Antagonism of TIM-1 blocks the development of disease in a humanized mouse model of allergic asthma (1)
The murine system supports the role of TIM-1 in Th2-dependent inflammation. The TIM gene family has been associated with Th2 cytokine expression and AHR, and anti-mouse TIM-1 mAbs reduce Th2 cytokine secretion and disease pathology in models of lung inflammation, allergic conjunctivitis, and allergic gut inflammation.
TIM-1 possesses both cation-dependent and cation-independent binding activity on mouse DCs. Both the murine TIM-1–Fc and TIM-1–IgV–Fc proteins bound to DCs. EGTA (1 mM) reduced binding of murine TIM-1–Fc to DCs. The binding of murine TIM-1 to these DCs required only the IgV domain. Anti-mouse TIM-1 mAb 4A2 reduced binding of murine TIM-1 proteins to DCs in the presence of 1 mM EGTA to background level. Other anti-mouse TIM-1 mAbs or rat IgG2a isotype control mAb did not affect binding of the TIM-1 fusion proteins to murine myeloid DCs in the presence of 1 mM EGTA.
A model using hu-PBMC SCID mice was established. SCID mice were reconstituted i.p. with PBMCs from asthmatic donors allergic to the house dust mite Dermatophagoides pteronyssinus allergen. Following reconstitution, recipient mice received multiple i.p. sensitizations with D. pteronyssinus to maintain and boost the allergen-specific immune response and were subsequently challenged with aerosolized D. pteronyssinus to trigger the allergic asthmatic phenotype.
In asthmatic hu-PBMC SCID mice, mice treated with anti-human TIM-1 mAb A6G2 had a markedly reduced influx of leukocytes into the airways. Measurement of cytokines in the BALF and lung homogenates of anti-human TIM-1 mAb A6G2–treated mice revealed a strong reduction of human IL-4, whereas no significant changes in the IFN-γ or TNF-α levels. The reduction in lung inflammation with anti-human TIM-1 mAb A6G2 was comparable to that observed with the anti-human IL-13 mAb, while the isotype control mAb (IgG) and anti-human TIM-1 mAb A3H1 had no effect on these readouts. AHR substantially improved in mice treated with anti-human TIM-1 mAb A6G2 or anti-human IL-13 mAb. Neither the isotype control antibodies nor anti-human TIM-1 mAb A3H1 affected the outcome of AHR, with values comparable to the positive control.
Similar to the therapeutic benefit seen in the murine OVA-induced asthma model with anti-murine TIM-1 mAb 4A2, treatment of asthmatic hu-PBMC SCID mice with the anti-human TIM-1 mAb A6G2 strongly reduced BALF and tissue levels of the Th2 cytokine IL-4, reduced lung inflammation, and prevented AHR. These effects resulted from a suppression of the Th2 response rather than an induction of the Th1 response, since neither neutrophil numbers nor IFN-γ levels were increased in the lungs of treated mice.