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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

Different polarized MΦ subsets. Abbreviations: IC, immune complex; TLR, Toll-like receptor; IL-1R, IL-1 receptor; Ox-PL-PPC, ox-PL 1-palmitoyl-2arachidonoyl-sn-glycero-3-phosphorylcholine; HH-complexes, hapto-hemoglobin; oxRBC, oxidized red blood cells; CSF, colony stimulating factor; CXCL4, chemokine (C-X-C motif) ligand 4.
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toxins-04-00676-f002: Different polarized MΦ subsets. Abbreviations: IC, immune complex; TLR, Toll-like receptor; IL-1R, IL-1 receptor; Ox-PL-PPC, ox-PL 1-palmitoyl-2arachidonoyl-sn-glycero-3-phosphorylcholine; HH-complexes, hapto-hemoglobin; oxRBC, oxidized red blood cells; CSF, colony stimulating factor; CXCL4, chemokine (C-X-C motif) ligand 4.

Mentions: Inflammation is a complex and dynamic physiological process, which requires a well-balanced and controlled interaction of diverse cells. One of the cell types critically involved in initiation but also resolution of inflammation is macrophages. Across the different phases of an inflammatory response to e.g., infections or skin damage, their functions cover the production of pro-inflammatory cytokines and cytotoxic compounds, secretion of various growth factors to promote the function of other cells contributing to the resolution of inflammation, fighting invading microbes, and scavenging cell debris. In fact, these factors are neither produced simultaneously nor by the same kind of macrophages. Several recent reports have made clear that “the” macrophage does not exist, but that the term macrophage is rather used in a broader context for the description of a population of very versatile cells that share some common denominators. Due to their ability to adopt to a changing cytokine milieu and, vice versa, to influence the milieu by production of an array of soluble mediators, macrophages are nowadays considered to be very plastic and flexible cells [67]. Acquiring diverse functional phenotypes in response to environmental cues is reflected in the classification of polarized rather than activated macrophages. Mirroring the Th1/Th2 dichotomy, polarized macrophages were sub-divided into M1 and M2. M1 polarization, also referred to as classical activation, results from stimulation with Interferon-γ (IFN-γ), alone or in concert with bacterial lipopolysaccharide (LPS) [68]. The source of IFN-γ can be both innate and adaptive immune cells. Upon stress or first encounter to pathogens, natural killer (NK) cells, as part of the innate immunity, produce IFN-γ, thus polarizing macrophages to M1. In addition, an increased capacity of antigen presenting [69,70], these M1 cells are characterized by an enhanced microbicidal and tumoricidal activity mediated by the production of increased levels of superoxide anions, and oxygen and nitrogen radicals, which in summary confers direct host resistance to infections [71,72,73]. However, the capability of NK cells to provide sustainable amounts of IFN-γ is limited. Since M1 macrophages induce a Th1 response by secretion of high levels of pro-inflammatory cytokines, such as interleukin (IL)-12, IL-23, and tumor necrosis factor (TNF)-α, the polarization of macrophages to M1 can be amplified by a continued supply with IFN-γ by T cells. In contrast to T cells, which act in an antigen-specific manner, M1 polarized macrophages kill unspecifically, merely restricted by the distance to the target cell. While M1 macrophages represent the one extreme of polarization, the second extreme is summarized under the term alternatively activated macrophages or M2 macrophages [52]. During the past decade, this term has been expanded to a more heterogeneous cell population [74,75]. The nomenclature of alternatively activated macrophages is somewhat confusing and changes over time. Terms used are: M2, alternatively activated macrophages, type II activated macrophages, deactivated macrophages, M2a, M2b and M2c and a few more. In effort to find a more informative and clear classification of polarized macrophages Mosser and Edwards [49] suggested the following three sub-populations based on their functions: host defense, wound healing and immune regulation. This classification is in accordance with that proposed by Mantovani et al. [69], where M1 would refer to host defense, M2a to wound healing and M2b together with M2c to immune regulation. For discrimination of different macrophage phenotypes, Mantovani et al. not only considered the function, but also the respective stimuli generating the sub-populations. Thereby, M2a is produced by IL-4 or IL-13 both of which activate STAT6 via binding to the IL-4 α-subunit, which is shared in both receptors [76,77,78,79,80]. M2b results from a combined exposure to immune complexes with Toll-like receptor (TLR)- or IL-1 receptor (IL1R)-ligands, whereas M2c is induced by IL-10 [69]. Supplementary to Mossers and Edwards’s classification, Mantovani et al. discriminate between M2b macrophages, which in addition to immunoregulatory functions also induce Th2 driven inflammation, and M2c macrophages, which are thought to be predominantly responsible for negative/deactivating immunoregulation. More recently, additional sub-populations of macrophages were discovered (Figure 2).


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)

Different polarized MΦ subsets. Abbreviations: IC, immune complex; TLR, Toll-like receptor; IL-1R, IL-1 receptor; Ox-PL-PPC, ox-PL 1-palmitoyl-2arachidonoyl-sn-glycero-3-phosphorylcholine; HH-complexes, hapto-hemoglobin; oxRBC, oxidized red blood cells; CSF, colony stimulating factor; CXCL4, chemokine (C-X-C motif) ligand 4.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

toxins-04-00676-f002: Different polarized MΦ subsets. Abbreviations: IC, immune complex; TLR, Toll-like receptor; IL-1R, IL-1 receptor; Ox-PL-PPC, ox-PL 1-palmitoyl-2arachidonoyl-sn-glycero-3-phosphorylcholine; HH-complexes, hapto-hemoglobin; oxRBC, oxidized red blood cells; CSF, colony stimulating factor; CXCL4, chemokine (C-X-C motif) ligand 4.
Mentions: Inflammation is a complex and dynamic physiological process, which requires a well-balanced and controlled interaction of diverse cells. One of the cell types critically involved in initiation but also resolution of inflammation is macrophages. Across the different phases of an inflammatory response to e.g., infections or skin damage, their functions cover the production of pro-inflammatory cytokines and cytotoxic compounds, secretion of various growth factors to promote the function of other cells contributing to the resolution of inflammation, fighting invading microbes, and scavenging cell debris. In fact, these factors are neither produced simultaneously nor by the same kind of macrophages. Several recent reports have made clear that “the” macrophage does not exist, but that the term macrophage is rather used in a broader context for the description of a population of very versatile cells that share some common denominators. Due to their ability to adopt to a changing cytokine milieu and, vice versa, to influence the milieu by production of an array of soluble mediators, macrophages are nowadays considered to be very plastic and flexible cells [67]. Acquiring diverse functional phenotypes in response to environmental cues is reflected in the classification of polarized rather than activated macrophages. Mirroring the Th1/Th2 dichotomy, polarized macrophages were sub-divided into M1 and M2. M1 polarization, also referred to as classical activation, results from stimulation with Interferon-γ (IFN-γ), alone or in concert with bacterial lipopolysaccharide (LPS) [68]. The source of IFN-γ can be both innate and adaptive immune cells. Upon stress or first encounter to pathogens, natural killer (NK) cells, as part of the innate immunity, produce IFN-γ, thus polarizing macrophages to M1. In addition, an increased capacity of antigen presenting [69,70], these M1 cells are characterized by an enhanced microbicidal and tumoricidal activity mediated by the production of increased levels of superoxide anions, and oxygen and nitrogen radicals, which in summary confers direct host resistance to infections [71,72,73]. However, the capability of NK cells to provide sustainable amounts of IFN-γ is limited. Since M1 macrophages induce a Th1 response by secretion of high levels of pro-inflammatory cytokines, such as interleukin (IL)-12, IL-23, and tumor necrosis factor (TNF)-α, the polarization of macrophages to M1 can be amplified by a continued supply with IFN-γ by T cells. In contrast to T cells, which act in an antigen-specific manner, M1 polarized macrophages kill unspecifically, merely restricted by the distance to the target cell. While M1 macrophages represent the one extreme of polarization, the second extreme is summarized under the term alternatively activated macrophages or M2 macrophages [52]. During the past decade, this term has been expanded to a more heterogeneous cell population [74,75]. The nomenclature of alternatively activated macrophages is somewhat confusing and changes over time. Terms used are: M2, alternatively activated macrophages, type II activated macrophages, deactivated macrophages, M2a, M2b and M2c and a few more. In effort to find a more informative and clear classification of polarized macrophages Mosser and Edwards [49] suggested the following three sub-populations based on their functions: host defense, wound healing and immune regulation. This classification is in accordance with that proposed by Mantovani et al. [69], where M1 would refer to host defense, M2a to wound healing and M2b together with M2c to immune regulation. For discrimination of different macrophage phenotypes, Mantovani et al. not only considered the function, but also the respective stimuli generating the sub-populations. Thereby, M2a is produced by IL-4 or IL-13 both of which activate STAT6 via binding to the IL-4 α-subunit, which is shared in both receptors [76,77,78,79,80]. M2b results from a combined exposure to immune complexes with Toll-like receptor (TLR)- or IL-1 receptor (IL1R)-ligands, whereas M2c is induced by IL-10 [69]. Supplementary to Mossers and Edwards’s classification, Mantovani et al. discriminate between M2b macrophages, which in addition to immunoregulatory functions also induce Th2 driven inflammation, and M2c macrophages, which are thought to be predominantly responsible for negative/deactivating immunoregulation. More recently, additional sub-populations of macrophages were discovered (Figure 2).

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