This decrease was independent of an associated anti-TB treatment. interferon (IFN)-. In the 68 patients with inflammatory diseases (rheumatoid arthritis, spondylarthropathy or Crohn’s disease), including 31 patients with a previous or latent tuberculosis (TB), 14 weeks of anti-TNF- treatment had no effect on the proliferation of CD4+ T lymphocytes. In contrast, the number of IFN–releasing CD4+ T lymphocytes decreased for PPD ( em p /em 0.005) and CFP-10 ( em p /em 0.01) in patients with previous TB and for PPD ( em p /em 0.05) in other patients (all vaccinated with Bacille Calmette-Gurin). Treatments with Ifx and with Eta affected IFN- release to a similar extent. em In vitro /em addition of TNF antagonists to CD4+ T lymphocytes stimulated with mycobacterial antigens inhibited their proliferation and their expression of membrane-bound TNF (mTNF). These effects occurred late in cultures, suggesting a direct effect of TNF antagonists on activated mTNF+ CD4+ T lymphocytes, and Ifx and Ada were more efficient than Eta. Therefore, TNF antagonists have a dual action on anti-mycobacterial CD4+ T lymphocytes. Administered em in vivo /em , they decrease the frequency of the subpopulation of memory CD4+ T lymphocytes rapidly releasing IFN- upon challenge with mycobacterial antigens. Added em in vitro /em , they inhibit the activation of CD4+ T lymphocytes by mycobacterial antigens. Such a dual effect may Dioscin (Collettiside III) explain the increased incidence of TB in patients treated with TNF antagonists as well as possible differences between TNF antagonists for the incidence and the clinical presentation of TB reactivation. Introduction Tumour necrosis factor (TNF) antagonists such as the anti-TNF monoclonal antibodies (mAbs) infliximab (Ifx) and adalimumab (Ada) and the soluble TNF receptor etanercept (Eta) are efficacious in several immune-mediated inflammatory diseases (IMIDs), including rheumatoid arthritis (RA), spondylarthropathies (SA), Crohn’s disease (CD), psoriasis arthritis, and juvenile arthritis [1-8]. However, they are Dioscin (Collettiside III) also associated with an increased incidence of infections, especially infection with em Mycobacterium tuberculosis /em ( em Mtb /em ). Tuberculosis (TB) in patients treated with TNF antagonists is characterised by a high frequency of extra-pulmonary and disseminated lesions and with few granulomas in involved organs. Because most cases of TB develop soon after treatment initiation, they correspond to a reactivation of a latent TB infection [9-11]. All three TNF antagonists have been associated with increased incidence of TB. However, this incidence seems to be lower for Eta than for Ifx [12,13], and the median delay between treatment initiation and occurrence of TB was shorter with Ifx . Membrane-anchored TNF (mTNF) is expressed by activated macrophages and T lymphocytes [14,15]. Although Ifx and Eta both neutralise soluble TNF, Ifx binds more efficiently to mTNF than does Eta. Thus, Ifx but not Eta induces apoptosis of activated monocytes and lamina propria T lymphocytes from patients with CD [15,16]. The mechanism by which TNF antagonists reactivate latent TB is not fully understood. In animal models, TNF plays a central role in the containment of mycobacterial infections, and T cell-derived soluble TNF as well as mTNF are essential in protecting against em Mtb /em infection [17-22]. Detection of latent TB is crucial before starting treatment with TNF antagonists because it requires a preventive treatment for TB reactivation before TNF antagonist administration [23-25]. However, this detection is difficult, especially in individuals vaccinated with the Bacille de Calmette Gurin (BCG). Diagnosis of latent TB may benefit from new em in vitro /em assays testing the Mouse monoclonal to CIB1 immune response Dioscin (Collettiside III) against proteins such as culture filtrate protein (CFP)-10 and early secreted antigenic target (ESAT)-6, which are encoded in the genome of em Mtb /em and of a few other mycobacterial species ( em Mycobacterium kansasii /em , em Mycobacterium szulgai /em , and em Mycobacterium marinum /em ) but not in that of BCG and other mycobacteria. Presence of an immune response against CFP-10 and ESAT-6 is a relatively specific indicator of em Mtb /em infection and has allowed for precise diagnosis of active as well as latent TB in several studies of BCG-vaccinated individuals [26-32]. In the present work, we analysed the effect of TNF antagonists on the immune response against mycobacterial antigens, either CFP-10 or purified protein derivative (PPD), which contains antigens shared by all mycobacterial species, including BCG. This effect was studied in two different conditions. In patients with an active form of RA, SA, or CD, the impact of treatment with TNF antagonists on circulating T lymphocytes was evaluated by analyzing em ex vivo /em their proliferation and their rapid release of interferon (IFN)- in response to mycobacterial antigens. We also determined whether TNF antagonists added em in vitro /em to blood cells alter their activation by mycobacterial antigens. Materials and methods Characteristics of patients Patients were consecutively enrolled in the study between April 2003 and May 2005. They were divided into four groups, depending Dioscin (Collettiside III) on previous or latent TB and IMID. Previous TB was defined as a previous known history of TB with adequate treatment. Latent TB was defined according to French recommendations :.