Method to inhibit airway hyperresponsiveness using aerosolized t cell receptor antibodies

Abstract

Disclosed is a method to reduce airway hyperresponsivesness in an animal by the direct delivery to the lungs of aerosolized antibodies against T cell receptors. The method is particularly useful for treating airway hyperresponsiveness associated with allergic inflammation, is effective at extremely low doses of antibody, and does not have a substantial effect on the peripheral immune system.

Description

GOVERNMENT RIGHTS

[0001] This invention was supported, in part, by Grant Nos. R01 HL-65410; AI-40611; HL-36557; HL-61005; and R01 AI-44920, all awarded by the National Institutes of Health, and Grant No. R825702, awarded by the Environmental Protection Agency. The government has certain rights to this invention.FIELD OF THE INVENTION

[0002] This invention generally relates to the use of aerosolized antibodies against T cell receptors for the inhibition of airway hyperresponsiveness (AHR). Specifically, aerosolized antibodies against receptors on both αβ and γδ T cells are disclosed for the treatment of AHR.BACKGROUND OF THE INVENTION

[0003] A variety of inflammatory agents can provoke airflow limitation, including allergens, cold air, exercise, infections and air pollution. In particular, allergens and other agents in allergic or sensitized mammals (i.e., antigens and haptens) cause the release of inflammatory mediators that recruit cells involved in inflammation. Such cells include lymph...

Examples

example 1

[0095]The following example describes the comparison of aerosolized versus intravenously given mAbs against TCR-β in ovalbumin (OVA) sensitized and challenged mice.

[0096]The classical animal model of allergic inflammation (see, e.g., Takeda et al., (1997). J. Exp. Med, 186, 449-454; Renz et al., 1992, J. Allergy Clin. Immunol. 89:1127-1138; Larsen et al., 1992, J. Clin. Invest. 89:747-752; and Saloga et al., 1993, J. Clin. Invest. 91:133-141) was used to assess the ability of aerosolized mAbs to influence AHR. The present inventors and others have previously shown that αβ T cells are necessary for the development of allergic inflammation and airway hyperresponsiveness (AHR) (Holt, J. Exp. Med. 183:1297-1301 (1996); Lahn et al., Nature Med. 5:1150-6 (1999)). In this experiment, C57BL / 6 mice were injected twice with Alum / OVA intraperitoneally (sensitization) before a three day exposure to aerosolized OVA (challenge). The exact procedure has been previously published (Lahn et al., Natu...

example 2

[0101]The following example describes the comparison of aerosolized versus intravenously given mAbs against TCR-δ in ovalbumin (OVA) sensitized and challenged mice.

[0102]In this example, experiments were conducted as described in Example 1, but with the use of a mAb against TCR-δ (a 1:1 mixture of mAbs GL3 (Goodman et al., J. Exp. Med. 170:1569 (1989)) and 403A10 Itohara et al., Proc. Natl. Acad. Sci. USA 86:5094-5098 (1989)). As previously published (Lahn et al., Nature Med. 5:1150-6 (1999)), the intravenous injection of mAbs against TCR-δ (▾ in FIGS. 1C and 1D) caused only a slight increase in AHR when compared to 2ip3N treated C57BL / 6 mice in the absence of antibody (□ in FIGS. 1C and 1D). The significant differences between 2ip3N treated mice and 2ip3N mice treated with i.v. anti-TCR-δ are shown by “ω” in FIG. 1C. Again, the addition of 10 μg / ml of anti-TCR-δ to the last OVA aerosol application (▴ in FIGS. 1C and 1D) had a similar effect as the intravenous injection of the same ...

example 3

[0103]The following example describes the comparison of aerosolized mAbs against TCR-Vγ1 and TCR-Vγ4 in ovalbumin (OVA) sensitized and challenged mice.

[0104]Finally, the γδ T cell subsets Vγ1 and Vγ4 were examined for their contribution to the regulation of AHR. Experiments were performed as described in Examples 1 and 2 above, but with the use of mAbs against γδ TCR subsets having Vγ1 or Vγ4.

[0105]The aerosol application of mAbs against Vγ1 showed a significant reduction in AHR of 2ip3N treated C57BL / 6 mice (top in FIGS. 1E and 1F). The significant differences between 2ip3N treated mice and 2ip3N treated mice with aerosol anti-Vγ1 are indicated by “τ” in FIGS. 1E and 1F). This result indicates that the removal of this particular subset of γδ T cells, which may be recruited during allergic inflammation to the lung, has a beneficial effect on regulating AHR associated with allergic inflammation. Thus, an aerosol of a particular subset of γδ T cells in humans, presumably the Vγ9 subs...

GOVERNMENT RIGHTS

[0001] This invention was supported, in part, by Grant Nos. R01 HL-65410; AI-40611; HL-36557; HL-61005; and R01 AI-44920, all awarded by the National Institutes of Health, and Grant No. R825702, awarded by the Environmental Protection Agency. The government has certain rights to this invention.FIELD OF THE INVENTION

[0002] This invention generally relates to the use of aerosolized antibodies against T cell receptors for the inhibition of airway hyperresponsiveness (AHR). Specifically, aerosolized antibodies against receptors on both αβ and γδ T cells are disclosed for the treatment of AHR.BACKGROUND OF THE INVENTION

[0003] A variety of inflammatory agents can provoke airflow limitation, including allergens, cold air, exercise, infections and air pollution. In particular, allergens and other agents in allergic or sensitized mammals (i.e., antigens and haptens) cause the release of inflammatory mediators that recruit cells involved in inflammation. Such cells include lymph...

Examples

example 1

[0095]The following example describes the comparison of aerosolized versus intravenously given mAbs against TCR-β in ovalbumin (OVA) sensitized and challenged mice.

[0096]The classical animal model of allergic inflammation (see, e.g., Takeda et al., (1997). J. Exp. Med, 186, 449-454; Renz et al., 1992, J. Allergy Clin. Immunol. 89:1127-1138; Larsen et al., 1992, J. Clin. Invest. 89:747-752; and Saloga et al., 1993, J. Clin. Invest. 91:133-141) was used to assess the ability of aerosolized mAbs to influence AHR. The present inventors and others have previously shown that αβ T cells are necessary for the development of allergic inflammation and airway hyperresponsiveness (AHR) (Holt, J. Exp. Med. 183:1297-1301 (1996); Lahn et al., Nature Med. 5:1150-6 (1999)). In this experiment, C57BL / 6 mice were injected twice with Alum / OVA intraperitoneally (sensitization) before a three day exposure to aerosolized OVA (challenge). The exact procedure has been previously published (Lahn et al., Natu...

example 2

[0101]The following example describes the comparison of aerosolized versus intravenously given mAbs against TCR-δ in ovalbumin (OVA) sensitized and challenged mice.

[0102]In this example, experiments were conducted as described in Example 1, but with the use of a mAb against TCR-δ (a 1:1 mixture of mAbs GL3 (Goodman et al., J. Exp. Med. 170:1569 (1989)) and 403A10 Itohara et al., Proc. Natl. Acad. Sci. USA 86:5094-5098 (1989)). As previously published (Lahn et al., Nature Med. 5:1150-6 (1999)), the intravenous injection of mAbs against TCR-δ (▾ in FIGS. 1C and 1D) caused only a slight increase in AHR when compared to 2ip3N treated C57BL / 6 mice in the absence of antibody (□ in FIGS. 1C and 1D). The significant differences between 2ip3N treated mice and 2ip3N mice treated with i.v. anti-TCR-δ are shown by “ω” in FIG. 1C. Again, the addition of 10 μg / ml of anti-TCR-δ to the last OVA aerosol application (▴ in FIGS. 1C and 1D) had a similar effect as the intravenous injection of the same ...

example 3

[0103]The following example describes the comparison of aerosolized mAbs against TCR-Vγ1 and TCR-Vγ4 in ovalbumin (OVA) sensitized and challenged mice.

[0104]Finally, the γδ T cell subsets Vγ1 and Vγ4 were examined for their contribution to the regulation of AHR. Experiments were performed as described in Examples 1 and 2 above, but with the use of mAbs against γδ TCR subsets having Vγ1 or Vγ4.

[0105]The aerosol application of mAbs against Vγ1 showed a significant reduction in AHR of 2ip3N treated C57BL / 6 mice (top in FIGS. 1E and 1F). The significant differences between 2ip3N treated mice and 2ip3N treated mice with aerosol anti-Vγ1 are indicated by “τ” in FIGS. 1E and 1F). This result indicates that the removal of this particular subset of γδ T cells, which may be recruited during allergic inflammation to the lung, has a beneficial effect on regulating AHR associated with allergic inflammation. Thus, an aerosol of a particular subset of γδ T cells in humans, presumably the Vγ9 subs...

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