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Selective Dependence of Kidney Dendritic Cells on CX3CR1—Implications for Glomerulonephritis Therapy

  • Katharina Hochheiser
  • Christian Kurts
Conference paper
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 850)

Abstract

As central regulators of the adaptive immune response, dendritic cells (DCs) are found in virtually all lymphatic and non-lymphatic organs. A compact network of DCs also spans the kidneys. DCs play a central role in maintenance of organ homeostasis as well as in induction of immune responses against invading pathogens. They can mediate protective or destructive functions in a context-dependent manner.

We recently identified CX3CR1 as a kidney-specific “homing receptor” for DCs. There was a strong reduction of DCs in the kidneys of CX3CR1-deficient mice compared to controls. This reduction was not observed in other organs except the small intestine. As a possible underlying reason we found a strong expression of the CX3CR1 ligand fractalkine in the kidneys. Due to this CX3CR1-dependent reduction of DCs, especially in the renal cortex, a glomerulonephritis (GN) model was ameliorated in CX3CR1-deficient mice. In contrast, the immune defense against the most common renal infection, bacterial pyelonephritis (PN), was not significantly influenced by CX3CR1-deficiency. This was explained by the much smaller CX3CR1-dependency of medullary DCs, which recruit effector cells into the kidney during PN. Additionally, once neutrophils had been recruited by mechanisms distinct from CX3CR1, they carried out some of the functions of DCs.

Taken together, we suggest CX3CR1 as a therapeutic target for GN treatment, as the absence of CX3CR1 selectively influences DCs in the kidney without rendering mice more susceptible towards bacterial kidney infections.

Keywords

Kidney DCs Kidney physiology Glumeronephritis (GN) Interstitial nephritis (tubulointerstitium) CX3CR1 

References

  1. Abbate, M., Zoja, C., & Remuzzi, G. (2006). How does proteinuria cause progressive renal damage? Journal of the American Society of Nephrology, 17, 2974–2984.CrossRefPubMedGoogle Scholar
  2. Adams, D. O., & Hamilton, T. A. (1984). The cell biology of macrophage activation. Annual Review of Immunology, 2, 283–318.CrossRefPubMedGoogle Scholar
  3. Andrews, P. M. (1977). A scanning and transmission electron microscopic comparison of puromycin aminonucleoside-induced nephrosis to hyperalbuminemia-induced proteinuria with emphasis on kidney podocyte pedicel loss. Laboratory Investigation: A Journal of Technical Methods and Pathology, 36, 183–197.Google Scholar
  4. Assmann, K. J., Tangelder, M. M., Lange, W. P., Schrijver, G., & Koene, R. A. (1985). Anti-GBM nephritis in the mouse: Severe proteinuria in the heterologous phase. Virchows Arch A Pathological Anatomy and Histopathology, 406, 285–299.CrossRefPubMedGoogle Scholar
  5. Banchereau, J., Briere, F., Caux, C., Davoust, J., Lebecque, S., Liu, Y. J., Pulendran, B., & Palucka, K. (2000). Immunobiology of dendritic cells. Annual Review of Immunology, 18, 767–811.CrossRefPubMedGoogle Scholar
  6. Beauchamp, D., & Bergeron, M. G. (1999). Pharmacologic basis for the treatment of pyelonephritis. Current Infectious Disease Reports, 1, 371–378.CrossRefPubMedGoogle Scholar
  7. Bohle, A. (1982). Importance of the renal interstitium for kidney function. Klinische Wochenschrift, 60, 1186–1190.CrossRefPubMedGoogle Scholar
  8. Bryant, P., & Ploegh, H. (2004). Class II MHC peptide loading by the professionals. Current Opinion in Immunology, 16, 96–102.CrossRefPubMedGoogle Scholar
  9. Chassin, C., Goujon, J. M., Darche, S., du Merle, L., Bens, M., Cluzeaud, F., Werts, C., Ogier-Denis, E., Le Bouguenec, C., Buzoni-Gatel, D., et al. (2006). Renal collecting duct epithelial cells react to pyelonephritis-associated Escherichia coli by activating distinct TLR4-dependent and -independent inflammatory pathways. Journal of Immunology, 177, 4773–4784.CrossRefGoogle Scholar
  10. Delamarre, L., Pack, M., Chang, H., Mellman, I., & Trombetta, E. S. (2005). Differential lysosomal proteolysis in antigen-presenting cells determines antigen fate. Science, 307, 1630–1634.CrossRefPubMedGoogle Scholar
  11. Dong, X., Swaminathan, S., Bachman, L. A., Croatt, A. J., Nath, K. A., & Griffin, M. D. (2005). Antigen presentation by dendritic cells in renal lymph nodes is linked to systemic and local injury to the kidney. Kidney International, 68, 1096–1108.CrossRefPubMedGoogle Scholar
  12. Duffield, J. S., Tipping, P. G., Kipari, T., Cailhier, J. F., Clay, S., Lang, R., Bonventre, J. V., & Hughes, J. (2005). Conditional ablation of macrophages halts progression of crescentic glomerulonephritis. The American Journal of Pathology, 167, 1207–1219.PubMedCentralCrossRefPubMedGoogle Scholar
  13. Edgtton, K. L., Kausman, J. Y., Li, M., O’Sullivan, K., Lo, C., Hutchinson, P., Yagita, H., Holdsworth, S. R., & Kitching, A. R. (2008). Intrarenal antigens activate CD4+ cells via co-stimulatory signals from dendritic cells. Journal of the American Society of Nephrology, 19, 515–526.PubMedCentralCrossRefPubMedGoogle Scholar
  14. Geissmann, F., Manz, M. G., Jung, S., Sieweke, M. H., Merad, M., & Ley, K. (2010a). Development of monocytes, macrophages, and dendritic cells. Science, 327, 656–661.PubMedCentralCrossRefPubMedGoogle Scholar
  15. Geissmann, F., Gordon, S., Hume, D. A., Mowat, A. M., & Randolph, G. J. (2010b). Unravelling mononuclear phagocyte heterogeneity. Nature Reviews Immunology, 10, 453–460.PubMedCentralCrossRefPubMedGoogle Scholar
  16. Georgas, K., Rumballe, B., Wilkinson, L., Chiu, H. S., Lesieur, E., Gilbert, T., & Little, M. H. (2008). Use of dual section mRNA in situ hybridisation/immunohistochemistry to clarify gene expression patterns during the early stages of nephron development in the embryo and in the mature nephron of the adult mouse kidney. HistoChemistry and Cell Biology, 130, 927–942.CrossRefPubMedGoogle Scholar
  17. Ginhoux, F., Liu, K., Helft, J., Bogunovic, M., Greter, M., Hashimoto, D., Price, J., Yin, N., Bromberg, J., Lira, S. A., et al. (2009). The origin and development of nonlymphoid tissue CD103+ DCs. The Journal of Experimental Medicine, 206, 3115–3130.PubMedCentralCrossRefPubMedGoogle Scholar
  18. Hang, L., Haraoka, M., Agace, W. W., Leffler, H., Burdick, M., Strieter, R., & Svanborg, C. (1999). Macrophage inflammatory protein-2 is required for neutrophil passage across the epithelial barrier of the infected urinary tract. Journal of Immunology, 162, 3037–3044.Google Scholar
  19. Haraldsson, B., & Sorensson, J. (2004). Why do we not all have proteinuria? An update of our current understanding of the glomerular barrier. News in Physiological Sciences, 19, 7–10.PubMedGoogle Scholar
  20. Haskell, C. A., Hancock, W. W., Salant, D. J., Gao, W., Csizmadia, V., Peters, W., Faia, K., Fituri, O., Rottman, J. B., & Charo, I. F. (2001). Targeted deletion of CX(3)CR1 reveals a role for fractalkine in cardiac allograft rejection. The Journal of clinical investigation, 108, 679–688.PubMedCentralCrossRefPubMedGoogle Scholar
  21. Hewitt, I. K., Zucchetta, P., Rigon, L., Maschio, F., Molinari, P. P., Tomasi, L., Toffolo, A., Pavanello, L., Crivellaro, C., Bellato, S., et al. (2008). Early treatment of acute pyelonephritis in children fails to reduce renal scarring: Data from the Italian renal infection study trials. Pediatrics, 122, 486–490.CrossRefPubMedGoogle Scholar
  22. Heymann, F., Meyer-Schwesinger, C., Hamilton-Williams, E. E., Hammerich, L., Panzer, U., Kaden, S., Quaggin, S. E., Floege, J., Grone, H. J., & Kurts, C. (2009). Kidney dendritic cell activation is required for progression of renal disease in a mouse model of glomerular injury. The Journal of Clinical Investigation, 119, 1286–1297.PubMedCentralCrossRefPubMedGoogle Scholar
  23. Hochheiser, K., Engel, D. R., Hammerich, L., Heymann, F., Knolle, P. A., Panzer, U., & Kurts, C. (2011). Kidney dendritic cells become pathogenic during crescentic glomerulonephritis with proteinuria. Journal of the American Society of Nephrology, 22, 306–316.PubMedCentralCrossRefPubMedGoogle Scholar
  24. Hochheiser, K., Heuser, C., Krause, T. A., Teteris, S., Ilias, A., Weisheit, C., Hoss, F., Tittel, A. P., Knolle, P. A., Panzer, U., et al. (2013). Exclusive CX3CR1 dependence of kidney DCs impacts glomerulonephritis progression. The Journal of clinical investigation, 123, 4242–4254.PubMedCentralCrossRefPubMedGoogle Scholar
  25. Hume, D. A., & Gordon, S. (1983). Mononuclear phagocyte system of the mouse defined by immunohistochemical localization of antigen F4/80. Identification of resident macrophages in renal medullary and cortical interstitium and the juxtaglomerular complex. The Journal of Experimental Medicine, 157, 1704–1709.PubMedCentralCrossRefPubMedGoogle Scholar
  26. Karlmark, K. R., Zimmermann, H. W., Roderburg, C., Gassler, N., Wasmuth, H. E., Luedde, T., Trautwein, C., & Tacke, F. (2010). The fractalkine receptor CX(3)CR1 protects against liver fibrosis by controlling differentiation and survival of infiltrating hepatic monocytes. Hepatology, 52, 1769–1782.CrossRefPubMedGoogle Scholar
  27. Kitching, A. R., Turner, A. L., Wilson, G. R., Semple, T., Odobasic, D., Timoshanko, J. R., O’Sullivan, K. M., Tipping, P. G., Takeda, K., Akira, S., et al. (2005). IL-12p40 and IL-18 in crescentic glomerulonephritis: IL-12p40 is the key Th1-defining cytokine chain, whereas IL-18 promotes local inflammation and leukocyte recruitment. Journal of the American Society of Nephrology, 16, 2023–2033.CrossRefPubMedGoogle Scholar
  28. Kleinewietfeld, M., Manzel, A., Titze, J., Kvakan, H., Yosef, N., Linker, R. A., Muller, D. N., & Hafler, D. A. (2013). Sodium chloride drives autoimmune disease by the induction of pathogenic TH17 cells. Nature, 496, 518–522.PubMedCentralCrossRefPubMedGoogle Scholar
  29. Kruger, T., Benke, D., Eitner, F., Lang, A., Wirtz, M., Hamilton-Williams, E. E., Engel, D., Giese, B., Muller-Newen, G., Floege, J., et al. (2004). Identification and functional characterization of dendritic cells in the healthy murine kidney and in experimental glomerulonephritis. Journal of the American Society of Nephrology, 15, 613–621.CrossRefPubMedGoogle Scholar
  30. Kurts, C., Kosaka, H., Carbone, F. R., Miller, J. F., & Heath, W. R. (1997). Class I-restricted cross-presentation of exogenous self-antigens leads to deletion of autoreactive CD8(+) T cells. The Journal of Experimental Medicine, 186, 239–245.PubMedCentralCrossRefPubMedGoogle Scholar
  31. Kurts, C., Heymann, F., Lukacs-Kornek, V., Boor, P., & Floege, J. (2007). Role of T cells and dendritic cells in glomerular immunopathology. Seminars in Immunopathology, 29, 317–335.CrossRefPubMedGoogle Scholar
  32. Landsman, L., Bar-On, L., Zernecke, A., Kim, K. W., Krauthgamer, R., Shagdarsuren, E., Lira, S. A., Weissman, I. L., Weber, C., & Jung, S. (2009). CX3CR1 is required for monocyte homeostasis and atherogenesis by promoting cell survival. Blood, 113, 963–972.CrossRefPubMedGoogle Scholar
  33. Li, L., Huang, L., Sung, S. S., Vergis, A. L., Rosin, D. L., Rose, C. E. Jr., Lobo, P. I., & Okusa, M. D. (2008). The chemokine receptors CCR2 and CX3CR1 mediate monocyte/macrophage trafficking in kidney ischemia-reperfusion injury. Kidney International, 74, 1526–1537.PubMedCentralCrossRefPubMedGoogle Scholar
  34. Lukacs-Kornek, V., Burgdorf, S., Diehl, L., Specht, S., Kornek, M., & Kurts, C. (2008). The kidney-renal lymph node-system contributes to cross-tolerance against innocuous circulating antigen. Journal of Immunology, 180, 706–715.CrossRefGoogle Scholar
  35. Machnik, A., Neuhofer, W., Jantsch, J., Dahlmann, A., Tammela, T., Machura, K., Park, J. K., Beck, F. X., Muller, D. N., Derer, W., et al. (2009). Macrophages regulate salt-dependent volume and blood pressure by a vascular endothelial growth factor-C-dependent buffering mechanism. Natural Medicines, 15, 545–552.CrossRefGoogle Scholar
  36. Merad, M., Sathe, P., Helft, J., Miller, J., & Mortha, A. (2013). The dendritic cell lineage: Ontogeny and function of dendritic cells and their subsets in the steady state and the inflamed setting. Annual Review of Immunology, 31, 563–604.CrossRefPubMedGoogle Scholar
  37. Miller, J. C., Brown, B. D., Shay, T., Gautier, E. L., Jojic, V., Cohain, A., Pandey, G., Leboeuf, M., Elpek, K. G., Helft, J., et al. (2012). Deciphering the transcriptional network of the dendritic cell lineage. Nature Immunology, 13, 888–899.PubMedCentralCrossRefPubMedGoogle Scholar
  38. Mulvey, M. A., Lopez-Boado, Y. S., Wilson, C. L., Roth, R., Parks, W. C., Heuser, J., & Hultgren, S. J. (1998). Induction and evasion of host defenses by type 1-piliated uropathogenic Escherichia coli. Science, 282, 1494–1497.CrossRefPubMedGoogle Scholar
  39. Murphy, P. M., Baggiolini, M., Charo, I. F., Hebert, C. A., Horuk, R., Matsushima, K., Miller, L. H., Oppenheim, J. J., & Power, C. A. (2000). International union of pharmacology. XXII. Nomenclature for chemokine receptors. Pharmacological Reviews, 52, 145–176.PubMedGoogle Scholar
  40. Naik, S. H. (2008). Demystifying the development of dendritic cell subtypes, a little. Immunology and Cell Biology, 86, 439–452.CrossRefPubMedGoogle Scholar
  41. Nelson, P. J., Rees, A. J., Griffin, M. D., Hughes, J., Kurts, C., & Duffield, J. (2012). The renal mononuclear phagocytic system. Journal of the American Society of Nephrology, 23, 194–203.PubMedCentralCrossRefPubMedGoogle Scholar
  42. Panzer, U., Steinmetz, O. M., Stahl, R. A., & Wolf, G. (2006). Kidney diseases and chemokines. Current Drug Targets, 7, 65–80.CrossRefPubMedGoogle Scholar
  43. Patole, P. S., Schubert, S., Hildinger, K., Khandoga, S., Khandoga, A., Segerer, S., Henger, A., Kretzler, M., Werner, M., Krombach, F., et al. (2005). Toll-like receptor-4: Renal cells and bone marrow cells signal for neutrophil recruitment during pyelonephritis. Kidney International, 68, 2582–2587.CrossRefPubMedGoogle Scholar
  44. Paust, H. J., Turner, J. E., Steinmetz, O. M., Peters, A., Heymann, F., Holscher, C., Wolf, G., Kurts, C., Mittrucker, H. W., Stahl, R. A., et al. (2009). The IL-23/Th17 axis contributes to renal injury in experimental glomerulonephritis. Journal of the American Society of Nephrology, 20, 969–979.PubMedCentralCrossRefPubMedGoogle Scholar
  45. Randolph, G. J., Angeli, V., & Swartz, M. A. (2005). Dendritic-cell trafficking to lymph nodes through lymphatic vessels. Nature Reviews Immunology, 5, 617–628.CrossRefPubMedGoogle Scholar
  46. Rees, A. (2009). Cross dendritic cells anger T cells after kidney injury. Journal of the American Society of Nephrology, 20, 3–5.CrossRefPubMedGoogle Scholar
  47. Riedel, J. H., Paust, H. J., Turner, J. E., Tittel, A. P., Krebs, C., Disteldorf, E., Wegscheid, C., Tiegs, G., Velden, J., Mittrucker, H. W., et al. (2012). Immature renal dendritic cells recruit regulatory CXCR6(+) invariant natural killer T cells to attenuate crescentic GN. Journal of the American Society of Nephrology, 23, 1987–2000.PubMedCentralCrossRefPubMedGoogle Scholar
  48. Roake, J. A., Rao, A. S., Morris, P. J., Larsen, C. P., Hankins, D. F., & Austyn, J. M. (1995). Dendritic cell loss from nonlymphoid tissues after systemic administration of lipopolysaccharide, tumor necrosis factor, and interleukin 1. The Journal of Experimental Medicine, 181, 2237–2247.CrossRefPubMedGoogle Scholar
  49. Ryan, J., Ma, F. Y., Kanellis, J., Delgado, M., Blease, K., & Nikolic-Paterson, D. J. (2011). Spleen tyrosine kinase promotes acute neutrophil-mediated glomerular injury via activation of JNK and p38 MAPK in rat nephrotoxic serum nephritis. Laboratory Investigation: A Journal of Technical Methods and Pathology, 91, 1727–1738.CrossRefGoogle Scholar
  50. Samuelsson, P., Hang, L., Wullt, B., Irjala, H., & Svanborg, C. (2004). Toll-like receptor 4 expression and cytokine responses in the human urinary tract mucosa. Infection and Immunity, 72, 3179–3186.PubMedCentralCrossRefPubMedGoogle Scholar
  51. Scholz, J., Lukacs-Kornek, V., Engel, D. R., Specht, S., Kiss, E., Eitner, F., Floege, J., Groene, H. J., & Kurts, C. (2008). Renal dendritic cells stimulate IL-10 production and attenuate nephrotoxic nephritis. Journal of the American Society of Nephrology, 19, 527–537.PubMedCentralCrossRefPubMedGoogle Scholar
  52. Serbina, N. V., & Pamer, E. G. (2006). Monocyte emigration from bone marrow during bacterial infection requires signals mediated by chemokine receptor CCR2. Nature Immunology, 7, 311–317.CrossRefPubMedGoogle Scholar
  53. Shaughnessy, L. M., & Swanson, J. A. (2007). The role of the activated macrophage in clearing Listeria monocytogenes infection. Frontiers in Bioscience: A Journal and Virtual Library, 12, 2683–2692.CrossRefGoogle Scholar
  54. Shortman, K., & Liu, Y. J. (2002). Mouse and human dendritic cell subtypes. Nature reviews. Immunology, 2, 151–161.CrossRefPubMedGoogle Scholar
  55. Shortman, K., & Naik, S. H. (2007). Steady-state and inflammatory dendritic-cell development. Nature Reviews Immunology, 7, 19–30.CrossRefPubMedGoogle Scholar
  56. Soos, T. J., Sims, T. N., Barisoni, L., Lin, K., Littman, D. R., Dustin, M. L., & Nelson, P. J. (2006). CX3CR1+ interstitial dendritic cells form a contiguous network throughout the entire kidney. Kidney International, 70, 591–596.PubMedGoogle Scholar
  57. Steinman, R. M., & Cohn, Z. A. (1973). Identification of a novel cell type in peripheral lymphoid organs of mice. I. Morphology, quantitation, tissue distribution. The Journal of Experimental Medicine, 137, 1142–1162.PubMedCentralCrossRefPubMedGoogle Scholar
  58. Steinman, R. M., Hawiger, D., & Nussenzweig, M. C. (2003). Tolerogenic dendritic cells. Annual Review of Immunology, 21, 685–711.CrossRefPubMedGoogle Scholar
  59. Strutz, F. M. (2009). EMT and proteinuria as progression factors. Kidney International, 75, 475–481.CrossRefPubMedGoogle Scholar
  60. Tacke, F., Alvarez, D., Kaplan, T. J., Jakubzick, C., Spanbroek, R., Llodra, J., Garin, A., Liu, J., Mack, M., van Rooijen, N., et al. (2007). Monocyte subsets differentially employ CCR2, CCR5, and CX3CR1 to accumulate within atherosclerotic plaques. The Journal of Clinical Investigation, 117, 185–194.PubMedCentralCrossRefPubMedGoogle Scholar
  61. Timoshanko, J. R., Kitching, A. R., Holdsworth, S. R., & Tipping, P. G. (2001). Interleukin-12 from intrinsic cells is an effector of renal injury in crescentic glomerulonephritis. Journal of the American Society of Nephrology, 12, 464–471.PubMedGoogle Scholar
  62. Timoshanko, J. R., Kitching, A. R., Semple, T. J., Tipping, P. G., & Holdsworth, S. R. (2006). A pathogenetic role for mast cells in experimental crescentic glomerulonephritis. Journal of the American Society of Nephrology, 17, 150–159.CrossRefPubMedGoogle Scholar
  63. Tipping, P. G., & Holdsworth, S. R. (2006). T cells in crescentic glomerulonephritis. Journal of the American Society of Nephrology, 17, 1253–1263.CrossRefPubMedGoogle Scholar
  64. Tipping, P. G., Huang, X. R., Qi, M., Van, G. Y., & Tang, W. W. (1998). Crescentic glomerulonephritis in CD4- and CD8-deficient mice. Requirement for CD4 but not CD8 cells. The American Journal of Pathology, 152, 1541–1548.PubMedCentralPubMedGoogle Scholar
  65. Tittel, A. P., Heuser, C., Ohliger, C., Knolle, P. A., Engel, D. R., & Kurts, C. (2011). Kidney dendritic cells induce innate immunity against bacterial pyelonephritis. Journal of the American Society of Nephrology, 22, 1435–1441.PubMedCentralCrossRefPubMedGoogle Scholar
  66. Tittel, A. P., Heuser, C., Ohliger, C., Llanto, C., Yona, S., Hammerling, G. J., Engel, D. R., Garbi, N., & Kurts, C. (2012). Functionally relevant neutrophilia in CD11c diphtheria toxin receptor transgenic mice. Nature Methods, 9, 385–390.CrossRefPubMedGoogle Scholar
  67. Turner, J. E., Paust, H. J., Steinmetz, O. M., Peters, A., Meyer-Schwesinger, C., Heymann, F., Helmchen, U., Fehr, S., Horuk, R., Wenzel, U., et al. (2008). CCR5 deficiency aggravates crescentic glomerulonephritis in mice. Journal of Immunology, 181, 6546–6556.CrossRefGoogle Scholar
  68. Turner, J. E., Paust, H. J., Bennstein, S. B., Bramke, P., Krebs, C., Steinmetz, O. M., Velden, J., Haag, F., Stahl, R. A., & Panzer, U. (2012). Protective role for CCR5 in murine lupus nephritis. American Journal of Physiology: Renal Physiology, 302, F1503–1515.CrossRefGoogle Scholar
  69. Vremec, D., Zorbas, M., Scollay, R., Saunders, D. J., Ardavin, C. F., Wu, L., & Shortman, K. (1992). The surface phenotype of dendritic cells purified from mouse thymus and spleen: Investigation of the CD8 expression by a subpopulation of dendritic cells. The Journal of Experimental Medicine, 176, 47–58.CrossRefPubMedGoogle Scholar
  70. Wakim, L. M., Waithman, J., van Rooijen, N., Heath, W. R., & Carbone, F. R. (2008). Dendritic cell-induced memory T cell activation in nonlymphoid tissues. Science, 319, 198–202.CrossRefPubMedGoogle Scholar
  71. Wu, C., Yosef, N., Thalhamer, T., Zhu, C., Xiao, S., Kishi, Y., Regev, A., & Kuchroo, V. K. (2013). Induction of pathogenic TH17 cells by inducible salt-sensing kinase SGK1. Nature, 496, 513–517.PubMedCentralCrossRefPubMedGoogle Scholar
  72. Wynn, T. A., Chawla, A., & Pollard, J. W. (2013). Macrophage biology in development, homeostasis and disease. Nature, 496, 445–455.PubMedCentralCrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  1. 1.Institute of Experimental Immunology(IMMEI)Rheinische Friedrich-Wilhelms UniversityBonnGermany

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