Macrophage inflammatory protein–1α as a costimulatory signal for mast cell–mediated immediate hypersensitivity reactions
Dai Miyazaki, … , Ricardo M. Richardson, Santa Jeremy Ono
Dai Miyazaki, … , Ricardo M. Richardson, Santa Jeremy Ono
Published February 1, 2005
Citation Information: J Clin Invest. 2005;115(2):434-442. https://doi.org/10.1172/JCI18452.
View: Text | PDF
Article Immunology

Macrophage inflammatory protein–1α as a costimulatory signal for mast cell–mediated immediate hypersensitivity reactions

Abstract

Regulation of the immune response requires the cooperation of multiple signals in the activation of effector cells. For example, T cells require signals emanating from both the TCR for antigen (upon recognition of MHC/antigenic peptide) and receptors for costimulatory molecules (e.g., CD80 and CD60) for full activation. Here we show that IgE-mediated reactions in the conjunctiva also require multiple signals. Immediate hypersensitivity reactions in the conjunctiva were inhibited in mice deficient in macrophage inflammatory protein–1α (MIP-1α) despite normal numbers of tissue mast cells and no decrease in the levels of allergen-specific IgE. Treatment of sensitized animals with neutralizing antibodies with specificity for MIP-1α also inhibited hypersensitivity in the conjunctiva. In both cases (MIP-1α deficiency and antibody treatment), the degranulation of mast cells in situ was affected. In vitro sensitization assays showed that MIP-1α is indeed required for optimal mast cell degranulation, along with cross-linking of the high-affinity IgE receptor, FcεRI. The data indicate that MIP-1α constitutes an important second signal for mast cell degranulation in the conjunctiva in vivo and consequently for acute-phase disease. Antagonizing the interaction of MIP-1α with its receptor CC chemokine receptor 1 (CCR1) or signal transduction from CCR1 may therefore prove to be effective as an antiinflammatory therapy on the ocular surface.

Authors

Dai Miyazaki, Takao Nakamura, Masako Toda, Kam-Wa Cheung-Chau, Ricardo M. Richardson, Santa Jeremy Ono

×

Figure 6

Options: View larger image (or click on image) Download as PowerPoint
In vivo neutralization of MIP-1α inhibits mast cell activation and clini...
In vivo neutralization of MIP-1α inhibits mast cell activation and clinical symptoms in the allergen-challenged conjunctiva. (A) Suppression of allergen-induced immediate hypersensitivity by anti–MIP-1α antibody treatment. Mice primed for immediate hypersensitivity reaction were administered anti–MIP-1α monoclonal antibody (30 μg/injection) intravenously 1 hour before allergen challenge. Clinical scores assessed on day 3 were significantly reduced (n = 12 per group; P < 0.05). (B) Each clinical symptom, including conjunctival edema, lid edema, conjunctival redness, and tearing, was reduced by antibody treatment. (C) The frequency of degranulated mast cells following allergen challenge was also significantly reduced (n = 12 per group; P < 0.05). (D) Late-phase recruitment of mast cells was also assessed in WT mice and following MIP-1α blockade at 24 hours after challenge. Mast cell recruitment was significantly suppressed by antibody treatment (n = 12 per group; P < 0.05). (E) An analysis of mast cell degranulation and clinical scores showed a positive correlation between these 2 indices. (F) Kinetics of inhibitory effect of MIP-1α antibody treatment on clinical scores (100 μg/injection). Clinical scores were significantly suppressed on days 1, 2, and 3 (P < 0.05). Values are expressed as mean ± SEM.