MACROPHAGE INFLAMMATORY PROTEIN-1-ALPHA (MIP-1-ALPHA) IS REQUIRED FORTHE EFFERENT PHASE OF PULMONARY CELL-MEDIATED-IMMUNITY TO A CRYPTOCOCCUS-NEOFORMANS INFECTION

Our objective was to define the role of the chemokine macrophage-infla mmatory protein-1 alpha (MIP-1 alpha) in the efferent phase oi pulmona ry cell-mediated immunity (CMI) against Cryptococcus neoformans. Follo wing intratracheal inoculation of C. neoformans (24067) into CBA/J mic e, the development of CMI was required for leukocyte recruitment into alae lungs at 2 wk postinfection, MIP-1 alpha mRNA was expressed by da y 6 postinfection, and MIP-1 alpha protein in bronchoalveolar lavage f luid was detectable at day 6, but significantly elevated at days 19 an d 33. Administration of neutralizing anti-MIP-1 alpha Abs from days 7 to 13 blocked the increase in bronchoalveolar lavage fluid MIP-1 alpha and resulted in a 37% decrease in total leukocytes in the lungs at da y 16. There were 66% fewer macrophages/monocytes and 42% fewer neutrop hils in the lungs of anti-MIP-1 alpha-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(+) l ymphocytes between the two groups of mice, Neutralization of MIP-1 alp ha did not significantly decrease the levels of monocyte chemotactic p rotein-1 (MCP-1); however, neutralization of MCP-1 significantly decre ased MIP-1 alpha levels, demonstrating that induction of MIP-1 alpha w as largely dependent on MCP-1 production. Neutralization of MIP-1 alph a also blocked the cellular recruitment phase of a recall response to cryptococcal Ag in the lungs of immunized mice, Thus, in both the cont exts of active cryptococcal infection or rechallenge with cryptococcal Ag, MIP-1 alpha was required during the efferent phase of CMI for max imal leukocyte recruitment into the lungs, most notably the recruitmen t of phagocytic effector cells (neutrophils and macrophages).