Immunomodulation with CD40 Stimulation and Interleukin-2 Protects Mice from Disseminated Cryptococcosis

• Published in: Infection and Immunity Vol. 74; no. 4; pp. 2161 - 2168
• Main Authors: Zhou, Qing, Gault, Ruth A, Kozel, Thomas R, Murphy, William J
• Format: Journal Article
• Language: English
• Published: Washington, DC American Society for Microbiology 01.04.2006
• Subjects: agonists; animal models; Animals; Antibodies - administration & dosage; Antibodies - therapeutic use; Antibodies, Fungal - blood; Antibodies, Monoclonal - administration & dosage; Antibodies, Monoclonal - therapeutic use; antifungal properties; Antigens, Fungal - immunology; Biological and medical sciences; blood serum; bone marrow transplant; brain; CD40 Antigens - immunology; CD8-Positive T-Lymphocytes - immunology; Cells, Cultured; Cryptococcosis - blood; Cryptococcosis - genetics; Cryptococcosis - immunology; Cryptococcosis - prevention & control; Cryptococcus neoformans; Cryptococcus neoformans - immunology; Dendritic Cells - immunology; Fundamental and applied biological sciences. Psychology; Fungal and Parasitic Infections; Genetic Predisposition to Disease; immunomodulation; immunotherapy; interferon-gamma; Interferon-gamma - blood; Interferon-gamma - genetics; Interferon-gamma - physiology; interleukin-2; Interleukin-2 - administration & dosage; Interleukin-2 - therapeutic use; kidneys; Leukocyte Count; Lymphocyte Count; Mice; Mice, Inbred C57BL; Mice, Knockout; Microbiology; Polysaccharides - immunology; Spleen - cytology; Spleen - immunology; T-lymphocytes; tumor necrosis factor-alpha; Tumor Necrosis Factor-alpha - metabolism; yeasts; Mycosis; Microbiology; Immunomodulation; Cytokine; Rodentia; Cryptococcosis; Immunity; Infection; Vertebrata; Mammalia; Interleukin 2; Mouse; Disseminated
• ISSN: 0019-9567; 1098-5522
• DOI: 10.1128/IAI.74.4.2161-2168.2006

Cryptococcus neoformans is a ubiquitous fungus that can cause life-threatening infections during immunosuppressive states such as AIDS and after bone marrow transplantation. In this study we investigated the antifungal efficacy of an agonist antibody to CD40, an important costimulator of immune function, in combination with interleukin 2 (IL-2) in a murine model of disseminated cryptococcosis. Only the combination of anti-CD40 and IL-2 significantly prolonged the survival time of infected mice. This protection was correlated with decreased yeast burdens in the brain and kidney. Increased immune cell populations in the spleens, as well as increased serum gamma interferon (IFN-[gamma]) and tumor necrosis factor alpha levels were observed in infected mice treated with anti-CD40 and IL-2. Further experiments with IFN-[gamma] knockout mice demonstrated that the protection induced by anti-CD40 and IL-2 treatment was dependent on IFN-[gamma]. Depletion of CD4⁺ T cells did not affect the increased serum IFN-[gamma] levels induced by anti-CD40 and IL-2 treatment and, importantly, did not affect the antifungal effect of combination therapy. These studies indicate that immunotherapy using anti-CD40 and IL-2 has therapeutic potential in augmenting host resistance to disseminated cryptococcosis and that IFN-[gamma] is essential for efficacy.