Role Of Antibodies In Protection Research Articles

Role of antibody in immunity and control of chicken coccidiosis

Research has been carried out worldwide to try to elucidate the mechanism of protective immunity against coccidiosis. It was concluded from early studies that cellular immunity is the key to protection against Eimeria, whereas humoral immunity plays a very minor role in resistance against infection. By contrast, other studies have pointed towards the ability of antibody to block parasite invasion, development and transmission and to provide passive and maternal immunity against challenge infection. Herein, recent results demonstrate the ability of antibodies (raised by live immunization or against purified stage-specific Eimeria antigens) to inhibit parasite development in vitro and in vivo and readdress the question of the role of antibody in protection against coccidiosis.

Investigations on the protective role of passively transferred antibodies against avian metapneumovirus infection in turkeys

The avian metapneumovirus (aMPV) is the causative agent of an acute respiratory disease in turkeys, which causes considerable economic losses to the poultry industry. Currently attenuated live and inactivated vaccines are widely used to control the disease, but vaccine breaks are frequently observed. For improvement of current vaccination strategies it is necessary to gain enhanced knowledge of the immune mechanisms against aMPV infection. Field observations suggest that vaccine-induced aMPV-specific antibodies are not indicative for protection. In the present study we investigated the role of antibodies in protection of turkeys against aMPV. In two experiments, commercial turkey poults received aMPV-specific antibodies by intravenous injection. The antibody transfer resulted in increased antibody levels in the sera. Virus-specific antibodies were also detected on mucosal surfaces such as the trachea, conjunctivae and gall bladder. Turkeys were subsequently challenged with a virulent aMPV subtype A strain. Development of clinical signs, virus detection by polymerase chain reaction and histopathological changes of tracheal mucosa in challenged turkeys with and without passively transferred antibodies were comparable with each other. Our results suggest that humoral immunity does not provide sufficient protection against aMPV infection. Thus, the measurement of vaccine-induced aMPV antibody response may not be considered as an adequate indicator of vaccine efficacy. Further research on the protective role of cell-mediated immune mechanisms is necessary to improve current vaccine strategies.

How the host fights against Candida infections

Candida albicans is the predominant cause of both superficial and invasive forms of candidosis, although the proportion of serious infections attributed to other members of the genus is rising.. The spectrum of host defences include cell mediated immunity which is comprised of cytokine release by lymphocytes and activation of natural killer cells and lymphocytes by interleukins.. An increasing body of evidence supports a role for specific antibody in protection against invasive Candida infection. Clinical observations indicate that mucocutaneous Candida infections are commonly associated with defective cell-mediated immune responses. Innate immunity is the dominant protective mechanism against disseminated candidosis. Quantitative and qualitative abnormalities of neutrophils and monocytes are associated with systemic candidosis. In the present review virulence factors and the spectrum of immune responses are discussed in relation to the perspective for the development of appropriate vaccines against Candida. Here we present an overview of toll-like receptor signalling, cellular-dependent responses, the role of specific antibodies in protection against Candida, and the array of immune mechanisms that operate in gastrointestinal, vaginal and oral candidosis.

The Neglected Role of Antibody in Protection Against Bacteremia Caused by Nontyphoidal Strains of Salmonella in African Children

MacLennan CA, Gondwe EN, Msefula CL, et al. J Clin Invest. 2008;118(4):1553–1562 PURPOSE OF THE STUDY. To investigate whether specific antibody protects against nontyphoidal Salmonella (NTS) bacteremia. POPULATION STUDIED AND METHODS. Admissions for NTS bacteremia during 1 year were reviewed (N = 352). Sera from 65 healthy Malawian children (median age, 24 months: range, 3–107 months) was used for in vitro NTS-killing assays. Purified immunoglobulin G (IgG) from patient sera was used to delineate the role of antibody versus complement. Immunoglobulin and complement deposition on bacteria was also assessed by flow cytometry. Complement dependency was tested by heat inactivation and by using C9-deficient serum. RESULTS. Overall, 82% of the children with NTS bacteremia were <36 months old, but there was a nonuniform distribution with fewer-than-expected cases in children <4 months old (actual: 9.7% vs 16.7%), suggesting a role for passive humoral immunity. From healthy donors, 9 of 25 children <16 months of age had serum with normal in vitro killing, whereas 40 of 40 children >16 months of age did so. NTS killing in vitro was complement and membrane attack complex dependent. Effective killing corresponded to a specific IgG or IgM Salmonella titer of 1.5 U and was associated with the deposition of complement (C3 and C9) measured by flow cytometry. Resistance to killing by alternative complement activation was mediated by long-chain lipopolysaccharide and the rck gene product. CONCLUSIONS. Salmonella-specific antibody that overcomes the complement resistance of NTS develops by 2 years of life in Malawian children and is mediated by specific IgG or IgM antibody. REVIEWER COMMENTS. NTS is the most common cause of bacteremia in Malawi and much of tropical Africa and is associated with high rates of mortality even with appropriate culture facilities and access to antibiotics. The finding that specific antibody is protective against this invasive, facultative intracellular pathogen supports the importance of vaccine development for this pathogen.

77 The role of IgE antibodies in protection against Plasmodium falciparum

77 The role of IgE antibodies in protection against Plasmodium falciparum

The neglected role of antibody in protection against bacteremia caused by nontyphoidal strains of Salmonella in African children

Nontyphoidal strains of Salmonella (NTS) are a common cause of bacteremia among African children. Cell-mediated immune responses control intracellular infection, but they do not protect against extracellular growth of NTS in the blood. We investigated whether antibody protects against NTS bacteremia in Malawian children, because we found this condition mainly occurs before 2 years of age, with relative sparing of infants younger than 4 months old. Sera from all healthy Malawian children tested aged more than 16 months contained anti-Salmonella antibody and successfully killed NTS. Killing was mediated by complement membrane attack complex and not augmented in the presence of blood leukocytes. Sera from most healthy children less than 16 months old lacked NTS-specific antibody, and sera lacking antibody did not kill NTS despite normal complement function. Addition of Salmonella-specific antibody, but not mannose-binding lectin, enabled NTS killing. All NTS strains tested had long-chain lipopolysaccharide and the rck gene, features that resist direct complement-mediated killing. Disruption of lipopolysaccharide biosynthesis enabled killing of NTS by serum lacking Salmonella-specific antibody. We conclude that Salmonella-specific antibody that overcomes the complement resistance of NTS develops by 2 years of life in Malawian children. This finding and the age-incidence of NTS bacteremia suggest that antibody protects against NTS bacteremia and support the development of vaccines against NTS that induce protective antibody.

Induction and protective role of antibodies in Legionella pneumophila infection

Legionella pneumophila (Lpn) is a ubiquitous Gram-negative bacterium found in aquatic environments and is the causative agent of Legionnaires' disease, a severe form of pneumonia. We have used Lpn-permissive A/J mice as a model to analyze the B cell response upon intravenous (i.v.) and intranasal (i.n.) infection with Lpn. A strong antibody (Ab) response was observed upon i.v. infection with wild-type (WT) Lpn and an icmT mutant strain, which is unable to replicate within permissive host cells. In contrast to i.v. infection, only WT but not icmT mutant Lpn was able to induce specific Ab responses upon i.n. infection. After primary i.n. infection with WT Lpn, a strict compartmentalization of Lpn-specific Ab isotypes was observed, as IgG was found exclusively systemically, while IgA was detectable only locally in the lung. Regardless of the infection route, isotype switching to IgG and to IgA was strictly dependent on CD4+ T cells, whereas IgM production was completely Th-independent. Finally, we analyzed the protective capacity of the Lpn-specific Ab response. Actively or passively immunized mice or mice that were infected with opsonized Lpn had 50-100-fold reduced bacterial titers compared to naive animals, clearly demonstrating the capacity of Ab to protect against infection with Lpn.

Antibodies enhance the protective effect of CD4+ T lymphocytes in SCID mice perorally infected with Encephalitozoon cuniculi

The role of antibodies in the immune response to microsporidiosis was studied using a novel anti-exospore monoclonal antibody (MAb) P5/H1, which recognizes surface antigens of Encephalitozoon cuniculi. The effect of the MAb on microsporidial infection in vivo was to prolong the survival of previously CD4+ reconstituted, perorally infected and intraperitoneally MAb-treated SCID mice. The MAb decreased the numbers of E. cuniculi spores in peritoneal smears obtained post mortem. These results suggest a possible role for antibodies in protection against perorally acquired E. cuniculi infection.

Active treatment of murine tumors with a highly attenuated vaccinia virus expressing the tumor associated antigen 5T4 (TroVax) is CD4+ T cell dependent and antibody mediated.

5T4 is a tumor associated antigen that is expressed on the surface of a wide spectrum of human adenocarcinomas. The highly attenuated virus, modified vaccinia Ankara, has been engineered to express human 5T4 (h5T4). In a pre-clinical murine model, the recombinant virus (TroVax) induces protection against challenge with CT26-h5T4 (a syngeneic tumor line expressing h5T4). Anti-tumor activity is long lived, with protection still evident 6 months after the final vaccination. In a therapeutic setting, injection of mice with TroVax results in a reduction in tumor burden of >90%. Depletion of CD8+ T cells has no effect upon therapy in the active treatment model, whereas depletion of CD4+ T cells completely abrogates anti-tumor activity. In a prophylactic setting, depletion of CD4+ and CD8+ T cells after the induction of a h5T4 immune response has no deleterious effect on protection following challenge with CT26-h5T4. In light of these studies, the role of antibodies in protection against tumor challenge was investigated. 5T4 specific polyclonal serum decreased tumor burden by approximately 70%. Thus, we conclude that CD4+ T cells are essential for the induction of a protective immune response and that antibodies are the likely effector moiety in this xenogeneic murine tumor model.

Antibodies to a cell surface histone-like protein protect against Histoplasma capsulatum.

A protective role for antibodies has not previously been described for host defense against the pathogenic fungus Histoplasma capsulatum (Hc). Mouse mAb's were generated from mice immunized with Hc yeast that binds the cell surface of Hc. Administration of mAb's before Hc infection reduced fungal burden, decreased pulmonary inflammation, and prolonged survival in a murine infection model. Protection mediated by mAb's was associated with enhanced levels of IL-4, IL-6, and IFN-gamma in the lungs of infected mice. The mAb's increased phagocytosis of yeast by J774.16 cells through a CR3-dependent process. Ingestion of mAb-opsonized Hc by J774.16 macrophage-like cells was associated with yeast cell growth inhibition and killing. The mAb's bound to a 17-kDa antigen expressed on the surface of Hc. The antigen was identified as a histone H2B-like protein. This study establishes that mAb's to a cell surface protein of Hc alter the intracellular fate of the fungus and mediate protection in a murine model of lethal histoplasmosis, and it suggests a new candidate antigen for vaccine development.

Passive transfer studies to elucidate the role of antibody-mediated protection against HIV-1

In order to understand immune correlates of protection and to develop effective immunization strategies, it is important to know if antibodies can confer protection against HIV-1 infection or disease. The recent development of the pathogenic simian/human immunodeficiency virus (SHIV)-macaque model based on env genes from primary HIV-1 isolates permits the in vivo evaluation of anti-HIV-1 envelope glycoprotein immune responses. Using this model, we and others initially showed that passively infused antibody can protect against an intravenous SHIV-challenge. However, HIV-1 is most often transmitted across mucosal surfaces and the intravenous challenge model may not accurately predict the role of antibody in protection against mucosal exposure. We, therefore, adapted the SHIV89.6PD model to allow evaluation of anti-HIV-1 antibodies against vaginal challenge. In order to make comparisons to our prior intravenous challenge study, we used the same SHIV89.6PD stock and antibodies. Our data show that antibodies can confer protection against vaginal exposure to a pathogenic SHIV; if virus transmission occurs, their presence can ameliorate the subsequent pathogenic manifestations of virus infection. Compared to our previous intravenous challenge study, greater protection was achieved after vaginal challenge. Because the highest level of protection occurred when the most potent combinations of antibodies were used, the data confirm that in vitro neutralization assays on peripheral blood mononuclear cells (PBMC) targets cells are a relevant measure of protective antibody activity.

Group B Streptococcal Disease in Nonpregnant Adults

Group B streptococcal (GBS) disease in nonpregnant adults is increasing, particularly in elderly persons and those with significant underlying diseases. Diabetes, neurological impairment, and cirrhosis increase risk for invasive GBS disease. Skin, soft-tissue, and osteoarticular infections, pneumonia, and urosepsis are common presentations. Meningitis and endocarditis are less common but associated with serious morbidity and mortality. Disease is frequently nosocomial and may be related to the placement of an iv catheter. Recurrent infection occurs in 4.3% of survivors. Capsular serotypes Ia, III, and V account for the majority of disease in nonpregnant adults. Although group B streptococci are susceptible to penicillin, minimum inhibitory concentrations are 4-fold to 8-fold higher than for group A streptococci. Resistance to erythromycin and clindamycin is increasing. The role of antibodies in protection against GBS disease in nonpregnant adults is unresolved. However, the immunogenicity of GBS vaccines being developed for prevention of neonatal disease should be assessed for adults who are at risk.

Protection of macaques against vaginal transmission of a pathogenic HIV-1/SIV chimeric virus by passive infusion of neutralizing antibodies

The development of the human immunodeficiency virus-1 (HIV-1)/simian immunodeficiency virus (SIV) chimeric virus macaque model (SHIV) permits the in vivo evaluation of anti-HIV-1 envelope glycoprotein immune responses. Using this model, others, and we have shown that passively infused antibody can protect against an intravenous challenge. However, HIV-1 is most often transmitted across mucosal surfaces and the intravenous challenge model may not accurately predict the role of antibody in protection against mucosal exposure. After controlling the macaque estrous cycle with progesterone, anti-HIV-1 neutralizing monoclonal antibodies 2F5 and 2G12, and HIV immune globulin were tested. Whereas all five control monkeys displayed high plasma viremia and rapid CD4 cell decline, 14 antibody-treated macaques were either completely protected against infection or against pathogenic manifestations of SHIV-infection. Infusion of all three antibodies together provided the greatest amount of protection, but a single monoclonal antibody, with modest virus neutralizing activity, was also protective. Compared with our previous intravenous challenge study with the same virus and antibodies, the data indicated that greater protection was achieved after vaginal challenge. This study demonstrates that antibodies can affect transmission and subsequent disease course after vaginal SHIV-challenge; the data begin to define the type of antibody response that could play a role in protection against mucosal transmission of HIV-1.

Protection of gerbils from amebic liver abscess by vaccination with a 25-mer peptide derived from the cysteine-rich region of Entamoeba histolytica galactose-specific adherence lectin.

The protozoan parasite Entamoeba histolytica causes extensive morbidity and mortality through intestinal infection and amebic liver abscess. Here we show that immunization of gerbils with a single keyhole limpet hemocyanin-coupled 25-mer peptide derived from the 170-kDa subunit of the E. histolytica galactose-binding adhesin is sufficient to confer substantial protection against experimentally induced amebic liver abscesses. Vaccination provided total protection in 5 of 15 immunized gerbils, and abscesses were significantly smaller (P < 0.01) in the remaining vaccinated animals. The degree of protection correlated with the titer of antibodies to the peptide, and results of passive transfer experiments performed with SCID mice were consistent with a role for antibodies in protection. In addition, parenteral or oral vaccination of gerbils with 13-amino-acid subfragments of the peptide N-terminally fused to the B subunit of cholera toxin also significantly inhibited liver abscess formation (P < 0.05). These data indicate that small peptides derived from the galactose-binding adhesin administered by the parenteral or oral route can provide protection against amebic liver abscess and should be considered as components of a subunit vaccine against invasive amoebiasis.

Immune Protection against HSV-2 in B-Cell-Deficient Mice

The role of antibody in protection of the vaginal mucosa and sensory ganglia against HSV-2 infection was examined using HSV- immune, B-cell-deficient μMT mice. Significantly higher virus titers were detected in the vaginal mucosae of immune μMT mice compared to immune C57BL/6J mice 24 h after HSV-2 rechallenge. However, virus was rapidly cleared in immune μMT mice, and the infection was resolved with only a 2-day delay. Passive transfer of immune serum to immune μMT mice prior to rechallenge resulted in HSV-specific vaginal IgG levels comparable to those of immune C57BL/6J mice. Although transferred antibody failed to prevent reinfection of the majority of recipients, vaginal virus titers at 24 h and clearance kinetics were similar to those of immune C57BL/6J controls. Following vaginal rechallenge, HSV-2 did not spread to the sensory ganglia of immune C57BL/6J mice nor was the rechallenge virus detected in the ganglia of the majority of immune μMT mice. However, protection was severely compromised by T-cell depletion of immune C57BL/6J mice. These results suggest that HSV-specific antibody limits, but does not prevent, infection of the genital epithelia. Further, prevention of virus spread to the sensory ganglia in immune animals requires vigorous T-cell immune responses.

How are antibodies involved in the protective mechanism of susceptible mice infected with T. cruzi?

Host resistance to Trypanosoma cruzi is dependent on both natural and acquired immune responses. During the acute phase of the infection the presence of IFN-gamma, TNF-alpha, IL-12 and GM-CSF has been closely associated with resistance, whereas TGF-ss and IL-10 have been associated with susceptibility. Several investigators have demonstrated that antibodies are responsible for the survival of susceptible animals in the initial phase of infection and for the maintenance of low levels of parasitemia in the chronic phase. However, how this occurs is not yet understood. Our results and other data in the literature support the hypothesis that the protective role of antibodies in the acute phase of infection is dependent mostly on their ability to induce removal of bloodstream trypomastigotes from the circulation in addition to other concomitant cell-mediated events.

Protection of macaques against vaginal transmission of a pathogenic HIV-1/SIV chimeric virus by passive infusion of neutralizing antibodies.

The development of the human immunodeficiency virus-1 (HIV-1)/simian immunodeficiency virus (SIV) chimeric virus macaque model (SHIV) permits the in vivo evaluation of anti-HIV-1 envelope glycoprotein immune responses. Using this model, others, and we have shown that passively infused antibody can protect against an intravenous challenge. However, HIV-1 is most often transmitted across mucosal surfaces and the intravenous challenge model may not accurately predict the role of antibody in protection against mucosal exposure. After controlling the macaque estrous cycle with progesterone, anti-HIV-1 neutralizing monoclonal antibodies 2F5 and 2G12, and HIV immune globulin were tested. Whereas all five control monkeys displayed high plasma viremia and rapid CD4 cell decline, 14 antibody-treated macaques were either completely protected against infection or against pathogenic manifestations of SHIV-infection. Infusion of all three antibodies together provided the greatest amount of protection, but a single monoclonal antibody, with modest virus neutralizing activity, was also protective. Compared with our previous intravenous challenge study with the same virus and antibodies, the data indicated that greater protection was achieved after vaginal challenge. This study demonstrates that antibodies can affect transmission and subsequent disease course after vaginal SHIV-challenge; the data begin to define the type of antibody response that could play a role in protection against mucosal transmission of HIV-1.

Protection of Macaques against pathogenic simian/human immunodeficiency virus 89.6PD by passive transfer of neutralizing antibodies.

The role of antibody in protection against human immunodeficiency virus (HIV-1) has been difficult to study in animal models because most primary HIV-1 strains do not infect nonhuman primates. Using a chimeric simian/human immunodeficiency virus (SHIV) based on the envelope of a primary isolate (HIV-89.6), we performed passive-transfer experiments in rhesus macaques to study the role of anti-envelope antibodies in protection. Based on prior in vitro data showing neutralization synergy by antibody combinations, we evaluated HIV immune globulin (HIVIG), and human monoclonal antibodies (MAbs) 2F5 and 2G12 given alone, compared with the double combination 2F5/2G12 and the triple combination HIVIG/2F5/2G12. Antibodies were administered 24 h prior to intravenous challenge with the pathogenic SHIV-89.6PD. Six control monkeys displayed high plasma viremia, rapid CD4(+)-cell decline, and clinical AIDS within 14 weeks. Of six animals given HIVIG/2F5/2G12, three were completely protected; the remaining three animals became SHIV infected but displayed reduced plasma viremia and near normal CD4(+)-cell counts. One of three monkeys given 2F5/2G12 exhibited only transient evidence of infection; the other two had marked reductions in viral load. All monkeys that received HIVIG, 2F5, or 2G12 alone became infected and developed high-level plasma viremia. However, compared to controls, monkeys that received HIVIG or MAb 2G12 displayed a less profound drop in CD4(+) T cells and a more benign clinical course. These data indicate a general correlation between in vitro neutralization and protection and suggest that a vaccine that elicits neutralizing antibody should have a protective effect against HIV-1 infection or disease.

The role of antibodies in protection against candidiasis

The role of antibodies in protection against candidiasis

Serum antibodies to Trypanosoma cruzi antigens in Atacameños patients from highland of northern Chile

In the present work we have investigated the serum antibody spectrum to parasite antigens involved in human T. cruzi infection. Analysis was performed by conventional serology (IHA, IFAT and ELISA), complement-mediated lysis, anti-gal antibody assay and reactivity against recombinant and synthetic peptides and metacyclic antigens by immunowestern-blotting. All the sera showed a significant reactivity in IHA, IFAT and ELISA. We found that 84.2% of the sera showed lytic activity and thirty serum samples (78.9%) which showed a lytic activity higher than 50%, also showed anti-gal antibodies at serum dilutions higher than 1:1,600. Ninety-four percent of sera reacted with one or more of the recombinant DNA clones and 97.3% reacted with one or more of the synthetic peptides. A pool of serum samples with a lytic activity higher than 75% were able to produce 60% to 78% inhibition of cell invasion. Thirty-six of the serum samples (94.7%) were able to react by immunowestern blotting with a T. cruzi metacyclic antigen with molecular size of 70 kDa. The results of obtained give preliminary information about the humoral immune response and the possible role of antibodies in protection against T. cruzi infection of chronic patients from the highlands of Chile.