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Efficacy of Polyvalent Human Immunoglobulins in an Animal Model of Neuromyelitis Optica Evoked by Intrathecal Anti-Aquaporin 4 Antibodies

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ABSTRACT

Neuromyelitis Optica Spectrum Disorders (NMOSD) are associated with autoantibodies (ABs) targeting the astrocytic aquaporin-4 water channels (AQP4-ABs). These ABs have a direct pathogenic role by initiating a variety of immunological and inflammatory processes in the course of disease. In a recently-established animal model, chronic intrathecal passive-transfer of immunoglobulin G from NMOSD patients (NMO-IgG), or of recombinant human AQP4-ABs (rAB-AQP4), provided evidence for complementary and immune-cell independent effects of AQP4-ABs. Utilizing this animal model, we here tested the effects of systemically and intrathecally applied pooled human immunoglobulins (IVIg) using a preventive and a therapeutic paradigm. In NMO-IgG animals, prophylactic application of systemic IVIg led to a reduced median disease score of 2.4 on a 0–10 scale, in comparison to 4.1 with sham treatment. Therapeutic IVIg, applied systemically after the 10th intrathecal NMO-IgG injection, significantly reduced the disease score by 0.8. Intrathecal IVIg application induced a beneficial effect in animals with NMO-IgG (median score IVIg 1.6 vs. sham 3.7) or with rAB-AQP4 (median score IVIg 2.0 vs. sham 3.7). We here provide evidence that treatment with IVIg ameliorates disease symptoms in this passive-transfer model, in analogy to former studies investigating passive-transfer animal models of other antibody-mediated disorders.

No MeSH data available.


Schematic illustration of the study design. Repetitive intrathecal (i.th) application of purified patient IgG from two different patients (red and orange), recombinant human AQP4-ABs (rAB-AQP4, yellow), or control IgG (white), were performed in 3 series of five daily applications and 2 two-day breaks in between (3 weeks injection period in total). In a preventive, systemic strategy, pooled human immunoglobulin (IVIg) was applied intraperitoneally (i.p., blue). To test the therapeutic effect of IVIg in our model, IVIg was applied systemically only during the third series of i.th. passive transfer (purple). In a third approach, testing for direct antagonizing effects, IVIg was co-administered from the beginning of the experiments in an i.th. regime (green) immediately following injection of the pathogenic NMO immunoglobulin G fraction (NMO-IgG) or rAB-AQP4.
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ijms-17-01407-f001: Schematic illustration of the study design. Repetitive intrathecal (i.th) application of purified patient IgG from two different patients (red and orange), recombinant human AQP4-ABs (rAB-AQP4, yellow), or control IgG (white), were performed in 3 series of five daily applications and 2 two-day breaks in between (3 weeks injection period in total). In a preventive, systemic strategy, pooled human immunoglobulin (IVIg) was applied intraperitoneally (i.p., blue). To test the therapeutic effect of IVIg in our model, IVIg was applied systemically only during the third series of i.th. passive transfer (purple). In a third approach, testing for direct antagonizing effects, IVIg was co-administered from the beginning of the experiments in an i.th. regime (green) immediately following injection of the pathogenic NMO immunoglobulin G fraction (NMO-IgG) or rAB-AQP4.

Mentions: We set up a series of experiments, inducing a mild myelopathy through i.th. injection of the pathogenic NMO-IgG containing anti-AQP4-ABs. Therapeutic human IVIg was given to rats at different time points of the passive transfer, either co-administered intraperitoneally (i.p.) from onset of passive transfer (preventive strategy) or after the 10th i.th. injection at the height of the experimental disease (therapeutic strategy) (Figure 1). We used purified IgG from two different NMOSD patients or specific recombinant human AQP4-ABs (rAB-AQP4; Figure 1). As a third strategy, we tested the efficacy of IVIg when co-administrated with i.th., immediately following i.th. application of pathogenic NMO-IgG.


Efficacy of Polyvalent Human Immunoglobulins in an Animal Model of Neuromyelitis Optica Evoked by Intrathecal Anti-Aquaporin 4 Antibodies
Schematic illustration of the study design. Repetitive intrathecal (i.th) application of purified patient IgG from two different patients (red and orange), recombinant human AQP4-ABs (rAB-AQP4, yellow), or control IgG (white), were performed in 3 series of five daily applications and 2 two-day breaks in between (3 weeks injection period in total). In a preventive, systemic strategy, pooled human immunoglobulin (IVIg) was applied intraperitoneally (i.p., blue). To test the therapeutic effect of IVIg in our model, IVIg was applied systemically only during the third series of i.th. passive transfer (purple). In a third approach, testing for direct antagonizing effects, IVIg was co-administered from the beginning of the experiments in an i.th. regime (green) immediately following injection of the pathogenic NMO immunoglobulin G fraction (NMO-IgG) or rAB-AQP4.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC5037687&req=5

ijms-17-01407-f001: Schematic illustration of the study design. Repetitive intrathecal (i.th) application of purified patient IgG from two different patients (red and orange), recombinant human AQP4-ABs (rAB-AQP4, yellow), or control IgG (white), were performed in 3 series of five daily applications and 2 two-day breaks in between (3 weeks injection period in total). In a preventive, systemic strategy, pooled human immunoglobulin (IVIg) was applied intraperitoneally (i.p., blue). To test the therapeutic effect of IVIg in our model, IVIg was applied systemically only during the third series of i.th. passive transfer (purple). In a third approach, testing for direct antagonizing effects, IVIg was co-administered from the beginning of the experiments in an i.th. regime (green) immediately following injection of the pathogenic NMO immunoglobulin G fraction (NMO-IgG) or rAB-AQP4.
Mentions: We set up a series of experiments, inducing a mild myelopathy through i.th. injection of the pathogenic NMO-IgG containing anti-AQP4-ABs. Therapeutic human IVIg was given to rats at different time points of the passive transfer, either co-administered intraperitoneally (i.p.) from onset of passive transfer (preventive strategy) or after the 10th i.th. injection at the height of the experimental disease (therapeutic strategy) (Figure 1). We used purified IgG from two different NMOSD patients or specific recombinant human AQP4-ABs (rAB-AQP4; Figure 1). As a third strategy, we tested the efficacy of IVIg when co-administrated with i.th., immediately following i.th. application of pathogenic NMO-IgG.

View Article: PubMed Central - PubMed

ABSTRACT

Neuromyelitis Optica Spectrum Disorders (NMOSD) are associated with autoantibodies (ABs) targeting the astrocytic aquaporin-4 water channels (AQP4-ABs). These ABs have a direct pathogenic role by initiating a variety of immunological and inflammatory processes in the course of disease. In a recently-established animal model, chronic intrathecal passive-transfer of immunoglobulin G from NMOSD patients (NMO-IgG), or of recombinant human AQP4-ABs (rAB-AQP4), provided evidence for complementary and immune-cell independent effects of AQP4-ABs. Utilizing this animal model, we here tested the effects of systemically and intrathecally applied pooled human immunoglobulins (IVIg) using a preventive and a therapeutic paradigm. In NMO-IgG animals, prophylactic application of systemic IVIg led to a reduced median disease score of 2.4 on a 0–10 scale, in comparison to 4.1 with sham treatment. Therapeutic IVIg, applied systemically after the 10th intrathecal NMO-IgG injection, significantly reduced the disease score by 0.8. Intrathecal IVIg application induced a beneficial effect in animals with NMO-IgG (median score IVIg 1.6 vs. sham 3.7) or with rAB-AQP4 (median score IVIg 2.0 vs. sham 3.7). We here provide evidence that treatment with IVIg ameliorates disease symptoms in this passive-transfer model, in analogy to former studies investigating passive-transfer animal models of other antibody-mediated disorders.

No MeSH data available.