**4.1. Animal models**

**2. Specific antibodies: Players in the defense against TB**

immune response against *M. tuberculosis*.

58 Tuberculosis - Current Issues in Diagnosis and Management

could potentially be targeted by specific antibodies.

the host [15].

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

For many years Cell-Mediated Immunity (CMI) was viewed as the exclusive defense mecha‐ nism against intracellular pathogens. The Th1/Th2 classical paradigm prevailed for a long time and the development of vaccines followed this theory [6]. Based on this theory, only intracel‐ lular 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 *vice versa*. In the specific case of *M. tuberculosis*, it can be localized extracellularly at the beginning of the infection in the upper respiratory tract as well as during advanced stages of the disease, after rupture of granulomatous lesions occur [7]. This facultative intracellular pathogen was shown to have an extracellular phase [7] [8] that may include replication [7] which in turn

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 *Erhlichia* spp., specific antibodies were shown to mediate protection [12], possibly by blocking cellular entry or promoting the expression of proinflammatory cytokines. [13,14]. A combination of both humoral and cellular immune mechanisms could be the optimal choice controlling certain intracellular patho‐ gens,.In this regard, de Valliere and colleagues reported that human antimycobacterial antibodies enhanced Cell-Mediated Immune responses to mycobacteria that are beneficial to

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

*M. leprae* reactive salivary IgA antibodies were suggested to be important in a mucosal protective immunity [17]. In study carried out among the Mexican Totonaca Indian population, the presence of high antibody titers to Ag87 complex antigens were observed in patients with non-cavitary TB and in patients who were cured with anti-TB chemotherapy. In contrast,

responses to these antigens were predisposed to dissemination of *M. tuberculosis* [16].

**3. Epidemiological evidence of antibody mediated protection**

patients without such antibodies had a poor outcome of the disease [18].

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 [19].

The geographical location, genetic factors of the host, the presence of environmental myco‐ bacteria and other concomitant infections like helminthiasis, are factors that have to be considered when designing animal experiments [20]. 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 [28]. In prophylactic and therapeutic models, antibody formulations have been administered via the intranasal [29], intravenous [30] and intraperitoneal [26] routes and combined with cytokines and antibiotics [31, 32] before and/or after the infectious challenge. The administration of *M. tuberculosis* pre-coated with antibodies [27, 33] in different models of infection has also contributed to understanding the interactions between host and microbe.

Another approach has been the use of knockout mice models for IgA [34] polymeric immu‐ noglobulin receptor (pIgR) [34] and B cells [35,36,37,38], as will be discussed later.
