Therapeutic efficacy of monoclonal antibodies to Cryptococcus neoformans glucuronoxylomannan alone and in combination with amphotericin B

Mukherjee, Jean; Zuckier, Lionel S.; Scharff, Matthew D.; Casadevall, Arturo

doi:10.1128/aac.38.3.580

Cited by 137 publications

(108 citation statements)

References 44 publications

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“…In addition, conjugate-vaccinated mice died soon after their serum levels of GXM increased to that of the controls at the time they died. In light of evidence that Abs to GXM reduce GXM antigenemia in C. neoformans-infected mice (55,57,58), the reduction in fungal burden in the P13 conjugatevaccinated mice may be consistent with Ab-mediated protection. Finally, the fact that a statistically significant increase in survival was observed when immune serum was administered to naive infected mice suggests that conjugate-mediated protection was Ab mediated.…”

Section: Discussionmentioning

confidence: 80%

A Cryptococcal Capsular Polysaccharide Mimotope Prolongs the Survival of Mice withCryptococcus neoformansInfection

Fleuridor

Lees

Pirofski

2001

The Journal of Immunology

101

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Defined Abs to the Cryptococcus neoformans capsular polysaccharide glucuronoxylomannan (GXM) have been shown to be protective against experimental cryptococcosis. This suggests that if a vaccine could induce similar Abs it might protect against infection. However, the potential use of a GXM-based vaccine has been limited by evidence that GXM is a poor immunogen that can induce nonprotective and deleterious, as well as protective, Abs, and that the nature of GXM oligosaccharide epitopes that can elicit a protective response is unknown. In this study, we investigated whether a peptide surrogate for a GXM epitope could induce an Ab response to GXM in mice. The immunogenicity of peptide-protein conjugates produced by linking a peptide mimetic of GXM, P13, to either BSA, P13-BSA, or tetanus toxoid, P13-tetanus toxoid, was examined in BALB/c and CBA/n mice that received four s.c. injections of the conjugates at 14- to 30-day intervals. All mice immunized with conjugate produced IgM and IgG to P13 and GXM. Challenge of conjugate-immunized mice with C. neoformans revealed longer survival and lower serum GXM levels than control mice. These results indicate that 1) P13 is a GXM mimotope and 2) that it induced a protective response against C. neoformans in mice. P13 is the first reported mimotope of a C. neoformans Ag. Therefore, the P13 conjugates are vaccine candidates for C. neoformans and their efficacy in this study suggests that peptide mimotopes selected by protective Abs deserve further consideration as vaccine candidates for encapsulated pathogens.

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Section: Discussionmentioning

confidence: 80%

A Cryptococcal Capsular Polysaccharide Mimotope Prolongs the Survival of Mice withCryptococcus neoformansInfection

Fleuridor

Lees

Pirofski

2001

The Journal of Immunology

101

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“…Mice with partial complement deficiency succumb rapidly with disseminated infection when i.v. infected (33).…”

Section: Treatment Of A͞jcr Mice Infected With Cn With Radiolabeled Mmentioning

confidence: 99%

“…The i.v. infection results in rapid death of infected mice, and is a standard model used for antifungal susceptibility testing (33). Twenty-four hours after infection, groups 1, 2, and 3 received i.p.…”

Section: Treatment Of A͞jcr Mice Infected With Cn With Radiolabeled Mmentioning

confidence: 99%

Ionizing radiation delivered by specific antibody is therapeutic against a fungal infection

Dadachova

Nakouzi

Bryan³

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

100

115

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There is an urgent need for new antimicrobial therapies to combat drug resistance, new pathogens, and the relative inefficacy of current therapy in compromised hosts. Ionizing radiation can kill microorganisms quickly and efficiently, but this modality has not been exploited as a therapeutic antimicrobial strategy. We have developed methods to target ionizing radiation to a fungal cell by labeling a specific mAb with the therapeutic radioisotopes Rhenium-188 and Bismuth-213. Radiolabeled antibody killed cells of human pathogenic fungus Cryptococcus neoformans in vitro, thus converting an antibody with no inherent antifungal activity into a microbicidal molecule. Administration of radiolabeled antibody to mice with C. neoformans infection delivered 213 Bi and 188 Re to the sites of infection, reduced their organ fungal burden, and significantly prolonged their survival without apparent toxicity. This study establishes the principle that targeted radiation can be used for the therapy of an infectious disease, and suggests that it may have wide applicability as an antimicrobial strategy.

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“…After overnight incubation at 37°C in 8% CO 2 , medium in each well was replaced with fresh medium containing 4 ϫ 10 5 B. dermatitidis yeast. Binding and phagocytosis of yeast were analyzed in vitro as previously described (6,17,22,23). M and yeast were incubated at an E:T cell ratio of 1:4 for 1 and 6 h at 37°C in 8% CO 2 .…”

Section: Cells and Cell Linesmentioning

confidence: 99%

Exploiting Type 3 Complement Receptor for TNF-α Suppression, Immune Evasion, and Progressive Pulmonary Fungal Infection

Brandhorst

Wüthrich

Finkel-Jimenez

et al. 2004

The Journal of Immunology

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TNF-α is crucial in defense against intracellular microbes. Host immune cells use type 3 complement receptors (CR3) to regulate excess TNF-α production during physiological clearance of apoptotic cells. BAD1, a virulence factor of Blastomyces dermatitidis, is displayed on yeast and released during infection. BAD1 binds yeast to macrophages (Mφ) via CR3 and CD14 and suppresses TNF-α, which is required for resistance. We investigated whether blastomyces adhesin 1 (BAD1) exploits host receptors for immune deviation and pathogen survival. Soluble BAD1 rapidly entered Mφ, accumulated intracellularly by 10 min after introduction to cells, and trafficked to early and late endosomes. Inhibition of receptor recycling by monodansyl cadaverine blocked association of BAD1 with Mφ and reversed TNF-α suppression in vitro. Inhibition of BAD1 uptake with cytochalasin D and FcR-redirected delivery of soluble BAD1 as Ag-Ab complexes or of wild-type yeast opsonized with IgG similarly reversed TNF-α suppression. Hence, receptor-mediated entry of BAD1 is requisite in TNF-α suppression, and the route of entry is critical. Binding of soluble BAD1 to Mφ of CR3−/− and CD14−/− mice was reduced to 50 and 33%, respectively, of that in wild-type mice. Mφ of CR3−/− and CD14−/− mice resisted soluble BAD1 TNF-α suppression in vitro, but, in contrast to CR3−/− cells, CD14−/− cells were still subject to suppression mediated by surface BAD1 on wild-type yeast. CR3−/− mice resisted both infection and TNF-α suppression in vivo, in contrast to wild-type and CD14−/− mice. BAD1 of B. dermatitidis thus co-opts normal host cell physiology by exploiting CR3 to subdue TNF-α production and foster pathogen survival.

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Therapeutic efficacy of monoclonal antibodies to Cryptococcus neoformans glucuronoxylomannan alone and in combination with amphotericin B

Abstract: The therapeutic efficacy of the immunoglobulin Gl (IgGl) monoclonal antibody (MAb)

Cited by 137 publications

References 44 publications

A Cryptococcal Capsular Polysaccharide Mimotope Prolongs the Survival of Mice withCryptococcus neoformansInfection

A Cryptococcal Capsular Polysaccharide Mimotope Prolongs the Survival of Mice withCryptococcus neoformansInfection

Ionizing radiation delivered by specific antibody is therapeutic against a fungal infection

Exploiting Type 3 Complement Receptor for TNF-α Suppression, Immune Evasion, and Progressive Pulmonary Fungal Infection

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