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Anti-4-1BB monoclonal antibodies abrogate T cell-dependent humoral immune responses in vivo through the induction of helper T cell anergy.

Mittler RS, Bailey TS, Klussman K, Trailsmith MD, Hoffmann MK - J. Exp. Med. (1999)

Bottom Line: Here we show that anti-mouse 4-1BB monoclonal antibodies (mAbs) inhibit thymus-dependent antibody production by B cells.The immune response to the type II T cell-independent antigen trinintrophenol-conjugated Ficoll, however, was not suppressed.Inhibition of humoral immunity occurred only when anti-4-1BB mAb was given within 1 wk after immunization.

View Article: PubMed Central - PubMed

Affiliation: Bristol-Myers Squibb Pharmaceutical Research Institute, Department of Immunology and Transplantation, Seattle, Washington 98121, USA. Rmittler26@aol.com

ABSTRACT
The 4-1BB receptor (CDw137), a member of the tumor necrosis factor receptor superfamily, has been shown to costimulate the activation of T cells. Here we show that anti-mouse 4-1BB monoclonal antibodies (mAbs) inhibit thymus-dependent antibody production by B cells. Injection of anti-4-1BB mAbs into mice being immunized with cellular or soluble protein antigens induced long-term anergy of antigen-specific T cells. The immune response to the type II T cell-independent antigen trinintrophenol-conjugated Ficoll, however, was not suppressed. Inhibition of humoral immunity occurred only when anti-4-1BB mAb was given within 1 wk after immunization. Anti-4-1BB inhibition was observed in mice lacking functional CD8(+) T cells, indicating that CD8(+) T cells were not required for the induction of anergy. Analysis of the requirements for the anti-4-1BB-mediated inhibition of humoral immunity revealed that suppression could not be adoptively transferred with T cells from anti-4-1BB-treated mice. Transfer of BALB/c splenic T cells from sheep red blood cell (SRBC)-immunized and anti-4-1BB-treated mice together with normal BALB/c B cells into C.B-17 severe combined immunodeficient mice failed to generate an anti-SRBC response. However, B cells from the SRBC-immunized, anti-4-1BB-treated BALB/c mice, together with normal naive T cells, exhibited a normal humoral immune response against SRBC after transfer, demonstrating that SRBC-specific B cells were left unaffected by anti-4-1BB mAbs.

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Pharmacokinetics of 1D8 mAbs. Serum levels of anti–4-1BB mAbs at varying time points were determined by ELISA. Five 8–12-wk-old female BALB/c mice were given four doses of 200 mg of 1D8 mAb intravenously on days 0, 2, 4, and 6. At the indicated times, sera were collected from each mouse, and the concentration of serum 1D8 was determined by measuring its binding to 4-1BB–huIgG1 fusion protein immobilized on ELISA plates and comparing the results to those obtained from a standard curve generated using purified 1D8 mAb. The figure shows the clearance rates of five mice. Each assay was carried out in triplicate. Serum concentrations at various time points were determined as described. The results are shown as the mean ± SD of three mice.
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Figure 1: Pharmacokinetics of 1D8 mAbs. Serum levels of anti–4-1BB mAbs at varying time points were determined by ELISA. Five 8–12-wk-old female BALB/c mice were given four doses of 200 mg of 1D8 mAb intravenously on days 0, 2, 4, and 6. At the indicated times, sera were collected from each mouse, and the concentration of serum 1D8 was determined by measuring its binding to 4-1BB–huIgG1 fusion protein immobilized on ELISA plates and comparing the results to those obtained from a standard curve generated using purified 1D8 mAb. The figure shows the clearance rates of five mice. Each assay was carried out in triplicate. Serum concentrations at various time points were determined as described. The results are shown as the mean ± SD of three mice.

Mentions: We analyzed the serum half-life of all of our anti–4-1BB mAbs by pharmacokinetic analysis. 200 μg of the rat (IgG2A) mAb 1D8 was injected intravenously into the tail vein on days 0, 2, 4, and 6 into five mice. The mice were periodically bled, and serum levels of rat IgG2A were determined in triplicate by ELISA for each mouse and expressed as the mean ± SD. The serum half-life of anti–4-1BB mAb 1D8 was found to be 7.5 d (Fig. 1). Identical data were obtained for 12 other rat IgG2A isotype anti–4-1BB mAbs tested.


Anti-4-1BB monoclonal antibodies abrogate T cell-dependent humoral immune responses in vivo through the induction of helper T cell anergy.

Mittler RS, Bailey TS, Klussman K, Trailsmith MD, Hoffmann MK - J. Exp. Med. (1999)

Pharmacokinetics of 1D8 mAbs. Serum levels of anti–4-1BB mAbs at varying time points were determined by ELISA. Five 8–12-wk-old female BALB/c mice were given four doses of 200 mg of 1D8 mAb intravenously on days 0, 2, 4, and 6. At the indicated times, sera were collected from each mouse, and the concentration of serum 1D8 was determined by measuring its binding to 4-1BB–huIgG1 fusion protein immobilized on ELISA plates and comparing the results to those obtained from a standard curve generated using purified 1D8 mAb. The figure shows the clearance rates of five mice. Each assay was carried out in triplicate. Serum concentrations at various time points were determined as described. The results are shown as the mean ± SD of three mice.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2195697&req=5

Figure 1: Pharmacokinetics of 1D8 mAbs. Serum levels of anti–4-1BB mAbs at varying time points were determined by ELISA. Five 8–12-wk-old female BALB/c mice were given four doses of 200 mg of 1D8 mAb intravenously on days 0, 2, 4, and 6. At the indicated times, sera were collected from each mouse, and the concentration of serum 1D8 was determined by measuring its binding to 4-1BB–huIgG1 fusion protein immobilized on ELISA plates and comparing the results to those obtained from a standard curve generated using purified 1D8 mAb. The figure shows the clearance rates of five mice. Each assay was carried out in triplicate. Serum concentrations at various time points were determined as described. The results are shown as the mean ± SD of three mice.
Mentions: We analyzed the serum half-life of all of our anti–4-1BB mAbs by pharmacokinetic analysis. 200 μg of the rat (IgG2A) mAb 1D8 was injected intravenously into the tail vein on days 0, 2, 4, and 6 into five mice. The mice were periodically bled, and serum levels of rat IgG2A were determined in triplicate by ELISA for each mouse and expressed as the mean ± SD. The serum half-life of anti–4-1BB mAb 1D8 was found to be 7.5 d (Fig. 1). Identical data were obtained for 12 other rat IgG2A isotype anti–4-1BB mAbs tested.

Bottom Line: Here we show that anti-mouse 4-1BB monoclonal antibodies (mAbs) inhibit thymus-dependent antibody production by B cells.The immune response to the type II T cell-independent antigen trinintrophenol-conjugated Ficoll, however, was not suppressed.Inhibition of humoral immunity occurred only when anti-4-1BB mAb was given within 1 wk after immunization.

View Article: PubMed Central - PubMed

Affiliation: Bristol-Myers Squibb Pharmaceutical Research Institute, Department of Immunology and Transplantation, Seattle, Washington 98121, USA. Rmittler26@aol.com

ABSTRACT
The 4-1BB receptor (CDw137), a member of the tumor necrosis factor receptor superfamily, has been shown to costimulate the activation of T cells. Here we show that anti-mouse 4-1BB monoclonal antibodies (mAbs) inhibit thymus-dependent antibody production by B cells. Injection of anti-4-1BB mAbs into mice being immunized with cellular or soluble protein antigens induced long-term anergy of antigen-specific T cells. The immune response to the type II T cell-independent antigen trinintrophenol-conjugated Ficoll, however, was not suppressed. Inhibition of humoral immunity occurred only when anti-4-1BB mAb was given within 1 wk after immunization. Anti-4-1BB inhibition was observed in mice lacking functional CD8(+) T cells, indicating that CD8(+) T cells were not required for the induction of anergy. Analysis of the requirements for the anti-4-1BB-mediated inhibition of humoral immunity revealed that suppression could not be adoptively transferred with T cells from anti-4-1BB-treated mice. Transfer of BALB/c splenic T cells from sheep red blood cell (SRBC)-immunized and anti-4-1BB-treated mice together with normal BALB/c B cells into C.B-17 severe combined immunodeficient mice failed to generate an anti-SRBC response. However, B cells from the SRBC-immunized, anti-4-1BB-treated BALB/c mice, together with normal naive T cells, exhibited a normal humoral immune response against SRBC after transfer, demonstrating that SRBC-specific B cells were left unaffected by anti-4-1BB mAbs.

Show MeSH
Related in: MedlinePlus