Throughout history tuberculosis (TB) has been a health problem for humanity. In the beginning of civilization, when human population densities were sparse, this disease may have been fairly harmless. However, with the increase in population densities, probably from the 17th to 19th centuries, TB took epidemic proportions .
Bacille Calmette Guérin (BCG) is effective to prevent miliary and meningeal TB in infants . The reports about the efficacy of this vaccine for the prevention of adults pulmonary TB are contradictory and the consensus is that the protection conferred by BCG against this form of TB is questionable . The wide use of BCG vaccination has been unable to prevent nearly two million deaths associated with TB that are produced every year. Currently the World Health Organization no longer recommends BCG vaccination in children born from HIVpositive mothers which complicate the implementation of BCG vaccination programs . The implementation of standard drug treatment for TB is difficult in the areas of the highest incidence of the disease. Treatment is further complicated by the limited effectiveness of the current therapeutic schemes against drug resistant strains of TB [3-5].
Nowadays there is an increasing realization of the need for new animal models to test vaccine efficacy in more realistic scenarios, overcoming the limitations of current models in use. In addition, the elucidation of the significance of antibody-mediated defense against intracellular pathogens, in particular against
2. Specific antibodies: Players in the defense against TB
In order to develop improved vaccines and new methods for controlling TB, an important element is the discovery of markers to measure the effectors’ mechanisms of the protective immune response against
For many years Cell-Mediated Immunity (CMI) was viewed as the exclusive defense mechanism against intracellular pathogens. The Th1/Th2 classical paradigm prevailed for a long time and the development of vaccines followed this theory . Based on this theory, only intracellular pathogens could be effectively controlled by granulomatous inflammation induced by a Th1 response, whereas a Th2 response induces antibody production that controls extracellular pathogens and parasites. However, the question of what constitutes a true demarcation between “extracellular and intracellular” pathogens is important in this regard. During their infectious cycle, intracellular pathogens could be found in the extracellular space and
There are several prokaryotic and eukaryotic intracellular pathogens for which antibody have been shown to modify the course of infection by different mechanisms, as reviewed extensively by Casadevall and colleagues [9, 10, 11]. In the case of
3. Epidemiological evidence of antibody mediated protection
There is accumulating evidence, in the last few decades, regarding the effect of antibodies in the context of development of pulmonary or disseminated TB. Children with low serum IgG against sonicated mycobacterial antigens and LAM, or those who could not mount antibody responses to these antigens were predisposed to dissemination of
4. Experimental studies
4.1. Animal models
An important criterion for the evaluation of the role of specific antibodies in the protection against TB is the use of animal models. Currently, there is no optimal model to re-produce the infection as it occurs in humans .
The geographical location, genetic factors of the host, the presence of environmental mycobacteria and other concomitant infections like helminthiasis, are factors that have to be considered when designing animal experiments . Several animal models have been used to evaluate different aspects of mycobacterial infection and disease. A crucial aspect is the delivery of mycobacterial inoculum. In this regard, several routes of inoculation have been employed experimentally, including intravenous, intraperitoneal, intranasal, intratracheal and aerosol [21, 22].
The study of the distribution of monoclonal and polyclonal antibody formulations in different organs and tissues of mice after administration by different routes, including the use of backpack models have been reported [23-27]. Each model has its advantages and drawbacks.
For example, the backpack model is very useful for the evaluation of the protective role of IgA, but poses ethical problems in long term experiments due to the increase in tumour size over time produced by the inoculated hybridoma . In prophylactic and therapeutic models, antibody formulations have been administered via the intranasal , intravenous  and intraperitoneal  routes and combined with cytokines and antibiotics [31, 32] before and/or after the infectious challenge. The administration of
Another approach has been the use of knockout mice models for IgA  polymeric immunoglobulin receptor (pIgR)  and B cells [35,36,37,38], as will be discussed later.
4.2. Experimental studies with antibodies
A substantial number of studies utilizing anti mycobacterial antibodies have been conducted as far back as the end of the 19th century. These experiments can be grouped into several categories: serum therapies, mouse polyclonal antibodies, human polyclonal antibodies (including commercial human gamma globulins), secretory human IgA (hsIgA) and studies with monoclonal antibodies.
4.2.1. Serum therapies
Serum therapy experiments were conducted from the second half of the 19th century (reviewed in [39,40]). Immune sera was generated by immunizing animals with different mycobacterial fractions and administered either to animals or humans [39,40] The results obtained were either beneficiary, variable, inconclusive or contradictory, [39,40]. These variable results led to the perceived minor role of antibodies in the defense against
What factors could have led to the heterogeneity in study results? Recognizable differences in the methods used for serum preparations and their administration, as well as the lack of appropriate experimental controls probably accounted in part for the studies outcomes. Furthermore, it is important to recognize that immune serum is a polyclonal preparation that includes antibodies with multiple specificities and isotypes. Consequently, polyclonal sera may contain antibodies of different subclasses and functional categories that can affect theoutcome of infection. For example, IgG3 murine monoclonal antibodies protected against
For some microorganisms, such as
The animal model used is another important parameter that varies between different experiments cited in the literature . Timing, the route of infection, the magnitude of the infecting inoculum are some additional variables that could affect antibody protection studies .
Despite their variability, the results obtained with serum therapy were valuable, demonstrating some beneficial effect of serum on the course of TB in humans, mainly in cases of early or localized TB . Moreover, it was demonstrated that long periods of treatment were necessary to achieve a sustained effect .
4.2.2. Polyclonal mouse antibodies
A recent study re-examined the usefulness of immune serum in the context of a therapeutic vaccine against TB . This vaccine, named RUTI, is generated from detoxified
4.2.3. Human gammaglobulins
188.8.131.52. Specific human polyclonal antibodies
Evidence for the stimulatory role of specific polyclonal antibodies on cellular immunity in experimental mycobacterial infections was reported by de Valliere and colleagues in 2005 . In this study, serum samples containing specific antimycobacterial antibodies were obtained from volunteers vaccinated twice with BCG by the intradermal route. Significant titres of IgG antibodies against lipoarabinomannan (LAM) were detected in the sera. BCG internalization into phagocytic cells was significantly increased in the presence of these BCG induced antibodies as were the growth inhibitory effects of neutrophils and macrophages on mycobacteria. Furthermore, these antibodies induced significant production of IFN-γ by CD4+ and CD8+ T cells .
184.108.40.206. Commercial immunoglobulin formulations
Human Intravenous Immunoglobulin (IVIG) has been used to treat individuals with immune deficiencies and patients with inflammatory, autoimmune and infectious conditions [49, 50, 51]. Several groups tested the effect of human immunoglobulin preparation on mycobacterial infection. Roy and colleagues showed that treatment of
The same formulation was evaluated also in a mouse model of intratracheal infection with
The protective effect of the hIg formulation was abolished following pre-incubation with
Taken together, these studies provide support for the potential use of immunoglobulins against
220.127.116.11. Human secretory IgA
Human secretory IgA (hsIgA) is the major class of antibody associated with immune protection of the mucosal surfaces . Colostrum volume is above 102 mL in humans during the first three days after delivery . The high percentage of (hsIgA) in human colostrum  strongly suggests its important role in passive immune protection against gastrointestinal and respiratory infections . In one study performed by Alvarez and colleagues, hsIgA from human colostrum was obtained by anion exchange and gel filtration chromatographic methods, using DEAE Sepharose FF and Superose 6 preparative grade, respectively .
hsIgA was administered intranasally to BALB/c mice, and the level of this immunoglobulin in several biological fluids was determined by ELISA. The results showed the presence of this antibody in the saliva of animals that received the hsIgA, at all time intervals studied. In tracheobronchial lavage, hsIgA was detected at 2 and 3 hours after inoculation in animals that received the hsIgA . Similar studies were performed by Falero and colleagues with monoclonal antibodies of IgA and IgG class . Following demostration that hsIgA could be detected in several biological secretions after intranasal administration, the protective effect of this formulation against
The pneumonic areas were more prominent in the untreated animals than in the groups treated with hsIgA and
4.2.4. Monoclonal antibodies
Since the first report on the use of the monoclonal antibody Mab 9d8 against
Heparin Binding Hemagglutinin Adhesin (HBHA) is a surface-exposed glycoprotein involved in the mycobacterial binding to epithelial cells and in mycobacterial dissemination . Monoclonal antibodies 3941E4 (IgG2a) and 4058D2 (IgG3) directed against HBHA were used to coat mycobacteria before administration to mice. In this study, spleen CFUs was reduced while lung CFUs did not . These results suggest that binding of these antibodies to HBHA can impede mycobacterial dissemination.
The protective efficacy of a monoclonal antibody, TBA63 and IgA anti-Acr administered intranasally before and after the intranasal or aerosol challenge with
When the lungs of mice were histologically examined, granulomas were better organized in the infected animals that had received TBA63 than in controls or mice treated with TBA86. The reduction of CFU in lungs of the treated group was associated with milder histopathological changes, as indicated by the organization of the granulomas and less pneumonic area. The fact that this Mab promotes granuloma formation in mice infected intratracheally with
The 16 kDa protein (Acr antigen) has been defined as a major membrane protein peripherally associated with the membrane  carrying epitopes restricted to tubercle bacilli on the basis of B-cell recognition [68, 69]. The Acr antigen is present on the surface of tubercle bacilli and is highly expressed in organisms growing within infected macrophages, allowing it to be potentially targeted by specific antibodies either inside infected cells as well as extracellulary. A novel immunotherapy, combining treatment with anti-IL-4 antibodies, IgA antibody against 16 kDa protein and IFN-γ, showed the potential for passive immunoprophylaxis against TB. In genetically deficient IL-4-/- BALB/c mice, infection in both lungs and spleen was substantially reduced for up to 8 weeks. Administration of rIL-4 to IL-4-/- mice with increased bacterial counts to wild-type levels and make mice refractory to protection by IgA/IFN-γ .
More recently, Balu and colleagues reported that intranasal administration of a human IgA1 Mab, obtained using a single-chain variable fragment derived from an Ab phage library with high affinity for hspX and the human FcαRI (CD91) IgA receptor together with recombinant mouse IFN-γ significantly inhibited pulmonary infection with
Inhibition of the infection by the antibody was synergistic with human rIFN-γ in purified human monocytes cultures but not in whole blood cultures . The demonstration of the role of FcαRI (CD91) in human IgA mediated protection contributes to understanding the mechanisms involved as well as for using this knowledge for the future development of new immunotherapies for TB .
4.2.5. Transgenic mice
Mouse models with deficiency in antibody production can provide useful information for understanding certain roles of antibodies in protection against mycobacterial infections. Rodríguez and colleagues reported that after immunization of IgA deficient (IgA-/-) and wild type mice by the intranasal route with the mycobacterial surface antigen PstS-1, IgA-/- mice were more susceptible to BCG infection than IgA+/+ mice . Cytokine response analysis demonstrated reduction in the IFN-γ and TNF-α production in the lungs of IgA-/- as compared with IgA+/+ mice, suggesting that IgA may play a role in protection against mycobacterial infections in the respiratory tract. Furthermore, these authors demonstrated that immunized pIgR-/- mice were more susceptible to BCG infection than immunized wild-type mice .
In an attempt to elucidate whether antibody-mediated immunity has a special role in the defense against TB, different experiments with B cell knockout mice were performed by several authors. In 11016, Vordermeier and colleagues developed an infection model of TB in μ chain knockout Ig- mice. Organs from
In another series of experiments the role of B cells was evaluated during early immune responses to infection with a clinical strain of
Together these studies suggest that B cells may have an important role in host defense against
5. Mechanisms of action
The various effects of antibodies demonstrated in the studies analyzed, suggest that different mechanisms of action are involved in the effect of monoclonal and polyclonal antibodies on
Antibodies may be critical, during the extracellular phases of intracellular facultative pathogens. They may act by interfering with adhesion, by neutralizing toxins and by activating complement. Moreover, antibodies may be able to penetrate recently infected cells, bind internalised pathogens, and enhance antigen processing (76). Antibodies may also play a crucial role in modulating the immune response by activating faster secretion of selected cytokines that in turn, contribute to more efficient and rapid Th1 response [76,77], increasing the efficacy of co-stimulatory signals, enhancing Antibody Dependent Cellular Cytotoxicity (ADCC) and the homing of immune cells to the lungs after the respiratory infection [10,78, 79, 80, 81, 82, 83].
Examples of relevant potential action mechanisms of antibodies against
6. Potential uses of antibodies against TB
Future applications of antibody formulations for the control of TB may include several possibilities including treatment, prevention and diagnosis.
Antibody based therapy could potentially be useful in several scenarios. They could be used to shorten the standard treatment period of patients with uncomplicated TB when coupled with standard chemotherapy. However, they would be particularly important in the treatment of patients infected with Multidrug Resistant (MDR) and Extensively Drug Resistant (XDR) strains, in combination with the standard treatment.
6.2. Prophylactic use
Prophylactic use of antibodies could be applied in recent contacts of TB patients, with special attention to risk groups . In this regard, successful prophylactic use of antibodies in exposed individuals has been shown in the case of several other pathogens such as varicella, tetanus, Respiratory Synsicial Virus (RSV), rabies and Hepatitis B [85, 86]
The induction of specific protective antibody responses by vaccination, either alone or as an addition to the stimulation of cell mediated immunity could be a novel strategy for the development of new generation of prophylactic and therapeutic vaccines against TB.
The prevailing past dogma that discounted the role of antibodies in host protection against TB has resulted in a limited study of B cell immunodominant epitopes as targets for protective immunity .
6.3.1. Polysaccharide conjugate vaccines
Polysaccharide conjugate vaccines are considered to elicit specific protective antibody responses against a variety of pathogens . However, the polysaccharide conjugate vaccine against
All these vaccine candidates induced the production of specific IgG [61, 90, 91, 92] and some of them conferred variable levels of protection [61, 91] which validate this strategy as one of the potential avenues for the development of new generation of vaccines against tuberculosis
6.3.2. Identifying other B-cell immunodominant epitopes
With the development of bioinformatics tools for bacterial genome analysis, it has been possible to predict
In one study, bibliographic search was used to identify highly expressed proteins in active, latent and reactivation phases of TB . The subcellular localization of the selected proteins was defined according to the report on the identification and localization of 1044
The regions of the selected proteins containing promiscuous B and T cell epitopes were determined . Thus the
Considering the results of the
Bioinformatics tools for prediction of T and B epitopes were also employed for the design of multiepitopic constructions, which were used to obtain recombinant BCG strains. Based on this prediction, B cell epitopes from ESAT-6, CFP-10, Ag87B and MTP40 proteins were selected and combined with T cell epitopes of the 87B protein and fused to Mtb8.4 protein .
A significant IgG antibody response against specific B cell epitopes of ESAT-6 and CFP-10 was obtained in mice immunized with the recombinant strain. After studying the specific response of spleen cells by lymphoproliferation assay and detection of intracellular cytokines in CD4 + and CD8 + subpopulations, the recognition of T epitopes was also observed. The response showed a Th1 pattern after immunization with this recombinant strain (Mohamud, R, et al. manuscript in preparation). In another series of experiments, recombinant BCG strains expressing several combinations of multiepitopic constructions were used to immunize BALB/c mice subcutaneously and challenged intratracheally with the
Although no serological assays are currently recommended for diagnosis of TB , largely due to the possibility of false results and thus incorrect treatments, for many other pathogens, serological diagnostic tests has been of great value, particularly in poor countries. In some cases, antibody responses can constitute useful correlates of protection . In the specific case of TB, several studies of the antibody response have been reported . There is a substantial amount of variability in antibody response to TB . This variability has been attributed to several factors. Some of these factors are associated with the pathogen (strain variation, micro-environment and growth state of bacteria) and others are related to the host, primarily previous exposure to related antigens and host genetics .
However, it is important to consider that only a small fraction of the genomic regions of
7. Concluding remarks
The cumulative work reviewed above with regard to the use of antibody formulations and vaccines suggest that antibodies if present at the right moment at the site of infection could provide protection against
Various antibody formulations could potentially be used as immunotherapeutic agents in combination with the conventional treatment and in the management of patients affected by Multidrug Resistant (MDR) and Extensively Drug Resistant (XDR) strains.
The study of the role of specific antibodies in the defense against tuberculosis opens new possibilities for future development of new vaccines, diagnostics tools and therapies against this pathogen. It is likely that new discoveries will arise from the ongoing studies in this area that will expedite the introduction of new strategies in the fight against tuberculosis.
AcknowledgmentsThe authors' work was partly supported by the Ministry of Science, Technology &Innovation, Malaysia [Grant No. 304.PPSK.6350081.N106 & 10-01-05-MEB002] and USM Research University Grant [1021.PPSK.832005], CONACyT (contract 86657) and the Ministry of Science and Technology, Cuba.
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