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Macrophage-targeted therapy: CD64-based immunotoxins for treatment of chronic inflammatory diseases.

Hristodorov D, Mladenov R, Huhn M, Barth S, Thepen T - Toxins (Basel) (2012)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Experimental Medicine and Immunotherapy, Institute of Applied Medical Engineering, University Hospital RWTH Aachen, Aachen 52074, Germany. dmitrij.hristodorov@rwth-aachen.de

ABSTRACT
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.

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Related in: MedlinePlus

Phenotypes of different polarized MΦ.
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toxins-04-00676-f003: Phenotypes of different polarized MΦ.

Mentions: In the context of atherosclerosis, a population of macrophages expressing a unique set of genes including Heme oxygenase-1 (HO-1), sufiredoxin-1, and thioredoxin-reductase in a nuclear factor, erythroid-derived 2, like 2(Nrf2) dependent manner was found within the aortas of 30 week western diet-fed Ldlr−/− mice by immunohistochemistry and flow cytometry. In vitro, this phenotype could be induced by ox-PL 1-palmitoyl- 2arachidonoyl-sn-glycero-3-phosphorylcholine resulting in the designation as Mox macrophages [81]. Furthermore, Mox macrophages seem to be closely related to the lately proposed hemorrhage-associated macrophages (Mha) [82,83]. Human monocytes can be differentiated to Mha macrophages in vitro using hapto-hemoglobin complexes or oxidized red blood cells leading to the up-regulation of CD163, HO-1 and IL-10 in an Nrf2-dependent manner. Moreover, a CSF/CXCL4-dependent macrophage subset, discovered in 2010 by Gleissner et al. [84], was termed M4. These macrophages were shown to be characterized by a mixed, but unique profile of transcripts including higher levels of CD86 and TNF-α (both M1-like), CD206, CCL18 and CCL20 (all M2-like) and lower levels of pentraxin 3 (PTX3), CD36 and IL-10 (M2-like). Although these cells have a weak phagocytic activity, the function of M4 macrophages remains poorly understood. Finally, the laboratory of Samuel Joseph Leibovich has characterized one further M2 subtype, termed M2d, which unlike previously described M2-like macrophages, are the result of a switching event from M1 macrophages as response to adenosine A2A receptor signaling induced by TLR agonists [85]. M2d macrophages were demonstrated to markedly decrease the expression of pro-inflammatory cytokines including IL-12 and TNF-α, while concurrently producing high levels of IL-10 and vascular endothelial growth factor (VEGF). Interestingly, the classical markers of wound healing or M2a macrophages were not up-regulated pointing to an M2c-resembling phenotype of M2d macrophages. The phenotypes of different polarized macrophages are summarized in Figure 3.


Macrophage-targeted therapy: CD64-based immunotoxins for treatment of chronic inflammatory diseases.

Hristodorov D, Mladenov R, Huhn M, Barth S, Thepen T - Toxins (Basel) (2012)

Phenotypes of different polarized MΦ.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3475223&req=5

toxins-04-00676-f003: Phenotypes of different polarized MΦ.
Mentions: In the context of atherosclerosis, a population of macrophages expressing a unique set of genes including Heme oxygenase-1 (HO-1), sufiredoxin-1, and thioredoxin-reductase in a nuclear factor, erythroid-derived 2, like 2(Nrf2) dependent manner was found within the aortas of 30 week western diet-fed Ldlr−/− mice by immunohistochemistry and flow cytometry. In vitro, this phenotype could be induced by ox-PL 1-palmitoyl- 2arachidonoyl-sn-glycero-3-phosphorylcholine resulting in the designation as Mox macrophages [81]. Furthermore, Mox macrophages seem to be closely related to the lately proposed hemorrhage-associated macrophages (Mha) [82,83]. Human monocytes can be differentiated to Mha macrophages in vitro using hapto-hemoglobin complexes or oxidized red blood cells leading to the up-regulation of CD163, HO-1 and IL-10 in an Nrf2-dependent manner. Moreover, a CSF/CXCL4-dependent macrophage subset, discovered in 2010 by Gleissner et al. [84], was termed M4. These macrophages were shown to be characterized by a mixed, but unique profile of transcripts including higher levels of CD86 and TNF-α (both M1-like), CD206, CCL18 and CCL20 (all M2-like) and lower levels of pentraxin 3 (PTX3), CD36 and IL-10 (M2-like). Although these cells have a weak phagocytic activity, the function of M4 macrophages remains poorly understood. Finally, the laboratory of Samuel Joseph Leibovich has characterized one further M2 subtype, termed M2d, which unlike previously described M2-like macrophages, are the result of a switching event from M1 macrophages as response to adenosine A2A receptor signaling induced by TLR agonists [85]. M2d macrophages were demonstrated to markedly decrease the expression of pro-inflammatory cytokines including IL-12 and TNF-α, while concurrently producing high levels of IL-10 and vascular endothelial growth factor (VEGF). Interestingly, the classical markers of wound healing or M2a macrophages were not up-regulated pointing to an M2c-resembling phenotype of M2d macrophages. The phenotypes of different polarized macrophages are summarized in Figure 3.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Experimental Medicine and Immunotherapy, Institute of Applied Medical Engineering, University Hospital RWTH Aachen, Aachen 52074, Germany. dmitrij.hristodorov@rwth-aachen.de

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus