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Differential clinical efficacy of anti-CD4 monoclonal antibodies in rat adjuvant arthritis is paralleled by differential influence on NF-kappaB binding activity and TNF-alpha secretion of T cells.

Pohlers D, Schmidt-Weber CB, Franch A, Kuhlmann J, Bräuer R, Emmrich F, Kinne RW - Arthritis Res. (2002)

Bottom Line: The in vitro effects of anti-CD4 preincubation on T-cell receptor (TCR)/CD3-induced cytokine production and signal transduction were also analyzed.Differential clinical effects at the onset of AA were paralleled by a differential influence of the mAbs on T-cell functions, i.e. in comparison with OX35 and W3/25, the 'accelerating' mAb RIB5/2 failed to increase the delayed-type hypersentivity (DTH) to Mycobacterium tuberculosis, increased the in vitro tumor necrosis factor (TNF)-alpha secretion, and more strongly induced NF-kappaB binding activity after anti-CD4 preincubation and subsequent TCR/CD3-stimulation.This fine regulation may explain the differential efficacy in the treatment of AA and may contribute to the understanding of such treatments in other immunopathologies.

View Article: PubMed Central - PubMed

Affiliation: Experimental Rheumatology Unit, Friedrich Schiller University, Jena, Germany.

ABSTRACT
The aim of this study was to analyze the differential effects of three anti-CD4 monoclonal antibodies (mAbs) (with distinct epitope specifities) in the treatment of rat adjuvant arthritis (AA) and on T-cell function and signal transduction. Rat AA was preventively treated by intraperitoneal injection of the anti-CD4 mAbs W3/25, OX35, and RIB5/2 (on days -1, 0, 3, and 6, i.e. 1 day before AA induction, on the day of induction [day 0], and thereafter). The effects on T-cell reactivity in vivo (delayed-type hypersensitivity), ex vivo (ConA-induced proliferation), and in vitro (mixed lymphocyte culture) were assessed. The in vitro effects of anti-CD4 preincubation on T-cell receptor (TCR)/CD3-induced cytokine production and signal transduction were also analyzed. While preventive treatment with OX35 and W3/25 significantly ameliorated AA from the onset, treatment with RIB5/2 even accelerated the onset of AA by approximately 2 days (day 10), and ameliorated the arthritis only in the late phase (day 27). Differential clinical effects at the onset of AA were paralleled by a differential influence of the mAbs on T-cell functions, i.e. in comparison with OX35 and W3/25, the 'accelerating' mAb RIB5/2 failed to increase the delayed-type hypersentivity (DTH) to Mycobacterium tuberculosis, increased the in vitro tumor necrosis factor (TNF)-alpha secretion, and more strongly induced NF-kappaB binding activity after anti-CD4 preincubation and subsequent TCR/CD3-stimulation. Depending on their epitope specificity, different anti-CD4 mAbs differentially influence individual proinflammatory functions of T cells. This fine regulation may explain the differential efficacy in the treatment of AA and may contribute to the understanding of such treatments in other immunopathologies.

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Concanavalin A (ConA) reactivity of total spleen T cells (day 13 of adjuvant arthritis) from rats preventively treated with anti-CD4 mAbs. Proliferation data from two individual animals of each treatment group are expressed as means ± SEM of triplicate cultures from one in vivo experiment. The corresponding arthritis score for the animals is shown below the graph.
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Figure 3: Concanavalin A (ConA) reactivity of total spleen T cells (day 13 of adjuvant arthritis) from rats preventively treated with anti-CD4 mAbs. Proliferation data from two individual animals of each treatment group are expressed as means ± SEM of triplicate cultures from one in vivo experiment. The corresponding arthritis score for the animals is shown below the graph.

Mentions: Upon stimulation with concanavalin A (ConA), total T cells from RIB5/2-treated animals showed lower proliferation rates than those from W3/25- or OX35-treated rats (Supplementary Fig. 2). In the mixed lymphocyte culture, RIB5/2 was also the most potent inhibitor of T-cell activation in the case of total T cells; however, this was not observed in purified CD4+ T cells (Supplementary Fig. 4).


Differential clinical efficacy of anti-CD4 monoclonal antibodies in rat adjuvant arthritis is paralleled by differential influence on NF-kappaB binding activity and TNF-alpha secretion of T cells.

Pohlers D, Schmidt-Weber CB, Franch A, Kuhlmann J, Bräuer R, Emmrich F, Kinne RW - Arthritis Res. (2002)

Concanavalin A (ConA) reactivity of total spleen T cells (day 13 of adjuvant arthritis) from rats preventively treated with anti-CD4 mAbs. Proliferation data from two individual animals of each treatment group are expressed as means ± SEM of triplicate cultures from one in vivo experiment. The corresponding arthritis score for the animals is shown below the graph.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC111020&req=5

Figure 3: Concanavalin A (ConA) reactivity of total spleen T cells (day 13 of adjuvant arthritis) from rats preventively treated with anti-CD4 mAbs. Proliferation data from two individual animals of each treatment group are expressed as means ± SEM of triplicate cultures from one in vivo experiment. The corresponding arthritis score for the animals is shown below the graph.
Mentions: Upon stimulation with concanavalin A (ConA), total T cells from RIB5/2-treated animals showed lower proliferation rates than those from W3/25- or OX35-treated rats (Supplementary Fig. 2). In the mixed lymphocyte culture, RIB5/2 was also the most potent inhibitor of T-cell activation in the case of total T cells; however, this was not observed in purified CD4+ T cells (Supplementary Fig. 4).

Bottom Line: The in vitro effects of anti-CD4 preincubation on T-cell receptor (TCR)/CD3-induced cytokine production and signal transduction were also analyzed.Differential clinical effects at the onset of AA were paralleled by a differential influence of the mAbs on T-cell functions, i.e. in comparison with OX35 and W3/25, the 'accelerating' mAb RIB5/2 failed to increase the delayed-type hypersentivity (DTH) to Mycobacterium tuberculosis, increased the in vitro tumor necrosis factor (TNF)-alpha secretion, and more strongly induced NF-kappaB binding activity after anti-CD4 preincubation and subsequent TCR/CD3-stimulation.This fine regulation may explain the differential efficacy in the treatment of AA and may contribute to the understanding of such treatments in other immunopathologies.

View Article: PubMed Central - PubMed

Affiliation: Experimental Rheumatology Unit, Friedrich Schiller University, Jena, Germany.

ABSTRACT
The aim of this study was to analyze the differential effects of three anti-CD4 monoclonal antibodies (mAbs) (with distinct epitope specifities) in the treatment of rat adjuvant arthritis (AA) and on T-cell function and signal transduction. Rat AA was preventively treated by intraperitoneal injection of the anti-CD4 mAbs W3/25, OX35, and RIB5/2 (on days -1, 0, 3, and 6, i.e. 1 day before AA induction, on the day of induction [day 0], and thereafter). The effects on T-cell reactivity in vivo (delayed-type hypersensitivity), ex vivo (ConA-induced proliferation), and in vitro (mixed lymphocyte culture) were assessed. The in vitro effects of anti-CD4 preincubation on T-cell receptor (TCR)/CD3-induced cytokine production and signal transduction were also analyzed. While preventive treatment with OX35 and W3/25 significantly ameliorated AA from the onset, treatment with RIB5/2 even accelerated the onset of AA by approximately 2 days (day 10), and ameliorated the arthritis only in the late phase (day 27). Differential clinical effects at the onset of AA were paralleled by a differential influence of the mAbs on T-cell functions, i.e. in comparison with OX35 and W3/25, the 'accelerating' mAb RIB5/2 failed to increase the delayed-type hypersentivity (DTH) to Mycobacterium tuberculosis, increased the in vitro tumor necrosis factor (TNF)-alpha secretion, and more strongly induced NF-kappaB binding activity after anti-CD4 preincubation and subsequent TCR/CD3-stimulation. Depending on their epitope specificity, different anti-CD4 mAbs differentially influence individual proinflammatory functions of T cells. This fine regulation may explain the differential efficacy in the treatment of AA and may contribute to the understanding of such treatments in other immunopathologies.

Show MeSH
Related in: MedlinePlus