title: Macrophage inflammatory protein-1alpha (MIP-1alpha) is required for the efferent phase of pulmonary cell-mediated immunity to a Cryptococcus neoformans infection.
abstract: Our objective was to define the role of the chemokine macrophage-inflammatory protein-1alpha (MIP-1alpha) in the efferent phase of pulmonary cell-mediated immunity (CMI) against Cryptococcus neoformans. Following intratracheal inoculation of C. neoformans (24067) into CBA/J mice, the development of CMI was required for leukocyte recruitment into the lungs at 2 wk postinfection. MIP-1alpha mRNA was expressed by day 6 postinfection, and MIP-1alpha protein in bronchoalveolar lavage fluid was detectable at day 6, but significantly elevated at days 19 and 33. Administration of neutralizing anti-MIP-1alpha Abs from days 7 to 13 blocked the increase in bronchoalveolar lavage fluid MIP-1alpha and resulted in a 37% decrease in total leukocytes in the lungs at day 16. There were 66% fewer macrophages/monocytes and 42% fewer neutrophils in the lungs of anti-MIP-1alpha-treated mice, and the pulmonary burden of C. neoformans was threefold higher. There was no significant difference in the number of eosinophils, CD4+, CD8+, or B220+ lymphocytes between the two groups of mice. Neutralization of MIP-1alpha did not significantly decrease the levels of monocyte chemotactic protein-1 (MCP-1); however, neutralization of MCP-1 significantly decreased MIP-1alpha levels, demonstrating that induction of MIP-1alpha was largely dependent on MCP-1 production. Neutralization of MIP-1alpha also blocked the cellular recruitment phase of a recall response to cryptococcal Ag in the lungs of immunized mice. Thus, in both the contexts of active cryptococcal infection or rechallenge with cryptococcal Ag, MIP-1alpha was required during the efferent phase of CMI for maximal leukocyte recruitment into the lungs, most notably the recruitment of phagocytic effector cells (neutrophils and macrophages).
authors.affiliation: Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor 48109, USA. ghuff@umich.edu
authors.forename: G B
authors.initials: GB
authors.lastname: Huffnagle
authors.forename: R M
authors.initials: RM
authors.lastname: Strieter
authors.forename: L K
authors.initials: LK
authors.lastname: McNeil
authors.forename: R A
authors.initials: RA
authors.lastname: McDonald
authors.forename: M D
authors.initials: MD
authors.lastname: Burdick
authors.forename: S L
authors.initials: SL
authors.lastname: Kunkel
authors.forename: G B
authors.initials: GB
authors.lastname: Toews
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000276:immunology; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D003453:Cryptococcosis / Q000276:immunology* / Q000473:pathology; D003455:Cryptococcus neoformans / Q000276:immunology*; D005260:Female; D007111:Immunity, Cellular; D008168:Lung / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D019402:Macrophage Inflammatory Proteins / Q000032:analysis / Q000276:immunology*; D016676:Macrophages, Alveolar / Q000276:immunology*; D051379:Mice; D008808:Mice, Inbred CBA; D012333:RNA, Messenger / Q000032:analysis
chemical_list: D000911:Antibodies, Monoclonal; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D019402:Macrophage Inflammatory Proteins; D012333:RNA, Messenger