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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.


i.th. application of IVIg attenuates NMO-IgG 2 induced disease symptoms. (a) IVIg co-administered i.th. from day 1 of i.th. application of NMO-IgG delayed the onset and reduced the severity of disease symptoms (Two-way ANOVA with Bonferroni post hoc test p < 0.001 for group comparison). Breaks on the X-axis indicate 2 day-pauses of NMO-IgG; (b) the median disease score over the entire experiment was significantly smaller in the animals treated with i.th. IVIg (Mann-Whitney U test, * p ≤ 0.05; plots show median ± 25th and 75th percentiles with whiskers of the 5th and 95th percentiles).
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ijms-17-01407-f003: i.th. application of IVIg attenuates NMO-IgG 2 induced disease symptoms. (a) IVIg co-administered i.th. from day 1 of i.th. application of NMO-IgG delayed the onset and reduced the severity of disease symptoms (Two-way ANOVA with Bonferroni post hoc test p < 0.001 for group comparison). Breaks on the X-axis indicate 2 day-pauses of NMO-IgG; (b) the median disease score over the entire experiment was significantly smaller in the animals treated with i.th. IVIg (Mann-Whitney U test, * p ≤ 0.05; plots show median ± 25th and 75th percentiles with whiskers of the 5th and 95th percentiles).

Mentions: IVIg may act by a multitude of mechanisms, including direct interaction with pathogenic IgG ABs, e.g., by anti-idiotypic effects, steric hindrance, or increased catabolism. To test local effects on the ABs in the i.th. passive-transfer rat model, IVIg was co-administered by i.th. injection immediately after applying the pathogenic IgG fractions containing ABs to AQP4. When applying NMO-IgG 2 together with IVIg i.th., disease progression was delayed and disease scores were reduced (Figure 3). To validate AB-specificity of this finding, we used specific rAB-AQP4 as the pathogen in passive-transfer experiments. In line with previous studies, i.th. application of rAB-AQP4 led to induction of similar disease signs as NMO-IgG. Upon adding i.th. IVIg, we found similar beneficial effects on disease progression and severity, as seen with patient NMO-IgG (Figure 4).


Efficacy of Polyvalent Human Immunoglobulins in an Animal Model of Neuromyelitis Optica Evoked by Intrathecal Anti-Aquaporin 4 Antibodies
i.th. application of IVIg attenuates NMO-IgG 2 induced disease symptoms. (a) IVIg co-administered i.th. from day 1 of i.th. application of NMO-IgG delayed the onset and reduced the severity of disease symptoms (Two-way ANOVA with Bonferroni post hoc test p < 0.001 for group comparison). Breaks on the X-axis indicate 2 day-pauses of NMO-IgG; (b) the median disease score over the entire experiment was significantly smaller in the animals treated with i.th. IVIg (Mann-Whitney U test, * p ≤ 0.05; plots show median ± 25th and 75th percentiles with whiskers of the 5th and 95th percentiles).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC5037687&req=5

ijms-17-01407-f003: i.th. application of IVIg attenuates NMO-IgG 2 induced disease symptoms. (a) IVIg co-administered i.th. from day 1 of i.th. application of NMO-IgG delayed the onset and reduced the severity of disease symptoms (Two-way ANOVA with Bonferroni post hoc test p < 0.001 for group comparison). Breaks on the X-axis indicate 2 day-pauses of NMO-IgG; (b) the median disease score over the entire experiment was significantly smaller in the animals treated with i.th. IVIg (Mann-Whitney U test, * p ≤ 0.05; plots show median ± 25th and 75th percentiles with whiskers of the 5th and 95th percentiles).
Mentions: IVIg may act by a multitude of mechanisms, including direct interaction with pathogenic IgG ABs, e.g., by anti-idiotypic effects, steric hindrance, or increased catabolism. To test local effects on the ABs in the i.th. passive-transfer rat model, IVIg was co-administered by i.th. injection immediately after applying the pathogenic IgG fractions containing ABs to AQP4. When applying NMO-IgG 2 together with IVIg i.th., disease progression was delayed and disease scores were reduced (Figure 3). To validate AB-specificity of this finding, we used specific rAB-AQP4 as the pathogen in passive-transfer experiments. In line with previous studies, i.th. application of rAB-AQP4 led to induction of similar disease signs as NMO-IgG. Upon adding i.th. IVIg, we found similar beneficial effects on disease progression and severity, as seen with patient NMO-IgG (Figure 4).

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&ndash;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.