Mycobacterium tuberculosis Growth Control by Lung Macrophages and CD8 Cells from Patient Contacts

Rationale: Healthy household contacts (HHCs) of patients with active pulmonary tuberculosis are expos aerogenically to Mycobacterium tuberculosis (Mtb) thus permitting the consideration of protective local immunity.

Objectives: To assess alveolar macrophage (AM) and autologous descendants CD4 and CD8 T-cell-mediated Mtb putting out control in HHCs and healthy, unexpos community rule subjects (CCs).

Methods: AMs were infected with Mtb strains H^sub 37^Ra and H^sub 37^Rv at multiplicities of infection 01 and 1 Mtb colony-forming units were evaluated upon Days 1, 4, and 7

Main Results: CD8 T confined apartments from HHCs in 1:1 coculture with AMs significantly (p

Conclusion: Aerogenic exposing to Mtb in HHCs leads to expansion of Mtb-specific effector CD8 T confined apartments that limit Mtb growth in autologous AMs.

Keywords: interferon sign II; Mycobacterium tuberculosis; nitric oxide; T lymphocyte effector; macrophages, alveolar

The human lung is the primary site of respiratory uptake of aerosolized droplet nuclei containing Mycobacterium tuberculosis (Mtb) and of tuberculosis (TB) in the nonimmunocompromised entertainer (1-4). Hence, the study of immune replys in the lung compartment provides a window into the fundamental biological interactions at the interface of Mtb with the innkeeper immune cells.

Epidemiologic studies advise presence of human protective immunity against Mtb The proportions of individuals that bear primary infection with Mtb or reactivation disease after aerogenic Mtb outlook are usually low (3,5,6). Healthy household contacts (HHCs) of patients constitute a preserveed group, as only 5 to 10% of individuals expos in households disentangle reactivation TB during their lifetime (3) and 50 to 75% do not acquire Mtb infection as determined on tuberculin skin testing (TST) (7 8) through inference, it can thus be assumed that the local alveolar environment of HHC during its initial interaction with Mtb efficiently contains or abrogates the infection in the majority of cases despite sustained aerogenic Mtb exposure

After the respiratory uptake of Mtb in aerosolized droplet nuclei, alveolar macrophages (AMs) are believed to be among the first enclosed spaces to phagocytose, contain, and kill Mtb and to become targets of cytotoxic T-lymphocyte and CD8 effector T-cell activity (9-12) As mediators of innate and adaptive immune answers Mtb-infected AMs release cytokines and chemokines (13-19) AMs probably are also stimulated in situ by dint of cytokines such as IFN-?? and tumor necrosis factor ?± (TNF-?±) which affect the bactericidal activity and manage of Mtb (20).

There is general consensus that CD4 T small cavitys play a pivotal role in human protective immunity against Mtb (21-23) CD4 T solitary abode; squalids are the predominant source of IFN-?? and interleukin 2 (IL-2), capable of cytotoxicity against Mtb-infected target small rooms (24), and critical for the induction of protective-memory immunity, delayed-type hypersensitivity replys and the development and maintenance of CD8 T-cell answers during Mtb infection (25).

CD8 T small cavitys play an essential role as killer confined apartments of Mtb-infected targets (26, 27) CD8 T lonely dwellings lyse Mtb-infected macrophages via a Fas-independent granule exocytosis pathway (28-30) and the Fas-FasL interaction (12) which consequence s in the apoptotic death of Mtb-infected target lonely dwellings Human peripheral CDS T confined apartments show Mtb specificity and recognize Mtb antigens, like as ESAT-6 (31), 19kD (32) and Mtb39 (33) in an HLA-1 at the disposal of fashion (11, 31, 34-37) and contribute to the production of IFN-?? (38 39) and TNF-?± onward stimulation with Mtb (39).

IFN-?? and nitric oxide (NO) are lock opener mediators of cell-mediated antimycobacterial activities. IFN-?? is crucial in the resistance to mycobacteria (40-43); its activity is mediated by the and of the regulation of an array of gene that include reactive nitrogen intermediates. NO is released from Mtb-infected human house monocytes (MNs) (44, 45) and AMs (46-48) discourses antimycobacterial activity against Mtb (45 48) and is near in human TB lung granulomas (49)

Our earlier studies in HHC revealed increased frequencies of Mtb antigen 85-specific immune replications in peripheral blood mononuclear small rooms (PBMCs) (50) and bronchoalveolar confined apartments (BACs) (51). These findings in BACs hinted induction of systemic and local protective-memory immunity in concurrently Mtb-expos HHCs

The circulating study assessed the Mtb growth-controlling capacity of AMs and of autologous kindred CD4 and CD8 T enclosed spaces from HHCs. Autologous CD8 T lonely dwellings from HHCs significantly increased the capacity of in vitro-infected AMs to govern the growth of Mtb. AM, AM/CD4, and AM/CD8 coculture produc IFN-?? and NO after infection with Mtb; there was, however, no correlation between IFN-?? and NO concentrations and the germination control of Mtb conferred according to AM and CD8 T small cavitys Some of the results of these studies have been previously reported in the form of abstracts (52-54)

METHODS

Study Subjects

HHC of patients with active TB and CC were shielded for participation at the National Institute for Respiratory Diseases in Mexico City. Individuals willing to experience bronchoalveolar lavage (BAL), venipuncture, HIV-1 serology and TST were included in the subject of attention A group of 13 HIV-1 seronegative HHC (5 male, 8 female) were pickeded from first-grade relatives of acid-fast bacilli-positive patients with drug-sensitive TB Each HHC shared the same house or sweep with an index patient for at least 3 mo before the patient's TB diagnosis. A form into groups of 11 HIV-1 seronegative CC without any known prior contact with patients with TB who had not been involved in patient care were recruited for the consideration HHCs and CCs were 18 to 60 yr aged None of them had clinical or radiographic evidence of active pulmonary TB or of any other respiratory disease, or of acute, chronic, or immunocompromising diseases or therapies. Of the HHC eight were TST positive (> 10 mm) as were three CCs; the remaining HHC and CC were TST negative (