doi:10.1097/00006231-200303000-00011

[26]   A. Signore, A. Cooke, P. Pozilli, G. Butcher, E. Simpson and P. C. L. Beverley, “Class-II and IL-2 Receptor Posi-tive Cells in the Pancreas of NOD Mice,” Diabetologia, Vol. 30, No. 11, 1987, pp. 902-905.

[27]   T. Kalliokoski, O. Simell, M. Haaparanta, T. Viljanen, O. Solin, J. Knuuti and P. Nuutila, “An Autoradiographic Study of [(18)F]FDG Uptake to Islets of Langerhans in NOD Mouse,” Diabetes Research and Clinical Practice, Vol. 70, No. 3, 2005, pp. 217-24. doi:10.1016/j.diabres.2005.04.008