The human pathogenic fungus Cryptococcus neoformans is a relatively frequent cause of severe disease in patients with impaired immune function. This fungus manifests an unusual combination of virulence characteristics that include a polysaccharide capsule, melanin synthesis and the capacity for intracellular parasitism. Cryptococcal infection is acquired by inhalation and there is consensus that an effective host response in the lung involves cellular immunity. However, there is also overwhelming evidence from many laboratories that antibody-mediated immunity can make a decisive contribution to host defense and, underscoring the clinical significance of this finding, a monoclonal antibody is currently in clinical evaluation. Studies over the past decade have taught us that antibody-mediated protection against C. neoformans cannot be fully explained by the classical mechanisms of immunoglobulin action that include opsonization, agglutination, complement activation, toxin neutralization and antibody-dependent cellular cytotoxicity. A fascinating aspect of the humoral immune effect is that passive antibody significantly prolongs survival in mice with pulmonary cryptococcal infection without initially reducing the fungal burden by a mechanism that potentiates the inflammatory response. Investigations in the past funding period established that antibody-mediated protection is associated with changes in selected cytokines and chemokines, specially IFN-alpha, IL-4, IL-10, MCP-l and MIP-1alpha. The effect of passive antibody on different mouse strains results in different changes in the cytokine response suggesting that the mechanism by which antibody function varies depending on the genetic background of the host. Studies of antibody-mediated protection in different mouse strains produced the remarkable result that IgG1 was protective against pulmonary C. neoformans infection in some mouse strains but not others. We refer to this phenomenon as "Ab-permissiveness." Ab-permissive mouse models are those in which Ab administration is associated with Ab-mediated protection, or efficacy, and Ab-non-permissive mouse models are those in which Ab administration does not mediate protection. These observations raise fundamental questions of mechanism(s) by which antibody-mediated immunity protects against C. neoformans and indicates important new relationships between the humoral and cellular arms of the immune system. This competing renewal application proposes to continue immunological studies to ascertain the mechanism by which antibody is protective against C. neoformans in the lung. The proposed work takes advantage of extensive preliminary studies that have allowed us to develop a tractable system for hypothesis testing. Three specific Aims are proposed: 1) To establish the role that certain cytokines and chemokines play in Ab-permissiveness in mice susceptible to pulmonary C. neoformans infection. 2) To establish the role that certain cytokines and chemokines play in mouse models of Ab-non-permissiveness. 3) To establish the mechanism by which B cell deficiency renders mice susceptible and Ab-non-permissive. By comparing the immune response in Ab-permissive and Ab-non-permissive murine strains we will learn the conditions and mechanisms by which Ab-mediates protection against C. neoformans.