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Noninvasive Detection of Complement Activation Through Radiologic Imaging

  • Joshua M. ThurmanEmail author
  • Bärbel Rohrer
Chapter
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 735)

Abstract

A wealth of experimental and clinical data demonstrates that the complement system is involved in the pathogenesis of numerous inflammatory diseases. Complement activation contributes to injury in disorders that involve nearly every tissue in the body. Concerted effort has been expended in recent years to develop therapeutic complement inhibitors. Eculizumab, an inhibitory antibody to C5, was recently approved for the treatment of several diseases, and many other complement inhibitors are in clinical development. As these drugs are developed, the need for improved methods of detecting and monitoring complement activation within particular tissues will be increasingly important. We have developed a magnetic resonance imaging (MRI)-based method for noninvasive detection of complement activation. This method utilizes iron-oxide nanoparticles that are targeted to sites of complement activation with a recombinant protein that contains the C3d-binding region of complement receptor (CR) 2. Iron-oxide nanoparticles darken (negatively enhance) images obtained by T2-weighted MRI. We have demonstrated that the CR2-targeted nanoparticles bind within the kidneys of mice with lupus-like kidney disease (MRL/lpr mice), causing a decrease in the T2 signal within the kidneys. This method discriminates diseased kidneys from healthy controls, and the magnitude of the negative enhancement in the cortex of MRL/lpr mice correlates with their disease severity. This method may be useful for idenepsying those patients most likely to benefit from complement inhibitors and for monitoring the response of these patients to treatment. These results may open up new avenues to develop tools for the monitoring of disease progression in complement-dependent diseases.

Keywords

Single Photon Emission Compute Tomography Lupus Nephritis Complement Activation Complement System Hemolytic Uremic Syndrome 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References

  1. Anderson DH, Radeke MJ, Gallo NB, Chapin EA, Johnson PT, Curletti CR, Hancox LS, Hu J, Ebright JN, Malek G et al (2010) The pivotal role of the complement system in aging and age-related macular degeneration: hypothesis re-visited. Prog Retin Eye Res 29:95–112CrossRefGoogle Scholar
  2. Atkinson C, Song H, Lu B, Qiao F, Burns TA, Holers VM, Tsokos GC, Tomlinson S (2005) Targeted complement inhibition by C3d recognition ameliorates tissue injury without apparent increase in susceptibility to infection. J Clin Invest 115:2444–2453CrossRefGoogle Scholar
  3. Atkinson C, Qiao F, Song H, Gilkeson GS, Tomlinson S (2008) Low-dose targeted complement inhibition protects against renal disease and other manifestations of autoimmune disease in MRL/lpr mice. J Immunol 180: 1231–1238CrossRefGoogle Scholar
  4. Badar A, DeFreitas S, McDonnell JM, Yahya N, Thakor D, Razavi R, Smith R, Sacks S, Mullen GE (2011) Recombinant complement receptor 2 radiolabeled with [99mTc(CO)3]+: a potential new radiopharmaceutical for imaging activated complement. PLoS One 6:e18275CrossRefGoogle Scholar
  5. Banati RB, Newcombe J, Gunn RN, Cagnin A, Turkheimer F, Heppner F, Price G, Wegner F, Giovannoni G, Miller DH et al (2000) The peripheral benzodiazepine binding site in the brain in multiple sclerosis: quantitative in vivo imaging of microglia as a measure of disease activity. Brain 123(Pt 11):2321–2337CrossRefGoogle Scholar
  6. Barrera P, Oyen WJ, Boerman OC, van Riel PL (2003) Scintigraphic detection of tumour necrosis factor in patients with rheumatoid arthritis. Ann Rheum Dis 62:825–828CrossRefGoogle Scholar
  7. Cameron JS, Turner DR, Heaton J, Williams DG, Ogg CS, Chantler C, Haycock GB, Hicks J (1983) Idiopathic mesangiocapillary glomerulonephritis. Comparison of types I and II in children and adults and long-term prognosis. Am J Med 74:175–192CrossRefGoogle Scholar
  8. de Cordoba SR, de Jorge EG (2008) Translational mini-review series on complement factor H: genetics and disease associations of human complement factor H. Clin Exp Immunol 151:1–13CrossRefGoogle Scholar
  9. di Belgiojoso GB, Tarantino A, Durante A, Guerra L (1975) Complement deposition in glomerular diseases. Proc Eur Dial Transplant Assoc 11:515–521PubMedGoogle Scholar
  10. Dodds AW, Ren XD, Willis AC, Law SK (1996) The reaction mechanism of the internal thioester in the human complement component C4. Nature 379:177–179CrossRefGoogle Scholar
  11. Elward K, Griffiths M, Mizuno M, Harris CL, Neal JW, Morgan BP, Gasque P (2005) CD46 plays a key role in tailoring innate immune recognition of apoptotic and necrotic cells. J Biol Chem 280:36342–36354CrossRefGoogle Scholar
  12. Fishelson Z, Horstmann RD, Muller-Eberhard HJ (1987) Regulation of the alternative pathway of complement by pH. J Immunol 138:3392–3395PubMedGoogle Scholar
  13. Gilbert HE, Aslam M, Guthridge JM, Holers VM, Perkins SJ (2006) Extended flexible linker structures in the complement chimaeric conjugate CR2-Ig by scattering, analytical ultracentrifugation and constrained modelling: implications for function and therapy. J Mol Biol 356:397–412CrossRefGoogle Scholar
  14. Gratz S, Rennen HJ, Boerman OC, Oyen WJ, Corstens FH (2001) Rapid imaging of experimental colitis with (99m)Tc-interleukin-8 in rabbits. J Nucl Med 42:917–923PubMedGoogle Scholar
  15. Griselli M, Herbert J, Hutchinson WL, Taylor KM, Sohail M, Krausz T, Pepys MB (1999) C-reactive protein and complement are important mediators of tissue damage in acute myocardial infarction. J Exp Med 190:1733–1740CrossRefGoogle Scholar
  16. He C, Imai M, Song H, Quigg RJ, Tomlinson S (2005) Complement inhibitors targeted to the proximal tubule prevent injury in experimental nephrotic syndrome and demonstrate a key role for c5b-9. J Immunol 174:5750–5757CrossRefGoogle Scholar
  17. Hebert LA, Cosio FG, Neff JC (1991) Diagnostic significance of hypocomplementemia. Kidney Int 39:811–821CrossRefGoogle Scholar
  18. Hebert LA, Cosio FG, Birmingham DJ (2001) Complement and complement regulatory proteins in renal disease. In: Neilson EG, Couser WG (eds) Immunologic renal diseases. Lippincott Williams & Wilkins, Philadelphia, pp 367–393Google Scholar
  19. Huang Y, Qiao F, Atkinson C, Holers VM, Tomlinson S (2008) A novel targeted inhibitor of the alternative pathway of complement and its therapeutic application in ischemia/reperfusion injury. J Immunol 181:8068–8076CrossRefGoogle Scholar
  20. Jaffer FA, Weissleder R (2005) Molecular imaging in the clinical arena. JAMA 293:855–862CrossRefGoogle Scholar
  21. Janssen BJ, Christodoulidou A, McCarthy A, Lambris JD, Gros P (2006) Structure of C3b reveals conformational changes that underlie complement activity. Nature 444:213–216CrossRefGoogle Scholar
  22. Josephson L, Lewis J, Jacobs P, Hahn PF, Stark DD (1988) The effects of iron oxides on proton relaxivity. Magn Reson Imaging 6:647–653CrossRefGoogle Scholar
  23. Lucignani G (2009) Nanoparticles for concurrent multimodality imaging and therapy: the dawn of new theragnostic synergies. Eur J Nucl Med Mol Imaging 36:869–874CrossRefGoogle Scholar
  24. Manzi S, Rairie JE, Carpenter AB, Kelly RH, Jagarlapudi SP, Sereika SM, Medsger TA Jr, Ramsey-Goldman R (1996) Sensitivity and specificity of plasma and urine complement split products as indicators of lupus disease activity. Arthritis Rheum 39:1178–1188CrossRefGoogle Scholar
  25. McAteer MA, Sibson NR, von Zur Muhlen C, Schneider JE, Lowe AS, Warrick N, Channon KM, Anthony DC, Choudhury RP (2007) In vivo magnetic resonance imaging of acute brain inflammation using microparticles of iron oxide. Nat Med 13:1253–1258CrossRefGoogle Scholar
  26. Moll S, Miot S, Sadallah S, Gudat F, Mihatsch MJ, Schifferli JA (2001) No complement receptor 1 stumps on podocytes in human glomerulopathies. Kidney Int 59:160–168CrossRefGoogle Scholar
  27. Morita Y, Ikeguchi H, Nakamura J, Hotta N, Yuzawa Y, Matsuo S (2000) Complement activation products in the urine from proteinuric patients. J Am Soc Nephrol 11:700–707PubMedGoogle Scholar
  28. Pickering MC, Cook HT, Warren J, Bygrave AE, Moss J, Walport MJ, Botto M (2002) Uncontrolled C3 activation causes membranoproliferative glomerulonephritis in mice deficient in complement factor H. Nat Genet 31:424–428CrossRefGoogle Scholar
  29. Pons F, Sanmarti R, Herranz R, Collado A, Piera C, Vidal-Sicart S, Munoz-Gomez J, Setoain J (1996) Scintigraphic evaluation of the severity of inflammation of the joints with 99TCm-HIG in rheumatoid arthritis. Nucl Med Commun 17:523–528CrossRefGoogle Scholar
  30. Porcel JM, Ordi J, Castro-Salomo A, Vilardell M, Rodrigo MJ, Gene T, Warburton F, Kraus M, Vergani D (1995) The value of complement activation products in the assessment of systemic lupus erythematosus flares. Clin Immunol Immunopathol 74:283–288CrossRefGoogle Scholar
  31. Ramos-Casals M, Campoamor MT, Chamorro A, Salvador G, Segura S, Botero JC, Yague J, Cervera R, Ingelmo M, Font J (2004) Hypocomplementemia in systemic lupus erythematosus and primary antiphospholipid syndrome: prevalence and clinical significance in 667 patients. Lupus 13:777–783CrossRefGoogle Scholar
  32. Ricker DM, Hebert LA, Rohde R, Sedmak DD, Lewis EJ, Clough JD (1991) Serum C3 levels are diagnostically more sensitive and specific for systemic lupus erythematosus activity than are serum C4 levels. The Lupus Nephritis Collaborative Study Group. Am J Kidney Dis 18:678–685CrossRefGoogle Scholar
  33. Ricklin D, Lambris JD (2007) Complement-targeted therapeutics. Nat Biotechnol 25:1265–1275CrossRefGoogle Scholar
  34. Ricklin D, Hajishengallis G, Yang K, Lambris JD (2010) Complement: a key system for immune surveillance and homeostasis. Nature Immunol 11:785–797CrossRefGoogle Scholar
  35. Rohrer B, Long Q, Coughlin B, Wilson RB, Huang Y, Qiao F, Tang PH, Kunchithapautham K, Gilkeson GS, Tomlinson S (2009) A targeted inhibitor of the alternative complement pathway reduces angiogenesis in a mouse model of age-related macular degeneration. Invest Ophthalmol Vis Sci 50:3056–3064CrossRefGoogle Scholar
  36. Rohrer B, Long Q, Coughlin B, Renner B, Huang Y, Kunchithapautham K, Ferreira VP, Pangburn MK, Gilkeson GS, Thurman JM et al (2010) A targeted inhibitor of the complement alternative pathway reduces RPE injury and angiogenesis in models of age-related macular degeneration. Adv Exp Med Biol 703:137–149CrossRefGoogle Scholar
  37. Roivainen A, Parkkola R, Yli-Kerttula T, Lehikoinen P, Viljanen T, Mottonen T, Nuutila P, Minn H (2003) Use of positron emission tomography with methyl-11C-choline and 2-18F-fluoro-2-deoxy-D-glucose in comparison with magnetic resonance imaging for the assessment of inflammatory proliferation of synovium. Arthritis Rheum 48:3077–3084CrossRefGoogle Scholar
  38. Rother RP, Rollins SA, Mojcik CF, Brodsky RA, Bell L (2007) Discovery and development of the complement inhibitor eculizumab for the treatment of paroxysmal nocturnal hemoglobinuria. Nat Biotechnol 25:1256–1264CrossRefGoogle Scholar
  39. Sargsyan SA, Serkova NJ, Renner B, Hasebroock KM, Larsen B, Stoldt C, McFann K, Pickering MC, Thurman JM (2011) Detection of glomerular complement C3 fragments by magnetic resonance imaging in murine lupus nephritis. Kidney Int, 81:152–159CrossRefGoogle Scholar
  40. Sargsyan SA, Serkova NJ, Renner B, Hasebroock KM, Larsen B, Stoldt C, McFann K, Pickering MC, Thurman JM (2012) Detection of glomerular complement C3 fragments by magnetic resonance imaging in murine lupus nephritis. Kidney Int, 81:152–159PubMedPubMedCentralGoogle Scholar
  41. Schulze M, Pruchno CJ, Burns M, Baker PJ, Johnson RJ, Couser WG (1993) Glomerular C3c localization indicates ongoing immune deposit formation and complement activation in experimental glomerulonephritis. Am J Pathol 142:179–187PubMedPubMedCentralGoogle Scholar
  42. Serkova NJ, Renner B, Larsen BA, Stoldt CR, Hasebroock KM, Bradshaw-Pierce EL, Holers VM, Thurman JM (2010) Renal inflammation: targeted iron oxide nanoparticles for molecular MR imaging in mice. Radiology 255:517–526CrossRefGoogle Scholar
  43. Shubayev VI, Pisanic TR II, Jin S (2009) Magnetic nanoparticles for theragnostics. Adv Drug Deliv Rev 61:467–477CrossRefGoogle Scholar
  44. Signore A, Picarelli A, Annovazzi A, Britton KE, Grossman AB, Bonanno E, Maras B, Barra D, Pozzilli P (2003) 123I-Interleukin-2: biochemical characterization and in vivo use for imaging autoimmune diseases. Nucl Med Commun 24:305–316CrossRefGoogle Scholar
  45. Song H, He C, Knaak C, Guthridge JM, Holers VM, Tomlinson S (2003) Complement receptor 2-mediated targeting of complement inhibitors to sites of complement activation. J Clin Invest 111:1875–1885CrossRefGoogle Scholar
  46. Swaak AJ, Groenwold J, Bronsveld W (1986) Predictive value of complement profiles and anti-dsDNA in systemic lupus erythematosus. Ann Rheum Dis 45:359–366CrossRefGoogle Scholar
  47. Thurman JM, Renner B, Kunchithapautham K, Ferreira VP, Pangburn MK, Ablonczy Z, Tomlinson S, Holers VM, Rohrer B (2009) Oxidative stress renders retinal pigment epithelial cells susceptible to complement-mediated injury. J Biol Chem 284:16939–16947CrossRefGoogle Scholar
  48. Vlaicu R, Rus HG, Niculescu F, Cristea A (1985) Immunoglobulins and complement components in human aortic atherosclerotic intima. Atherosclerosis 55:35–50CrossRefGoogle Scholar
  49. Walport MJ (2001) Complement. Second of two parts. N Engl J Med 344:1140–1144CrossRefGoogle Scholar
  50. Weis JJ, Tedder TF, Fearon DT (1984) Idenepsication of a 145,000 Mr membrane protein as the C3d receptor (CR2) of human B lymphocytes. Proc Natl Acad Sci USA 81:881–885CrossRefGoogle Scholar
  51. Weller GE, Lu E, Csikari MM, Klibanov AL, Fischer D, Wagner WR, Villanueva FS (2003) Ultrasound imaging of acute cardiac transplant rejection with microbubbles targeted to intercellular adhesion molecule-1. Circulation 108:218–224CrossRefGoogle Scholar
  52. West C (1998) Complement and glomerular diseases. In: Volanakis JE, Frank MM (eds) The human complement system in health and disease. Marcel Dekker, Inc., New York, pp 571–596CrossRefGoogle Scholar
  53. Zhou J, Fonseca MI, Pisalyaput K, Tenner AJ (2008) Complement C3 and C4 expression in C1q sufficient and deficient mouse models of Alzheimer’s disease. J Neurochem 106:2080–2092CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.Department of MedicineUniversity of Colorado Denver School of MedicineDenverUSA
  2. 2.Departments of Ophthalmology and Neurosciences, Division of ResearchMedical University of South CarolinaCharlestonUSA

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