A Human IgM Monoclonal Antibody Prolongs Survival of Mice with Lethal Cryptococcosis

Fleuridor, Richardson; Zhu, Zhen; Pirofski, Liise-anne

doi:10.1086/515688

Cited by 78 publications

(76 citation statements)

References 7 publications

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“…The mAb 2E9 is a human mAb to GXM (29) that prolongs the survival of mice with lethal cryptococcosis (11) and enhances the antifungal activity of human neutrophils in vitro (6). In view of its functional efficacy and shared Id expression with Abs to GXM found in human sera (11,29), we used 2E9 to screen a peptide library and identified a peptide mimic of the GXM epitope it recognized.…”

Section: G Raftmentioning

confidence: 99%

“…In view of its functional efficacy and shared Id expression with Abs to GXM found in human sera (11,29), we used 2E9 to screen a peptide library and identified a peptide mimic of the GXM epitope it recognized. This 10-amino acid peptide, P13, inhibited the GXM binding of serum Abs from HIV-uninfected, but not HIV-infected individuals (25,30), suggesting there was a qualitative (specificity) difference between Abs to GXM from susceptible compared with relatively resistant individuals.…”

Section: G Raftmentioning

confidence: 99%

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

Fleuridor

Lees

Pirofski

2001

The Journal of Immunology

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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: G Raftmentioning

confidence: 99%

Section: G Raftmentioning

confidence: 99%

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

Fleuridor

Lees

Pirofski

2001

The Journal of Immunology

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101

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“…The hallmark of an effective tissue response to C. neoformans is granuloma formation, and there is general consensus in the field that cellular immunity is critically important for host defense (4). However, there is now a large body of evidence that humoral immunity can make an important contribution to host defense, as evidenced by data from four independent research groups showing that administration of mAbs to the C. neoformans capsule can modify the course of infection in mice (5)(6)(7)(8).…”

Section: Ryptococcus Neoformans Is the Only Pathogenic Fungusmentioning

confidence: 99%

“…A better understanding of IgM efficacy against C. neoformans is important because IgM to GXM is common in human sera (18 -21), can protect against this pathogen (7,8), and does not cause acute lethal toxicity when administered to infected mice (22 …”

Section: Ryptococcus Neoformans Is the Only Pathogenic Fungusmentioning

confidence: 99%

Immunoglobulin M Efficacy AgainstCryptococcus neoformans: Mechanism, Dose Dependence, and Prozone-Like Effects in Passive Protection Experiments

Taborda

Casadevall

2001

The Journal of Immunology

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The IgM mAbs 12A1 and 13F1 are protective and nonprotective, respectively, against lethal Cryptococcus neoformans infection in mice. To better understand the variables that contribute to IgM efficacy against C. neoformans, we studied the effects of inoculum size, route of infection, and Ab dose for each of these mAbs. mAb 13F1 did not prolong survival under any condition studied. mAb 12A1 prolonged survival after the administration of certain Ab doses after i.p. infection with defined inocula and promoted phagocytosis, agglutination, and the formation of inflammatory cell rings around yeast cells in vivo. Large Ab doses of mAb 12A1 resulted in either no protection or enhanced infection, consistent with a prozone-like effect. Investigation of this phenomenon revealed that the fungal cell was protected against microbicidal nitrogen-derived oxidants when large amounts of Ab were bound to the C. neoformans capsule. mAb 12A1 was opsonic in vitro for peritoneal, but not splenic or alveolar macrophages. In summary, our results indicate that IgM efficacy against C. neoformans is a function of the route of infection, inoculum, and Ab dose and is associated with its ability to promote opsonization, agglutination, and phagocytic ring formation in vivo. The occurrence of the prozone-like phenomenon implies that high Ab titers are not necessarily beneficial in assuring protection against certain pathogens and that caution should be exercised in using high Ab titer as a measure for vaccine efficacy.

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“…Human IgM MAb specific to glucuronoxylomannan prolonged survival of C. neoformans-infected mice [99]. Based on these experimental data, a murine-derived anticryptococcal IgG1κ MAb 18B7 reacting to glucuronoxylomannan entered phase I, multi-institution, open-label, nonrandomized, dose-escalation study in HIV-infected subjects who had been successfully treated for cryptococcal meningitis [100].…”

Section: Role Of Antibodies In the Protection Against Fungal Infectiomentioning

confidence: 99%

The protective role of immunoglobulins in fungal infections and inflammation

2014

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International audienceIncreased incidence of fungal infections in the immunocompromised individuals and fungi-mediated allergy and inflammatory conditions in immunocompetent individuals is a cause of concern. Consequently, there is a need for efficient therapeutic alternatives to treat fungal infections and inflammation. Several studies have demonstrated that antibodies or immunoglobulins have a role in restricting the fungal burden and their clearance. However, based on the data from monoclonal antibodies, it is now evident that the efficacy of antibodies in fungal infections is dependent on epitope specificity, abundance of protective antibodies, and their isotype. Antibodies confer protection against fungal infections by multiple mechanisms that include direct neutralization of fungi and their antigens, inhibition of growth of fungi, modification of gene expression, signaling and lipid metabolism, causing iron starvation, inhibition of polysaccharide release, and biofilm formation. Antibodies promote opsonization of fungi and their phagocytosis, complement activation, and antibody-dependent cell toxicity. Passive administration of specific protective monoclonal antibodies could also prove to be beneficial in drug resistance cases, to reduce the dosage and associated toxic symptoms of anti-fungal drugs. The longer half-life of the antibodies and flexibilities to modify their structure/forms are additional advantages. The clinical data obtained with two monoclonal antibodies should incite interests in translating pre-clinical success into the clinics. The anti-inflammatory and immunoregulatory role of antibodies in fungal inflammation could be exploited by intravenous immunoglobulin or IVIg

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A Human IgM Monoclonal Antibody Prolongs Survival of Mice with Lethal Cryptococcosis

Cited by 78 publications

References 7 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

Immunoglobulin M Efficacy AgainstCryptococcus neoformans: Mechanism, Dose Dependence, and Prozone-Like Effects in Passive Protection Experiments

The protective role of immunoglobulins in fungal infections and inflammation

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