Diseases caused by chronic inflammation (e.g., arthritis, multiple sclerosis and diabetic ulcers) are multicausal, thus making treatment difficult and inefficient. Due to the age-associated nature of most of these disorders and the demographic transition towards an overall older population, efficient therapeutic intervention strategies will need to be developed in the near future. Over the past decades, elimination of activated macrophages using CD64-targeting immunotoxins has proven to be a promising way of resolving inflammation in animal models. More recent data have shown that the M1-polarized population of activated macrophages in particular is critically involved in the chronic phase. We recapitulate the latest progress in the development of IT. These have advanced from full-length antibodies, chemically coupled to bacterial toxins, into single chain variants of antibodies, genetically fused with fully human enzymes. These improvements have increased the range of possible target diseases, which now include chronic inflammatory diseases. At present there are no therapeutic strategies focusing on macrophages to treat chronic disorders. In this review, we focus on the role of different polarized macrophages and the potential of CD64-based IT to intervene in the process of chronic inflammation.
References
[1]
Cawley, D.B.; Herschman, H.R.; Gilliland, D.G.; Collier, R.J. Epidermal growth factor-toxin A chain conjugates: EGF-ricin A is a potent toxin while EGF-diphtheria fragment A is nontoxic. Cell 1980, 22, 563–570, doi:10.1016/0092-8674(80)90366-9.
[2]
Murphy, J.R.; Bishai, W.; Borowski, M.; Miyanohara, A.; Boyd, J.; Nagle, S. Genetic construction, expression, and melanoma-selective cytotoxicity of a diphtheria toxin-related alpha-melanocyte-stimulating hormone fusion protein. Proc. Natl. Acad. Sci. USA 1986, 83, 8258–8262, doi:10.1073/pnas.83.21.8258.
[3]
FitzGerald, D.J.; Padmanabhan, R.; Pastan, I.; Willingham, M.C. Adenovirus-induced release of epidermal growth factor and pseudomonas toxin into the cytosol of KB cells during receptor-mediated endocytosis. Cell 1983, 32, 607–617, doi:10.1016/0092-8674(83)90480-4.
[4]
Williams, D.P.; Parker, K.; Bacha, P.; Bishai, W.; Borowski, M.; Genbauffe, F.; Strom, T.B.; Murphy, J.R. Diphtheria toxin receptor binding domain substitution with interleukin-2: Genetic construction and properties of a diphtheria toxin-related interleukin-2 fusion protein. Protein. Eng. 1987, 1, 493–498, doi:10.1093/protein/1.6.493.
[5]
Von Minckwitz, G.; Harder, S.; Hovelmann, S.; Jager, E.; Al-Batran, S.E.; Loibl, S.; Atmaca, A.; Cimpoiasu, C.; Neumann, A.; Abera, A.; et al. Phase I clinical study of the recombinant antibody toxin scFv(FRP5)-ETA specific for the ErbB2/HER2 receptor in patients with advanced solid malignomas. Breast Cancer Res. 2005, 7, R617–R626, doi:10.1186/bcr1264.
[6]
Zhou, X.X.; Ji, F.; Zhao, J.L.; Cheng, L.F.; Xu, C.F. Anti-cancer activity of anti-p185HER-2 ricin A chain immunotoxin on gastric cancer cells. J. Gastroenterol. Hepatol. 2010, 25, 1266–1275.
[7]
Hu, C.C.; Ji, H.M.; Chen, S.L.; Zhang, H.W.; Wang, B.Q.; Zhou, L.Y.; Zhang, Z.P.; Sun, X.L.; Chen, Z.Z.; Cai, Y.Q.; et al. Investigation of a plasmid containing a novel immunotoxin VEGF165-PE38 gene for antiangiogenic therapy in a malignant glioma model. Int. J. Cancer 2010, 12, 2222–2229.
[8]
Wesche, J.; Rapak, A.; Olsnes, S. Dependence of ricin toxicity on translocation of the toxin A-chain from the endoplasmic reticulum to the cytosol. J. Biol. Chem. 1999, 27, 34443–34449.
[9]
Hetzel, C.; Bachran, C.; Fischer, R.; Fuchs, H.; Barth, S.; Stocker, M. Small cleavable adapters enhance the specific cytotoxicity of a humanized immunotoxin directed against CD64-positive cells. J. Immunother. 2008, 31, 370–376, doi:10.1097/CJI.0b013e31816a2d23.
[10]
Tagge, E.; Harris, B.; Burbage, C.; Hall, P.; Vesely, J.; Willingham, M.; Frankel, A. Synthesis of green fluorescent protein-ricin and monitoring of its intracellular trafficking. Bioconjug. Chem. 1997, 8, 743–750, doi:10.1021/bc9700749.
[11]
Mohanraj, D.; Ramakrishnan, S. Cytotoxic effects of ricin without an interchain disulfide bond: Genetic modification and chemical crosslinking studies. Biochim. Biophys. Acta 1995, 1243, 399–406, doi:10.1016/0304-4165(94)00166-U.
[12]
Chiron, M.F.; Fryling, C.M.; FitzGerald, D.J. Cleavage of pseudomonas exotoxin and diphtheria toxin by a furin-like enzyme prepared from beef liver. J. Biol. Chem. 1994, 269, 18167–18176.
[13]
Kaul, P.; Silverman, J.; Shen, W.H.; Blanke, S.R.; Huynh, P.D.; Finkelstein, A.; Collier, R.J. Roles of Glu 349 and Asp 352 in membrane insertion and translocation by diphtheria toxin. Protein Sci. 1996, 5, 687–692.
[14]
Lemichez, E.; Bomsel, M.; Devilliers, G.; vanderSpek, J.; Murphy, J.R.; Lukianov, E.V.; Olsnes, S.; Boquet, P. Membrane translocation of diphtheria toxin fragment A exploits early to late endosome trafficking machinery. Mol. Microbiol. 1997, 23, 445–457, doi:10.1111/j.1365-2958.1997.tb02669.x.
[15]
Kreitman, R.J. Recombinant immunotoxins for the treatment of chemoresistant hematologic malignancies. Curr. Pharm. Des. 2009, 15, 2652–2664, doi:10.2174/138161209788923949.
[16]
Krysko, D.V.; D’Herde, K.; Vandenabeele, P. Clearance of apoptotic and necrotic cells and its immunological consequences. Apoptosis 2006, 11, 1709–1726, doi:10.1007/s10495-006-9527-8.
[17]
Krysko, D.V.; Denecker, G.; Festjens, N.; Gabriels, S.; Parthoens, E.; D’Herde, K.; Vandenabeele, P. Macrophages use different internalization mechanisms to clear apoptotic and necrotic cells. Cell Death Differ. 2006, 13, 2011–2022, doi:10.1038/sj.cdd.4401900.
[18]
Blythman, H.E.; Casellas, P.; Gros, O.; Gros, P.; Jansen, F.K.; Paolucci, F.; Pau, B.; Vidal, H. Immunotoxins: Hybrid molecules of monoclonal antibodies and a toxin subunit specifically kill tumour cells. Nature 1981, 290, 145–146.
[19]
Surendranath, K.; Karande, A.A. A neutralizing antibody to the a chain of abrin inhibits abrin toxicity both in vitro and in vivo. Clin. Vaccine Immunol. 2008, 15, 737–743, doi:10.1128/CVI.00254-07.
[20]
Bolognesi, A.; Polito, L.; Tazzari, P.L.; Lemoli, R.M.; Lubelli, C.; Fogli, M.; Boon, L.; de Boer, M.; Stirpe, F. In vitro anti-tumour activity of anti-CD80 and anti-CD86 immunotoxins containing type 1 ribosome-inactivating proteins. Br. J. Haematol. 2000, 110, 351–361, doi:10.1046/j.1365-2141.2000.02193.x.
[21]
Endo, Y.; Mitsui, K.; Motizuki, M.; Tsurugi, K. The mechanism of action of ricin and related toxic lectins on eukaryotic ribosomes. The site and the characteristics of the modification in 28 S ribosomal RNA caused by the toxins. J. Biol. Chem. 1987, 262, 5908–5912.
[22]
Zamboni, M.; Brigotti, M.; Rambelli, F.; Montanaro, L.; Sperti, S. High-pressure-liquid-chromatographic and fluorimetric methods for the determination of adenine released from ribosomes by ricin and gelonin. Biochem. J. 1989, 259, 639–643.
[23]
Iglewski, B.H.; Liu, P.V.; Kabat, D. Mechanism of action of Pseudomonas aeruginosa exotoxin Aiadenosine diphosphate-ribosylation of mammalian elongation factor 2 in vitro and in vivo. Infect. Immun. 1977, 15, 138–144.
[24]
Van Ness, B.G.; Howard, J.B.; Bodley, J.W. ADP-ribosylation of elongation factor 2 by diphtheria toxin. Isolation and properties of the novel ribosyl-amino acid and its hydrolysis products. J. Biol. Chem. 1980, 255, 10717–10720.
[25]
Kondo, T.; FitzGerald, D.; Chaudhary, V.K.; Adhya, S.; Pastan, I. Activity of immunotoxins constructed with modified Pseudomonas exotoxin A lacking the cell recognition domain. J. Biol. Chem. 1988, 263, 9470–9475.
[26]
Kreitman, R.J.; Batra, J.K.; Seetharam, S.; Chaudhary, V.K.; FitzGerald, D.J.; Pastan, I. Single-chain immunotoxin fusions between anti-Tac and Pseudomonas exotoxin: Relative importance of the two toxin disulfide bonds. Bioconjug. Chem. 1993, 4, 112–120, doi:10.1021/bc00020a002.
[27]
Siegall, C.B.; Chaudhary, V.K.; FitzGerald, D.J.; Pastan, I. Functional analysis of domains II, Ib, and III of Pseudomonas exotoxin. J. Biol. Chem. 1989, 264, 14256–14261.
[28]
Williams, D.P.; Snider, C.E.; Strom, T.B.; Murphy, J.R. Structure/function analysis of interleukin-2-toxin (DAB486-IL-2). Fragment B sequences required for the delivery of fragment A to the cytosol of target cells. J. Biol. Chem. 1990, 265, 11885–11889.
[29]
Chaudhary, V.K.; FitzGerald, D.J.; Pastan, I. A proper amino terminus of diphtheria toxin is important for cytotoxicity. Biochem. Biophys. Res. Commun. 1991, 180, 545–551, doi:10.1016/S0006-291X(05)81099-X.
[30]
Madhumathi, J.; Verma, R.S. Therapeutic targets and recent advances in protein immunotoxins. Curr. Opin. Microbiol. 2012, 1, 300–309.
[31]
Kreitman, R.J. Immunotoxins for targeted cancer therapy. AAPS J. 2006, 8, E532–E551, doi:10.1208/aapsj080363.
[32]
Roscoe, D.M.; Jung, S.H.; Benhar, I.; Pai, L.; Lee, B.K.; Pastan, I. Primate antibody response to immunotoxin: Serological and computer-aided analysis of epitopes on a truncated form of Pseudomonas exotoxin. Infect. Immun. 1994, 62, 5055–5065.
[33]
Roscoe, D.M.; Pai, L.H.; Pastan, I. Identification of epitopes on a mutant form of Pseudomonas exotoxin using serum from humans treated with Pseudomonas exotoxin containing immunotoxins. Eur. J. Immunol. 1997, 27, 1459–1468, doi:10.1002/eji.1830270624.
[34]
Liu, W.; Onda, M.; Lee, B.; Kreitman, R.J.; Hassan, R.; Xiang, L.; Pastan, I. Recombinant immunotoxin engineered for low immunogenicity and antigenicity by identifying and silencing human B-cell epitopes. Proc. Natl. Acad. Sci. USA 2012, 109, 11782–11787.
[35]
Reddy, K.R. Development and pharmacokinetics and pharmacodynamics of pegylated interferon alfa-2a (40 kD). Semin. Liver Dis. 2004, 2, 33–38, doi:10.1055/s-2004-832926.
[36]
Graham, M.L. Pegaspargase: A review of clinical studies. Adv. Drug Deliv. Rev. 2003, 55, 1293–1302, doi:10.1016/S0169-409X(03)00110-8.
[37]
Tsutsumi, Y.; Onda, M.; Nagata, S.; Lee, B.; Kreitman, R.J.; Pastan, I. Site-specific chemical modification with polyethylene glycol of recombinant immunotoxin anti-Tac(Fv)-PE38 (LMB-2) improves antitumor activity and reduces animal toxicity and immunogenicity. Proc. Natl. Acad. Sci. USA 2000, 97, 8548–8553.
[38]
Li, Z.; Yu, T.; Zhao, P.; Ma, J. Immunotoxins and cancer therapy. Cell Mol. Immunol. 2005, 2, 106–112.
[39]
Keating, S.E.; Baran, M.; Bowie, A.G. Cytosolic DNA sensors regulating type I interferon induction. Trends Immunol. 2011, 32, 574–581, doi:10.1016/j.it.2011.08.004.
[40]
Lavelle, E.C.; Jarnicki, A.; McNeela, E.; Armstrong, M.E.; Higgins, S.C.; Leavy, O.; Mills, K.H. Effects of cholera toxin on innate and adaptive immunity and its application as an immunomodulatory agent. J. Leukoc Biol. 2004, 75, 756–763.
[41]
Peterson, M.L.; Ault, K.; Kremer, M.J.; Klingelhutz, A.J.; Davis, C.C.; Squier, C.A.; Schlievert, P.M. The innate immune system is activated by stimulation of vaginal epithelial cells with Staphylococcus aureus and toxic shock syndrome toxin 1. Infect. Immun. 2005, 73, 2164–2174.
[42]
Mathew, M.; Verma, R.S. Humanized immunotoxins: A new generation of immunotoxins for targeted cancer therapy. Cancer Sci. 2009, 100, 1359–1365, doi:10.1111/j.1349-7006.2009.01192.x.
[43]
Huhn, M.; Sasse, S.; Tur, M.K.; Matthey, B.; Schinkothe, T.; Rybak, S.M.; Barth, S.; Engert, A. Human angiogenin fused to human CD30 ligand (Ang-CD30L) exhibits specific cytotoxicity against CD30-positive lymphoma. Cancer Res. 2001, 61, 8737–8742.
[44]
Tur, M.K.; Neef, I.; Jager, G.; Teubner, A.; Stocker, M.; Melmer, G.; Barth, S. Immunokinases, a novel class of immunotherapeutics for targeted cancer therapy. Curr. Pharm. Des. 2009, 15, 2693–2699, doi:10.2174/138161209788923877.
[45]
Tur, M.K.; Neef, I.; Jost, E.; Galm, O.; Jager, G.; Stocker, M.; Ribbert, M.; Osieka, R.; Klinge, U.; Barth, S. Targeted restoration of down-regulated DAPK2 tumor suppressor activity induces apoptosis in Hodgkin lymphoma cells. J. Immunother. 2009, 32, 431–441, doi:10.1097/CJI.0b013e31819f1cb6.
[46]
Ten Cate, B.; de Bruyn, M.; Wei, Y.; Bremer, E.; Helfrich, W. Targeted elimination of leukemia stem cells; a new therapeutic approach in hemato-oncology. Curr. Drug Targets 2010, 11, 95–110, doi:10.2174/138945010790031063.
[47]
Wan, L.; Zeng, L.; Chen, L.; Huang, Q.; Li, S.; Lu, Y.; Li, Y.; Cheng, J.; Lu, X. Expression, purification, and refolding of a novel immunotoxin containing humanized single-chain fragment variable antibody against CTLA4 and the N-terminal fragment of human perforin. Protein Exp. Purif. 2006, 48, 307–313, doi:10.1016/j.pep.2006.02.005.
Mosser, D.M.; Edwards, J.P. Exploring the full spectrum of macrophage activation. Nat. Rev. Immunol. 2008, 8, 958–969, doi:10.1038/nri2448.
[50]
Metchnikoff, E. Le？ons sur la Pathologie Comparée de L’inflammation; Masson: Paris, France, 1892.
[51]
Biswas, S.K.; Mantovani, A. Macrophage plasticity and interaction with lymphocyte subsets: Cancer as a paradigm. Nat. Immunol. 2010, 11, 889–896, doi:10.1038/ni.1937.
[52]
Gordon, S.; Martinez, F.O. Alternative activation of macrophages: Mechanism and functions. Immunity 2010, 32, 593–604, doi:10.1016/j.immuni.2010.05.007.
[53]
Sica, A.; Bronte, V. Altered macrophage differentiation and immune dysfunction in tumor development. J. Clin. Invest. 2007, 11, 1155–1166, doi:10.1172/JCI31422.
[54]
Ross, R.; Odland, G. Human wound repair. II. Inflammatory cells, epithelial-mesenchymal interrelations, and fibrogenesis. J. Cell. Biol. 1968, 39, 152–168, doi:10.1083/jcb.39.1.152.
[55]
Banno, T.; Gazel, A.; Blumenberg, M. Effects of tumor necrosis factor-alpha (TNF alpha) in epidermal keratinocytes revealed using global transcriptional profiling. J. Biol. Chem. 2004, 279, 32633–32642.
[56]
McKay, I.A.; Leigh, I.M. Epidermal cytokines and their roles in cutaneous wound healing. Br. J. Dermatol. 1991, 12, 513–518.
[57]
Hancock, G.E.; Kaplan, G.; Cohn, Z.A. Keratinocyte growth regulation by the products of immune cells. J. Exp. Med. 1988, 16, 1395–1402.
[58]
Brauchle, M.; Angermeyer, K.; Hubner, G.; Werner, S. Large induction of keratinocyte growth factor expression by serum growth factors and pro-inflammatory cytokines in cultured fibroblasts. Oncogene 1994, 9, 3199–3204.
[59]
Hubner, G.; Brauchle, M.; Smola, H.; Madlener, M.; Fassler, R.; Werner, S. Differential regulation of pro-inflammatory cytokines during wound healing in normal and glucocorticoid-treated mice. Cytokine 1996, 8, 548–556, doi:10.1006/cyto.1996.0074.
[60]
Mori, R.; Shaw, T.J.; Martin, P. Molecular mechanisms linking wound inflammation and fibrosis: Knockdown of osteopontin leads to rapid repair and reduced scarring. J. Exp. Med. 2008, 20, 43–51.
[61]
Takehara, K. Growth regulation of skin fibroblasts. J. Dermatol. Sci. 2000, 2, S70–S77, doi:10.1016/S0923-1811(00)00144-4.
[62]
Stramer, B.M.; Mori, R.; Martin, P. The inflammation-fibrosis link? A Jekyll and Hyde role for blood cells during wound repair. J. Invest. Dermatol. 2007, 12, 1009–1017.
[63]
Brown, L.F.; Yeo, K.T.; Berse, B.; Yeo, T.K.; Senger, D.R.; Dvorak, H.F.; van de Water, L. Expression of vascular permeability factor (vascular endothelial growth factor) by epidermal keratinocytes during wound healing. J. Exp. Med. 1992, 17, 1375–1379.
[64]
Frank, S.; Hubner, G.; Breier, G.; Longaker, M.T.; Greenhalgh, D.G.; Werner, S. Regulation of vascular endothelial growth factor expression in cultured keratinocytes. Implications for normal and impaired wound healing. J. Biol. Chem. 1995, 270, 12607–12613.
[65]
Maruyama, K.; Asai, J.; Ii, M.; Thorne, T.; Losordo, D.W.; D’Amore, P.A. Decreased macrophage number and activation lead to reduced lymphatic vessel formation and contribute to impaired diabetic wound healing. Am. J. Pathol. 2007, 170, 1178–1191.
[66]
Schledzewski, K.; Falkowski, M.; Moldenhauer, G.; Metharom, P.; Kzhyshkowska, J.; Ganss, R.; Demory, A.; Falkowska-Hansen, B.; Kurzen, H.; Ugurel, S.; et al. Lymphatic endothelium-specific hyaluronan receptor LYVE-1 is expressed by stabilin-1+, F4/80+, CD11b+ macrophages in malignant tumours and wound healing tissue in vivo and in bone marrow cultures in vitro: Implications for the assessment of lymphangiogenesis. J. Pathol. 2006, 20, 67–77.
[67]
Sica, A.; Mantovani, A. Macrophage plasticity and polarization: In vivo veritas. J. Clin. Invest. 2012, 12, 787–795.
[68]
Hamilton, T.A.; Ohmori, Y.; Tebo, J. Regulation of chemokine expression by antiinflammatory cytokines. Immunol. Res. 2002, 25, 229–245, doi:10.1385/IR:25:3:229.
[69]
Mantovani, A.; Sica, A.; Sozzani, S.; Allavena, P.; Vecchi, A.; Locati, M. The chemokine system in diverse forms of macrophage activation and polarization. Trends Immunol. 2004, 25, 677–686, doi:10.1016/j.it.2004.09.015.
[70]
Verreck, F.A.; de Boer, T.; Langenberg, D.M.; Hoeve, M.A.; Kramer, M.; Vaisberg, E.; Kastelein, R.; Kolk, A.; de Waal-Malefyt, R.; Ottenhoff, T.H. Human IL-23-producing type 1 macrophages promote but IL-10-producing type 2 macrophages subvert immunity to (myco)bacteria. Proc. Natl. Acad. Sci. USA 2004, 101, 4560–4565.
[71]
Dale, D.C.; Boxer, L.; Liles, W.C. The phagocytes: Neutrophils and monocytes. Blood 2008, 112, 935–945, doi:10.1182/blood-2007-12-077917.
[72]
Mackaness, G.B. Cellular immunity and the parasite. Adv. Exp. Med. Biol. 1977, 9, 65–73.
Martinez, F.O.; Sica, A.; Mantovani, A.; Locati, M. Macrophage activation and polarization. Front. Biosci. 2008, 1, 453–461.
[75]
Edwards, J.P.; Zhang, X.; Frauwirth, K.A.; Mosser, D.M. Biochemical and functional characterization of three activated macrophage populations. J. Leukoc. Biol. 2006, 80, 1298–1307, doi:10.1189/jlb.0406249.
[76]
Martinez, F.O.; Helming, L.; Gordon, S. Alternative activation of macrophages: An immunologic functional perspective. Annu. Rev. Immunol. 2009, 2, 451–483.
[77]
Barner, M.; Mohrs, M.; Brombacher, F.; Kopf, M. Differences between IL-4R alpha-deficient and IL-4-deficient mice reveal a role for IL-13 in the regulation of Th2 responses. Curr. Biol. 1998, 8, 669–672, doi:10.1016/S0960-9822(98)70256-8.
[78]
Noben-Trauth, N.; Shultz, L.D.; Brombacher, F.; Urban, J.F., Jr.; Gu, H.; Paul, W.E. An interleukin 4 (IL-4)-independent pathway for CD4+ T cell IL-4 production is revealed in IL-4 receptor-deficient mice. Proc. Natl. Acad. Sci. USA 1997, 94, 10838–10843.
[79]
Gordon, S. Alternative activation of macrophages. Nat. Rev. Immunol. 2003, 3, 23–35, doi:10.1038/nri978.
[80]
Stein, M.; Keshav, S.; Harris, N.; Gordon, S. Interleukin 4 potently enhances murine macrophage mannose receptor activity: A marker of alternative immunologic macrophage activation. J. Exp. Med. 1992, 176, 287–292, doi:10.1084/jem.176.1.287.
[81]
Kadl, A.; Meher, A.K.; Sharma, P.R.; Lee, M.Y.; Doran, A.C.; Johnstone, S.R.; Elliott, M.R.; Gruber, F.; Han, J.; Chen, W.; et al. Identification of a novel macrophage phenotype that develops in response to atherogenic phospholipids via Nrf2. Circ. Res. 2010, 107, 737–746, doi:10.1161/CIRCRESAHA.109.215715.
Boyle, J.J.; Johns, M.; Lo, J.; Chiodini, A.; Ambrose, N.; Evans, P.C.; Mason, J.C.; Haskard, D.O. Heme induces heme oxygenase 1 via Nrf2: role in the homeostatic macrophage response to intraplaque hemorrhage. Arter. Thromb. Vasc. Biol. 2011, 31, 2685–2691, doi:10.1161/ATVBAHA.111.225813.
[84]
Gleissner, C.A.; Shaked, I.; Little, K.M.; Ley, K. CXC chemokine ligand 4 induces a unique transcriptome in monocyte-derived macrophages. J. Immunol. 2010, 184, 4810–4818.
[85]
Grinberg, S.; Hasko, G.; Wu, D.; Leibovich, S.J. Suppression of PLCbeta2 by endotoxin plays a role in the adenosine A(2A) receptor-mediated switch of macrophages from an inflammatory to an angiogenic phenotype. Am. J. Pathol. 2009, 175, 2439–2453, doi:10.2353/ajpath.2009.090290.
[86]
Loots, M.A.; Lamme, E.N.; Zeegelaar, J.; Mekkes, J.R.; Bos, J.D.; Middelkoop, E. Differences in cellular infiltrate and extracellular matrix of chronic diabetic and venous ulcers versus acute wounds. J. Invest. Dermatol. 1998, 111, 850–857.
[87]
Eming, S.A.; Krieg, T.; Davidson, J.M. Inflammation in wound repair: Molecular and cellular mechanisms. J. Invest. Dermatol. 2007, 127, 514–525, doi:10.1038/sj.jid.5700701.
[88]
Ambarus, C.A.; Noordenbos, T.; de Hair, M.J.; Tak, P.P.; Baeten, D.L. Intimal lining layer macrophages but not synovial sublining macrophages display an IL-10 polarized-like phenotype in chronic synovitis. Arthritis Res. Ther. 2012, 14, R74, doi:10.1186/ar3796.
[89]
Crielaard, B.J.; Lammers, T.; Morgan, M.E.; Chaabane, L.; Carboni, S.; Greco, B.; Zaratin, P.; Kraneveld, A.D.; Storm, G. Macrophages and liposomes in inflammatory disease: Friends or foes? Int. J. Pharm. 2011, 416, 499–506, doi:10.1016/j.ijpharm.2010.12.045.
[90]
Lumeng, C.N.; Bodzin, J.L.; Saltiel, A.R. Obesity induces a phenotypic switch in adipose tissue macrophage polarization. J. Clin. Invest. 2007, 117, 175–184.
[91]
Orme, J.; Mohan, C. Macrophage subpopulations in systemic lupus erythematosus. Discov. Med. 2012, 13, 151–158.
[92]
Sindrilaru, A.; Peters, T.; Wieschalka, S.; Baican, C.; Baican, A.; Peter, H.; Hainzl, A.; Schatz, S.; Qi, Y.; Schlecht, A.; et al. An unrestrained proinflammatory M1 macrophage population induced by iron impairs wound healing in humans and mice. J. Clin. Invest. 2011, 121, 985–997, doi:10.1172/JCI44490.
[93]
Vandooren, B.; Noordenbos, T.; Ambarus, C.; Krausz, S.; Cantaert, T.; Yeremenko, N.; Boumans, M.; Lutter, R.; Tak, P.P.; Baeten, D. Absence of a classically activated macrophage cytokine signature in peripheral spondylarthritis, including psoriatic arthritis. Arthritis Rheum. 2009, 60, 966–975, doi:10.1002/art.24406.
[94]
Singh, J.A.; Cameron, D.R. Summary of AHRQ’s comparative effectiveness review of drug therapy for rheumatoid arthritis (RA) in adults—an update. J. Manag. Care Pharm. 2012, 18 Suppl. C, 1–18.
[95]
Hodgkins, P.; Yen, L.; Yarlas, A.; Karlstadt, R.; Solomon, D.; Kane, S. Impact of MMX(R) mesalamine on improvement and maintenance of health-related quality of life in patients with ulcerative colitis. Inflamm. Bowel Dis. 2012.
[96]
Actis, G.C.; Rosina, F.; Pellicano, R.; Rizzetto, M. An aggressive medical approach for inflammatory bowel disease: Clinical challenges and therapeutic profiles in a retrospective hospital-based series. Curr. Clin. Pharmacol. 2012, 7, 209–213, doi:10.2174/157488412800958730.
Jia, Y.; Li, H.; Chen, W.; Li, M.; Lv, M.; Feng, P.; Hu, H.; Zhang, L. Prevention of murine experimental autoimmune encephalomyelitis by in vivo expression of a novel recombinant immunotoxin DT390-RANTES. Gene Ther. 2006, 13, 1351–1359, doi:10.1038/sj.gt.3302799.
[99]
Bruhl, H.; Cihak, J.; Stangassinger, M.; Schlondorff, D.; Mack, M. Depletion of CCR5-expressing cells with bispecific antibodies and chemokine toxins: A new strategy in the treatment of chronic inflammatory diseases and HIV. J. Immunol. 2001, 166, 2420–2426.
Van de Winkel, J.G.; Anderson, C.L. Biology of human immunoglobulin G Fc receptors. J. Leukoc. Biol. 1991, 49, 511–524.
[102]
Daeron, M. Structural bases of Fc gamma R functions. Int. Rev. Immunol. 1997, 1, 1–27, doi:10.3109/08830189709045701.
[103]
Daeron, M. Fc receptor biology. Annu. Rev. Immunol. 1997, 1, 203–234, doi:10.1146/annurev.immunol.15.1.203.
[104]
Thepen, T.; van Vuuren, A.J.; Kiekens, R.C.; Damen, C.A.; Vooijs, W.C.; van de Winkel, J.G. Resolution of cutaneous inflammation after local elimination of macrophages. Nat. Biotechnol. 2000, 18, 48–51.
[105]
Van Vuuren, A.J.; van Roon, J.A.; Walraven, V.; Stuij, I.; Harmsen, M.C.; McLaughlin, P.M.; van de Winkel, J.G.; Thepen, T. CD64-directed immunotoxin inhibits arthritis in a novel CD64 transgenic rat model. J. Immunol. 2006, 176, 5833–5838.
[106]
Fet, N.G.; Fiebeler, A.; Klinge, U.; Park, J.K.; Barth, S.; Thepen, T.; Tolba, R.H. Reduction of activated macrophages after ischaemia-reperfusion injury diminishes oxidative stress and ameliorates renal damage. Nephrol. Dial. Transplant. 2012, 2, 3149–3155.
[107]
Leemans, J.C.; Thepen, T.; Weijer, S.; Florquin, S.; van Rooijen, N.; van de Winkel, J.G.; van der Poll, T. Macrophages play a dual role during pulmonary tuberculosis in mice. J. Infect. Dis. 2005, 191, 65–74, doi:10.1086/426395.
[108]
Stahnke, B.; Thepen, T.; Stocker, M.; Rosinke, R.; Jost, E.; Fischer, R.; Tur, M.K.; Barth, S. Granzyme B-H22(scFv), a human immunotoxin targeting CD64 in acute myeloid leukemia of monocytic subtypes. Mol. Cancer Ther. 2008, 7, 2924–2932, doi:10.1158/1535-7163.MCT-08-0554.
[109]
Van de Winkel, J.G.; Capel, P.J. Human IgG Fc receptor heterogeneity: molecular aspects and clinical implications. Immunol. Today 1993, 14, 215–221, doi:10.1016/0167-5699(93)90166-I.
[110]
Ribbert, T.; Thepen, T.; Tur, M.K.; Fischer, R.; Huhn, M.; Barth, S. Recombinant, ETA’-based CD64 immunotoxins: Improved efficacy by increased valency, both in vitro and in vivo in a chronic cutaneous inflammation model in human CD64 transgenic mice. Br. J. Dermatol. 2010, 163, 279–286, doi:10.1111/j.1365-2133.2010.09824.x.
