MIP-1α contributes to the anticryptococcal delayed-type hypersensitivity reaction and protection against

Abstract

Leukocyte infiltration into infected tissues is essential for the clearance of microorganisms. In animals with a cell-mediated immune (CMI) response to the infectious agent, as opposed to naive animals, leukocyte migration is greatly enhanced into sites of the organism or antigen. The role of the chemotactic cytokine or chemokine, macrophage inflammatory protein-1α (MIP-1α), in the expression phase of the CMI response and in protection against Cryptococcus neoformans was assessed. With the use of a gelatin sponge model in mice as a means of detecting an anticryptococcal delayed-type hypersensitivity (DTH) reaction, we found that MIP-1α levels in fluids from cryptococcal antigen (CneF)-injected sponges in immunized mice (DTH-reactive sponges) were significantly increased over levels of MIP-1α in fluids from saline injected control sponges at 12 and 28-30 h after injection, MIP-1α levels peaked before increases in neutrophils and lymphocytes in the DTH-reactive sponges, suggesting that MIP-1α was responsible, at least in part, for attracting these leukocyte types. Immunized mice treated with neutralizing antibody to MIP-1α before sponge injection with CneF had reduced numbers of neutrophils and lymphocytes in the DTH-reactive sponges and showed reduced clearance of C. neoformans from the lungs, spleens, livers, and brains when compared with controls, Furthermore, injection of rmMIP-1α into sponges in naive mice resulted in an increase in the influx of neutrophils and lymphocytes into the sponges compared with saline injected sponges. Together our findings provide solid evidence that MIP-1α is a component of the anticryptococcal DTH reaction. In addition, MIP-1α influences neutrophil influx and attracts lymphocytes into the DTH reaction site. Finally, we showed that MIP-1α plays a role in protection against C. neoformans.