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

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.


Related in: MedlinePlus

Effects of preventive and therapeutic systemic injections of IVIg. (a) Repetitive i.th. injections of NMO-IgG 1 led to development of disease symptoms (NMO score). The NMO-score of the NMO-IgG injected animals (red circles) increased over the experimental period and reached a plateau phase at the end of i.th. injections. The progression of the disease was slowed by concurrent i.p. application of IVIg (blue circles). Rats of the therapeutic IVIg group, receiving IVIg i.p. later, i.e., starting at day 15 (purple circles), developed comparable disease symptoms as the animals of NMO-IgG 1 (red) in before IVIg was given. After starting the IVIg injections on day 15, the NMO-score decreases over the 5 following injection days. Control IgG injected animals showed only minor abnormalities from the start (white circles). Breaks on the X-axis indicate 2 day-pauses of NMO-IgG injections. Two-way ANOVA with Bonferroni post hoc tests revealed significant differences of all groups vs. the group receiving control IgG (p < 0.001) and the group of NMO 1 vs. NMO1 + IVIg i.p. day 0 (p < 0.001); (b) the median NMO-score determined from the score values over the entire experiment were significantly lower when i.p. injections of IVIg were given prophylactically (one-way ANOVA, Bonferroni post hoc test; * p < 0.05; *** p ≤ 0.001; plots show median ± 25th and 75th percentiles with whiskers of the 5th and 95th percentiles); (c) the treatment group receiving IVIg in the therapeutic paradigm from day 15 showed a reduction of the NMO score beginning with the 11th injection while the NMO score still slightly increases in the untreated and the prophylactic treatment group but there it remained at a lower final score level (one-way ANOVA Bonferroni post hoc test, * p < 0.05; plots show median ± 25th and 75th percentiles with whiskers of the 5th and 95th percentiles).
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC5037687&req=5

ijms-17-01407-f002: Effects of preventive and therapeutic systemic injections of IVIg. (a) Repetitive i.th. injections of NMO-IgG 1 led to development of disease symptoms (NMO score). The NMO-score of the NMO-IgG injected animals (red circles) increased over the experimental period and reached a plateau phase at the end of i.th. injections. The progression of the disease was slowed by concurrent i.p. application of IVIg (blue circles). Rats of the therapeutic IVIg group, receiving IVIg i.p. later, i.e., starting at day 15 (purple circles), developed comparable disease symptoms as the animals of NMO-IgG 1 (red) in before IVIg was given. After starting the IVIg injections on day 15, the NMO-score decreases over the 5 following injection days. Control IgG injected animals showed only minor abnormalities from the start (white circles). Breaks on the X-axis indicate 2 day-pauses of NMO-IgG injections. Two-way ANOVA with Bonferroni post hoc tests revealed significant differences of all groups vs. the group receiving control IgG (p < 0.001) and the group of NMO 1 vs. NMO1 + IVIg i.p. day 0 (p < 0.001); (b) the median NMO-score determined from the score values over the entire experiment were significantly lower when i.p. injections of IVIg were given prophylactically (one-way ANOVA, Bonferroni post hoc test; * p < 0.05; *** p ≤ 0.001; plots show median ± 25th and 75th percentiles with whiskers of the 5th and 95th percentiles); (c) the treatment group receiving IVIg in the therapeutic paradigm from day 15 showed a reduction of the NMO score beginning with the 11th injection while the NMO score still slightly increases in the untreated and the prophylactic treatment group but there it remained at a lower final score level (one-way ANOVA Bonferroni post hoc test, * p < 0.05; plots show median ± 25th and 75th percentiles with whiskers of the 5th and 95th percentiles).

Mentions: Repetitive i.th. applications of the two patient IgG fractions, NMO-IgG 1 and NMO-IgG 2, led to progressive disease symptoms in rats, starting with motor abnormalities and unilateral hindlimb weakness, up to paraplegia in some severely afflicted rats, thus confirming our previous reports with different NMO-IgG preparations (Figure 2a) [10]. Rats injected with control IgG showed no abnormalities or only minor effects. In the first preventive treatment experiment, IVIg was administered i.p. from the beginning of the i.th. passive-transfer injection series of NMO-IgG. IVIg treatment led to a delay of severe disease signs and a lower disease score at the end of the experiment (Figure 2a). The disease score over the whole period of the IVIg-treated group was significantly reduced when compared to the NMO-IgG injected group without concomitant IVIg application (Figure 2b).


Efficacy of Polyvalent Human Immunoglobulins in an Animal Model of Neuromyelitis Optica Evoked by Intrathecal Anti-Aquaporin 4 Antibodies
Effects of preventive and therapeutic systemic injections of IVIg. (a) Repetitive i.th. injections of NMO-IgG 1 led to development of disease symptoms (NMO score). The NMO-score of the NMO-IgG injected animals (red circles) increased over the experimental period and reached a plateau phase at the end of i.th. injections. The progression of the disease was slowed by concurrent i.p. application of IVIg (blue circles). Rats of the therapeutic IVIg group, receiving IVIg i.p. later, i.e., starting at day 15 (purple circles), developed comparable disease symptoms as the animals of NMO-IgG 1 (red) in before IVIg was given. After starting the IVIg injections on day 15, the NMO-score decreases over the 5 following injection days. Control IgG injected animals showed only minor abnormalities from the start (white circles). Breaks on the X-axis indicate 2 day-pauses of NMO-IgG injections. Two-way ANOVA with Bonferroni post hoc tests revealed significant differences of all groups vs. the group receiving control IgG (p < 0.001) and the group of NMO 1 vs. NMO1 + IVIg i.p. day 0 (p < 0.001); (b) the median NMO-score determined from the score values over the entire experiment were significantly lower when i.p. injections of IVIg were given prophylactically (one-way ANOVA, Bonferroni post hoc test; * p < 0.05; *** p ≤ 0.001; plots show median ± 25th and 75th percentiles with whiskers of the 5th and 95th percentiles); (c) the treatment group receiving IVIg in the therapeutic paradigm from day 15 showed a reduction of the NMO score beginning with the 11th injection while the NMO score still slightly increases in the untreated and the prophylactic treatment group but there it remained at a lower final score level (one-way ANOVA Bonferroni post hoc test, * p < 0.05; plots show median ± 25th and 75th percentiles with whiskers of the 5th and 95th percentiles).
© Copyright Policy
Related In: Results  -  Collection

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

ijms-17-01407-f002: Effects of preventive and therapeutic systemic injections of IVIg. (a) Repetitive i.th. injections of NMO-IgG 1 led to development of disease symptoms (NMO score). The NMO-score of the NMO-IgG injected animals (red circles) increased over the experimental period and reached a plateau phase at the end of i.th. injections. The progression of the disease was slowed by concurrent i.p. application of IVIg (blue circles). Rats of the therapeutic IVIg group, receiving IVIg i.p. later, i.e., starting at day 15 (purple circles), developed comparable disease symptoms as the animals of NMO-IgG 1 (red) in before IVIg was given. After starting the IVIg injections on day 15, the NMO-score decreases over the 5 following injection days. Control IgG injected animals showed only minor abnormalities from the start (white circles). Breaks on the X-axis indicate 2 day-pauses of NMO-IgG injections. Two-way ANOVA with Bonferroni post hoc tests revealed significant differences of all groups vs. the group receiving control IgG (p < 0.001) and the group of NMO 1 vs. NMO1 + IVIg i.p. day 0 (p < 0.001); (b) the median NMO-score determined from the score values over the entire experiment were significantly lower when i.p. injections of IVIg were given prophylactically (one-way ANOVA, Bonferroni post hoc test; * p < 0.05; *** p ≤ 0.001; plots show median ± 25th and 75th percentiles with whiskers of the 5th and 95th percentiles); (c) the treatment group receiving IVIg in the therapeutic paradigm from day 15 showed a reduction of the NMO score beginning with the 11th injection while the NMO score still slightly increases in the untreated and the prophylactic treatment group but there it remained at a lower final score level (one-way ANOVA Bonferroni post hoc test, * p < 0.05; plots show median ± 25th and 75th percentiles with whiskers of the 5th and 95th percentiles).
Mentions: Repetitive i.th. applications of the two patient IgG fractions, NMO-IgG 1 and NMO-IgG 2, led to progressive disease symptoms in rats, starting with motor abnormalities and unilateral hindlimb weakness, up to paraplegia in some severely afflicted rats, thus confirming our previous reports with different NMO-IgG preparations (Figure 2a) [10]. Rats injected with control IgG showed no abnormalities or only minor effects. In the first preventive treatment experiment, IVIg was administered i.p. from the beginning of the i.th. passive-transfer injection series of NMO-IgG. IVIg treatment led to a delay of severe disease signs and a lower disease score at the end of the experiment (Figure 2a). The disease score over the whole period of the IVIg-treated group was significantly reduced when compared to the NMO-IgG injected group without concomitant IVIg application (Figure 2b).

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.


Related in: MedlinePlus