Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
, 117 (3), 402-8

Blockade of OX40-ligand After Initial Triggering of the T Helper 2 Response Inhibits Mercuric Chloride-Induced Autoimmunity

Affiliations

Blockade of OX40-ligand After Initial Triggering of the T Helper 2 Response Inhibits Mercuric Chloride-Induced Autoimmunity

Iain A M MacPhee et al. Immunology.

Abstract

Mercuric chloride (HgCl2)-induced autoimmunity in Brown Norway rats is a spontaneously resolving autoimmune response driven by the activation of T helper type 2 lymphocytes (Th2 cells). Treatment with antibody to OX40-ligand (OX40-L) from the time of the first HgCl2 injection for 12 days had little effect. Delayed treatment commenced 8 days after the first HgCl2 injection significantly suppressed immunoglobulin E production, splenomegaly, weight loss and mortality. This makes OX40/OX40-L signalling an attractive therapeutic target for Th2-driven autoimmune diseases. Intravenous administration of the murine antibody to OX-40-L elicited a vigorous anti-mouse immunoglobulin antibody response that was significantly enhanced compared to the response to control immunoglobulin. It is likely that this response significantly reduced the plasma half-life of the anti-OX40-L antibody and this observation has clear implications for the interpretation of data from experiments where anti-OX40-L is used in vivo.

Figures

Figure 1
Figure 1
Early treatment with anti-OX40-L antibody had no effect on serum IgE concentrations. Serum IgE concentrations are shown for groups of nine animals pooled from two identical experiments treated with MOPC (isotype control immunoglobulin, closed circles) or anti-OX40-L (open circles) 100 µg intravenously on days 0, 1, 2, 4, 6, 8, 10 and 12. There was no statistically significant difference between the groups.
Figure 2
Figure 2
Late treatment with anti-OX40-L antibody suppressed IgE production. Serum IgE concentrations are shown for groups of 10 animals pooled from two identical experiments treated with MOPC (isotype control immunoglobulin, closed circles) or anti-OX40-L (open circles) 100 µg intravenously on days 8, 9, 10, 12, 14, 16, 18, 20. Difference between the groups was tested by repeated measures anova on log-transformed data: P = 0·006.
Figure 3
Figure 3
Late treatment with anti-OX40-L antibody suppressed lymphoproliferation. Spleen weights are shown for animals pooled from three separate experiments with similar design where animals were treated with MOPC, anti-OX40-L 100 µg intravenously or anti-CD80+CD86 (100 µg of each antibody) on days 8, 9, 10, 12, 14, 16, 18 and 20. Median values are indicated. The only statistically significant difference by Kruskall–Wallis anova was between the MOPC and anti-OX40-L-treated groups (P = 0·008).
Figure 7
Figure 7
Absence of synergy between late blockade of OX40-L and CD80/CD86. Serum IgE concentrations are shown for groups of five animals from a single experiment treated with antibodies from day 8: MOPC (closed circles), anti-OX40-L (open circles), CD80 plus CD86 (closed triangles) or anti-OX40-L plus CD80 plus CD86 (open triangles). Repeated measures anova on log-transformed data: anti-OX40-L versus MOPC (P = 0·003). There was no difference between anti-OX40-L-treated animals with or without CD80 and CD86 antibodies.
Figure 4
Figure 4
Late treatment with anti-OX40-L antibody reduced weight loss. The percentage weight on day 8 after the first HgCl2 injection (mean ± SEM) are shown for groups of 10 animals pooled from two identical experiments treated with MOPC (closed circles) or anti-OX40-L (open circles) from day 8. Difference between the groups was tested by repeated measures anova: P = 0·036.
Figure 5
Figure 5
Enhanced anti-mouse immunoglobulin antibody response to anti-OX40-LRepresentative raw data are presented in (a). Titres were related to a standard serum from mercuric chloride-treated animals injected intravenously with murine immunoglobulin (closed triangles) with serum from a non-immunized rat as a negative control (open triangles). Calculated values are shown for serum from animals treated with MOPC from day 8 (open squares), anti-OX40-L from day 0 (open circles) and anti-OX40-L from day 8 (closed squares) collected on day 20 and assayed on a single ELISA plate. Data for groups of five animals from a single experiment which has been repeated with similar results are shown in (b). All animals were injected with HgCl2. Antibody treatment groups are shown by: MOPC from day 0 (closed circles), MOPC from day 8 (open squares), anti-OX40-L from day 0 (open circles), anti-OX40-L from day 8 (closed squares).
Figure 6
Figure 6
Treatment with anti-OX40-L improved survival. Kaplan–Meier survival data are shown for animals injected with HgCl2 and MOPC (solid line, n = 27), anti-OX40-L from day 0 (dotted line, n = 9) or anti-OX40-L from day 8 (dashed line, n = 19). Treatment with anti-OX40-L from day 8 was significantly different from control (log-rank P < 0·02). The data shown were pooled from six independent experiments with identical experimental design.

Similar articles

See all similar articles

Cited by 2 articles

MeSH terms

Feedback