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Biomedical subjects

Liise-anne Pirofski

Publications and source records attributed to Liise-anne Pirofski.

At least 19 recordsLinked to original sources
PubMed2007

Pneumococcal capsular polysaccharide vaccine-mediated protection against serotype 3 Streptococcus pneumoniae in immunodeficient mice.

Pneumococcal capsular polysaccharide (PPS) vaccines are less immunogenic in immunocompromised than immunocompetent individuals. However, neither the efficacy of PPS vaccines in immunocompromised individuals nor the host cellular subsets required for vaccine efficacy against pneumococcal disease have been directly investigated. In this study, we vaccinated CD4-deficient (CD4(-/-)), CD8-deficient (CD8(-/-)), and secretory immunoglobulin M-deficient (sIgM(-/-)) mice and wild-type C57BL/6 (Wt) mice with a conjugate of PPS of serotype 3 and tetanus toxoid (PPS3-TT) and determined the antibody response and efficacy of vaccination against systemic and pulmonary challenge with serotype 3 pneumococcus in immunized and control mice. Our results showed that the isotype and predominant IgG subclass of the PPS3 response differed between immunodeficient mouse strains and between immunodeficient and Wt mice, with CD8(-/-) mice having the most robust response. Vaccination protected Wt, CD4(-/-), and sIgM(-/-) mice from death resulting from both systemic and pulmonary challenge, whereas CD8(-/-) mice were protected only from systemic and not from pulmonary challenge. Passive vaccination with PPS3-TT-induced sera from Wt, CD4(-/-), CD8(-/-), and sIgM(-/-) mice protected naïve Wt mice from death due to pulmonary challenge; however, CD8(-/-) mice were not protected by sera from Wt or CD8(-/-) mice. Our findings suggest that PPS-based vaccines can be effective in the setting of CD4 T-cell deficiency but that CD8 T cells could be required for vaccine-mediated protection against pulmonary challenge with serotype 3 pneumococcus.

Animals↗
PubMed2006

Immunomodulators as an antimicrobial tool.

The spectrum of infectious diseases has shifted in the past 50 years to include those caused by microbes that cause disease predominantly in immunocompromised individuals. This phenomenon has underscored the dependence of microbial virulence on the immune status of the host. The limited efficacy of the available antimicrobial armamentarium in immunocompromised individuals, combined with increasing resistance to these agents, has led to an urgent need for new therapies for infectious diseases. Immunomodulation represents a novel approach to antimicrobial therapy that depends on bolstering host immunity, rather than direct antimicrobial activity. Immunomodulators can be divided into those that are specific to pathogens (pathogen-specific) and those that are not specific to pathogens (non-specific). However, to date only a few immunomodulators have been evaluated for their efficacy as antimicrobial tools.

Anti-Inflammatory Agents↗
PubMed2006

A reappraisal of humoral immunity based on mechanisms of antibody-mediated protection against intracellular pathogens.

Sometime in the mid to late twentieth century the study of antibody-mediated immunity (AMI) entered the doldrums, as many immunologists believed that the function of AMI was well understood, and was no longer deserving of intensive investigation. However, beginning in the 1990s studies using monoclonal antibodies (mAbs) revealed new functions for antibodies, including direct antimicrobial effects and their ability to modify host inflammatory and cellular responses. Furthermore, the demonstration that mAbs to several intracellular bacterial and fungal pathogens were protective issued a serious challenge to the paradigm that host defense against such microbes was strictly governed by cell-mediated immunity (CMI). Hence, a new view of AMI is emerging. This view is based on the concept that a major function of antibody (Ab) is to amplify or subdue the inflammatory response to a microbe. In this regard, the "damage-response framework" of microbial pathogenesis provides a new conceptual viewpoint for understanding mechanisms of AMI. According to this view, the ability of an Ab to affect the outcome of a host-microbe interaction is a function of its capacity to modify the damage ensuing from such an interaction. In fact, it is increasingly apparent that the efficacy of an Ab cannot be defined either by immunoglobulin or epitope characteristics alone, but rather by a complex function of Ab variables, such as specificity, isotype, and amount, host variables, such as genetic background and immune status, and microbial variables, such as inoculum, mechanisms of avoiding host immune surveillance and pathogenic strategy. Consequently, far from being understood, recent findings in AMI imply a system with unfathomable complexity and the field is poised for a long overdue renaissance.

Animals↗
PubMed2006

Towards a vaccine for Cryptococcus neoformans: principles and caveats.

In the Damage-response framework of microbial pathogenesis, infectious diseases are one outcome of a host-microorganism interaction in a susceptible host. In cryptococcal disease, damage to the host is caused by Cryptococcus neoformans virulence determinants, the nature of the host response, or both. Further, the disease may be acute or reactivated from a latent state. Hence, a vaccine for C. neoformans would need to prevent disease resulting from either acute or reactivated infection. The evidence to support the development of a vaccine for C. neoformans that induces antibody-mediated immunity is discussed herein.

Animals↗
PubMed2006

Antibody response to Cryptococcus neoformans capsular polysaccharide glucuronoxylomannan in patients after solid-organ transplantation.

Cryptococcosis is an important complication of solid-organ transplantation, but the risk factors for disease are poorly understood. The goal of this study was to investigate whether specific or nonspecific serum immunoglobulin levels determined in samples obtained before and after solid-organ transplantation differed in patients who did or did not develop cryptococcosis after transplantation. We analyzed pretransplantation sera from 25 subjects, 15 who subsequently developed cryptococcosis and 10 who did not, and posttransplantation sera from 24 subjects, 13 who developed cryptococcosis and 11 who did not. All subjects received a tacrolimus-based immunosuppressive regimen. Total immunoglobulin levels were measured by immunodiffusion, and Cryptococcus neoformans capsular polysaccharide glucuronoxylomannan (GXM)-specific serum antibody levels were determined by enzyme-linked immunosorbent assays. The results showed that solid-organ transplantation had a significant effect on total immunoglobulin and GXM-reactive antibody levels. GXM-reactive antibody levels differed in subjects who did and did not develop cryptococcosis. In pretransplant serum samples, the levels of GXM-reactive immunoglobulin M (IgM) were significantly lower in subjects who developed cryptococcosis after transplantation than in those who did not. For posttransplant serum samples, the levels of GXM-reactive IgM and IgG were significantly higher among the subjects who developed cryptococcosis than among those who did not. These findings suggest that perturbations in the preexisting antibody or B-cell repertoire and/or related to treatment of rejection, transplantation, or immunosuppressive therapy could translate into an increased risk for transplant-associated cryptococcosis.

Adult↗
PubMed2005

The potential of antibody-mediated immunity in the defence against biological weapons.

Antibody-mediated immunity (AMI) has been used for the treatment and prevention of infectious diseases for > 100 years, and has a remarkable record of safety, efficacy and versatility. AMI can be used for defence against a wide variety of biological weapons, and passive antibody (Ab) therapy has the potential to provide immediate immunity to susceptible individuals. Recent advances in the Ab field make it possible to generate Abs with enhanced antimicrobial functions. There are significant gaps in our understanding of Ab function, such that the development of Ab-based strategies remains a largely empirical exercise. Nevertheless, the advantages inherent in the therapeutic and prophylactic use of AMI provide a powerful rationale for continued development that will undoubtedly yield many new vaccines and therapeutic Abs.

Animals↗
PubMed2004

VH3 gene expression in children with HIV infection.

OBJECTIVE: To study immunoglobulin heavy chain variable region (V(H)) gene expression in HIV-uninfected (HIV-) and HIV-infected (HIV+) children. METHODS: A retrospective, observational study was performed by PCR-ELISA to examine IgM and IgG V(H) gene family expression among peripheral CD19-positive B cells. The subjects were 10 HIV+ children with, and 11 HIV+ children without a history of invasive pneumococcal disease (IPD) and 12 HIV- children. The ages of the HIV+ and HIV- children, and the CD4 lymphocyte counts and viral loads (VL) of the HIV+ /IPD- and HIV+ /IPD- children were statistically similar. Rearranged V(H)3 gene libraries were constructed from 3 HIV+ /IPD- children to examine individual gene expression. RESULTS: The proportion of IgG V(H)3 expression among HIV+ /IPD- was lower than that of HIV- children, but the proportion of IgG V(H)3 expression among HIV+ /IPD+ children was not significantly different from that of HIV- children. IgG V(H)3 expression was positively, whereas IgM V(H)3 expression was inversely correlated with the VL among HIV+ /IPD+, but not HIV+ /IPD- children. IgM V(H) gene family expression did not differ between HIV+ and HIV- children. CONCLUSION: HIV+ children manifest qualitative and quantitative differences in V(H)3 expression, which may be influenced by IPD.

Bacteremia↗
PubMed2004

The weapon potential of a microbe.

The designation of a microbe as a potential biological weapon poses the vexing question of how such a decision is made given the many pathogenic microbes that cause disease. Analysis of the properties of microbes that are currently considered biological weapons against humans revealed no obvious relationship to virulence, except that all are pathogenic for humans. Notably, the weapon potential of a microbe rather than its pathogenic properties or virulence appeared to be the major consideration when categorizing certain agents as biological weapons. In an effort to standardize the assessment of the risk that is posed by microbes as biological warfare agents using the basic principles of microbial communicability (defined here as a parameter of transmission) and virulence, a simple formula is proposed for estimating the weapon potential of a microbe.

Bacteria↗
PubMed2004

Passive antibody therapy for infectious diseases.

Antibody-based therapies are currently undergoing a renaissance. After being developed and then largely abandoned in the twentieth century, many antibody preparations are now in clinical use. However, most of the reagents that are available target non-infectious diseases. Interest in using antibodies to treat infectious diseases is now being fuelled by the wide dissemination of drug-resistant microorganisms, the emergence of new microorganisms, the relative inefficacy of antimicrobial drugs in immunocompromised hosts and the fact that antibody-based therapies are the only means to provide immediate immunity against biological weapons. Given the need for new antimicrobial therapies and many recent technological advances in the field of immunoglobulin research, there is considerable optimism regarding renewed applications of antibody-based therapy for the prevention and treatment of infectious diseases.

Animals↗
PubMed2004

Immunogenicity and efficacy of Cryptococcus neoformans capsular polysaccharide glucuronoxylomannan peptide mimotope-protein conjugates in human immunoglobulin transgenic mice.

Peptide mimotopes of capsular polysaccharides have been proposed as antigens for vaccines against encapsulated pathogens. In this study, we determined the antibody response to and efficacy of P13, a peptide mimetic of the Cryptococcus neoformans capsular polysaccharide glucuronoxylomannan (GXM), in mice that produce human antibodies. P13 was conjugated to tetanus toxoid (TT) or diphtheria toxoid (DT) and administered subcutaneously in Alhydrogel with or without CpG to mice transgenic for human immunoglobulin loci (XenoMouse mice) and expressing either immunoglobulin G2 (IgG2) (G2 mice) or IgG4 (G4 mice). Mice were vaccinated and revaccinated two or three times. The serum antibody responses of the mice to GXM and P13 and antibody idiotype expression were analyzed by an enzyme-linked immunosorbent assay. The results showed that both P13-TT and P13-DT were antigenic, inducing a mimetic response to P13 in both G2 and G4 mice, and immunogenic, inducing a mimotope response including VH3 (idiotype)-positive antibodies to GXM in G2 but not G4 mice. CpG led to higher titers of IgG to P13 and GXM in P13-TT-vaccinated G2 mice. C. neoformans challenge of P13-protein conjugate-vaccinated and control G2 mice induced anamnestic IgG- and VH3-positive responses to GXM and was associated with a significantly decreased risk of death and a prolongation of survival in P13-DT-vaccinated mice compared to phosphate-buffered saline-treated or protein carrier-vaccinated mice. These findings reveal that P13 elicited a human antibody response with VH3 expression in human immunoglobulin transgenic mice that has been observed for human antibodies to GXM and support the concept that peptide mimotope-based vaccines may hold promise for the treatment of C. neoformans infections.

Animals↗
PubMed2004

Protective and nonprotective human immunoglobulin M monoclonal antibodies to Cryptococcus neoformans glucuronoxylomannan manifest different specificities and gene use profiles.

The features of protective murine antibodies to the Cryptococcus neoformans capsular polysaccharide glucuronoxylomannan (GXM) have been rigorously investigated; however, the characteristics of protective human antibodies to GXM have not been defined. We produced monoclonal antibodies (MAbs) from XenoMouse mice (transgenic mice that express human immunoglobulin M [IgM], IgG2, and kappa) which were immunized with a C. neoformans serotype D strain 24067 GXM-diphtheria toxoid conjugate. This study reports the specificity and efficacy of three human IgM MAbs, G14, G15, and G19, generated from these mice. Each MAb was specific for GXM, but G14 and G19 had different specificity based on their binding to serotype A strain H99 and SB4 GXMs, to which G15 did not bind. Nucleic acid sequence analysis revealed that G15 uses V(H)3-64 in the germ line configuration. G14 and G19 use V(H)6-1, which has somatic mutations. All of the MAbs use V kappa DPK22/A27. Studies of MAb efficacy in BALB/c mice showed that administration of 0.1 mg, but not 1 or 0.01 mg, of G15 prolonged survival against lethal C. neoformans strain 24067 challenge, whereas G14 and G19 were not protective at any dose. This panel of MAbs illustrates that serotype D GXM has epitopes that elicit human antibodies that can be either protective or nonprotective. Our findings suggest that V(H) gene use may influence GXM specificity and efficacy, and they provide insights into the possible contribution that V(H) gene use may have in resistance and susceptibility to cryptococcosis.

Amino Acid Sequence↗
PubMed2003

Qualitative change in antibody responses of human immunodeficiency virus-infected individuals to pneumococcal capsular polysaccharide vaccination associated with highly active antiretroviral therapy.

Variable region gene family 3 (V(H)3) is the predominant immunoglobulin (Ig) gene family used in human antibodies to pneumococcal capsular polysaccharide (PPS). This study examined whether highly active antiretroviral therapy (HAART) restores the ability of human immunodeficiency virus (HIV)-infected individuals to generate a V(H)3-positive response to PPS. The IgM, IgG, and V(H)3 (represented by antibodies expressing the determinant recognized by the monoclonal antibody D12) responses to PPS were determined for first-time recipients of a 23-valent PPS vaccine, both receiving and not receiving HAART, and second-time vaccine recipients receiving HAART. The results showed that only the individuals receiving HAART manifested a V(H)3-(D12)-positive response to PPS, despite a similar IgG response in each group. There was also a negative correlation between HIV load and PPS response for the groups receiving HAART. These findings suggest that HAART may influence qualitative aspects of the PPS response by restoring expression of certain V(H)3 genes used in the normal PPS response.

Adult↗
PubMed2003

The damage-response framework of microbial pathogenesis.

The late twentieth century witnessed the emergence of numerous infectious diseases that are caused by microorganisms that rarely cause disease in normal, healthy immunocompetent hosts. The emergence of these diseases shows that the existing concepts of pathogenicity and virulence do not take into account the fact that both the microorganism and the host contribute to microbial pathogenesis. To address this impediment to studies of host-microorganism interactions, we propose a new theoretical approach to understanding microbial pathogenesis, known as the 'damage-response' framework.

Animals↗
PubMed2003

Modulation of polymorphonuclear cell interleukin-8 secretion by human monoclonal antibodies to type 8 pneumococcal capsular polysaccharide.

Pneumococcal capsular polysaccharide (PS) vaccines induce type-specific immunoglobulin M (IgM), IgG, and IgA. Type-specific IgG to the PS is sufficient to confer protection against the homologous serotype of the pneumococcus, but the efficacies of type-specific IgM and IgA are less well understood. We examined the in vitro activities and efficacies in mice of two human monoclonal antibodies (MAbs) to type 8 PS, NAD (IgA) and D11 (IgM). MAb-mediated opsonophagocytic killing was evaluated after coculture of type 8 pneumococci with human polymorphonuclear cells (PMNs), type-specific or control MAbs, and human complement sources. The effects of the MAbs on PMN interleukin-8 (IL-8) and IL-6 secretion were determined in supernatants from cocultures containing pneumococci and PMNs by enzyme-linked immunosorbent assay. MAb efficacy was determined in an intratracheal model of type 8 infection in mice with classical complement pathway deficiency. Both MAbs were protective in 100% of infected mice. Neither MAb promoted a significant amount of killing of type 8 pneumococci compared to its isotype control MAb. Both type-specific MAbs mediated complement-dependent modulation of PMN IL-8 secretion, with increased secretion at effector/target (E:T) ratios of 500:1 and 50:1 and reduced secretion at 1:5. Trypan blue staining revealed that PMNs cocultured with D11 were less viable at an E:T ratio of 1:5 than PMNs cocultured with the control MAb. PMN IL-6 secretion was increased by both type-specific and control MAbs. These results suggest that certain type-specific IgM and IgAs might contribute to host defense by modulation of the inflammatory response to pneumococci.

Animals↗