Macrophage inflammatory protein-1alpha as a costimulatory signal for mast cell-mediated immediate hypersensitivity reactions.
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-1alpha (MIP-1alpha) 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-1alpha also inhibited hypersensitivity in the conjunctiva. In both cases (MIP-1alpha deficiency and antibody treatment), the degranulation of mast cells in situ was affected. In vitro sensitization assays showed that MIP-1alpha is indeed required for optimal mast cell degranulation, along with cross-linking of the high-affinity IgE receptor, FcepsilonRI. The data indicate that MIP-1alpha 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-1alpha 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.
Miyazaki
Dai
D
Department of Immunology, University College London, University of London, Institutes of Ophthalmology and Child Health, London, United Kingdom.
Nakamura
Takao
T
Toda
Masako
M
Cheung-Chau
Kam-Wa
KW
Richardson
Ricardo M
RM
Ono
Santa Jeremy
SJ
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000276:immunology; D018122:B7-1 Antigen / Q000276:immunology; D015550:Cell Degranulation / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D003228:Conjunctiva / Q000276:immunology / Q000473:pathology; D003233:Conjunctivitis, Allergic / Q000139:chemically induced / Q000188:drug therapy / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D006649:Histocompatibility Antigens / Q000276:immunology; D007073:Immunoglobulin E / Q000276:immunology; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D019402:Macrophage Inflammatory Proteins / Q000235:genetics / Q000276:immunology*; D008407:Mast Cells / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D010455:Peptides / Q000008:administration & dosage / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D054389:Receptors, CCR1; D019707:Receptors, Chemokine / Q000276:immunology; D017455:Receptors, IgE / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology
D000911:Antibodies, Monoclonal; D018122:B7-1 Antigen; C515301:Ccr1 protein, mouse; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D006649:Histocompatibility Antigens; D019402:Macrophage Inflammatory Proteins; D010455:Peptides; D011948:Receptors, Antigen, T-Cell; D054389:Receptors, CCR1; D019707:Receptors, Chemokine; D017455:Receptors, IgE; D007073:Immunoglobulin E