2002. the world’s population and causing over 2 million deaths annually (35). The incidence of tuberculosis (TB) has increased in recent years and this is attributed to a number of factors, including coinfection with human immunodeficiency virus and the emergence of multidrug-resistant strains of the bacterium (24). The chemotherapeutic regimens available for treatment of TB are far from ideal, requiring the ingestion of multiple anti-TB drugs in combination over prolonged periods. The side effects of current drug regimens, combined with the protracted duration of treatment, frequently result in poor patient compliance, treatment failures, and associated emergence of drug resistance with major financial AML1 implications (26). The close supervision of treatment that is needed to raise efficacy to acceptable levels, such as the World Health Organization’s DOTS program, pushes the cost beyond the reach of many of the world’s populations most in need. The development of novel, shorter treatments for TB is JNJ-7706621 now an urgent requirement. The possibilities of immunotherapy deserve more attention than they have received in the past, not least because immunotherapy could circumvent the problems of drug resistance. However, this must be approached with caution, because the disease is itself a consequence of the immune response and one must stimulate protective and not harmful aspects of the response. is a facultative intracellular pathogen, and it is cell-mediated Th1 type immunity, comprising cytokine-mediated monocyte activation and T-cell cytotoxicity toward infected macrophages, that is the major component of the protective immune response. The role of antibodies in protection is less clear but is being reevaluated in light of a number of recent publications (7, 13, 34). Indeed, it JNJ-7706621 was the concern of one of us (S.J.) that antibodies that were being administered to patients in the form of high-dose intravenous immunoglobulin (hdIVIg) might theoretically exacerbate latent or undiagnosed tuberculosis that led to the present study. IVIg is a human blood product prepared from the plasma of from 1,000 to 15,000 donors per batch. It has been widely used in the treatment of primary and secondary antibody deficiencies and in these circumstances it is administered at replacement dose (200 to 400 mg/kg of body weight at 2- to 4-week intervals) (28). In contrast, hdIVIg, given at 2 g/kg/month and used as an immunomodulatory agent, was first described for immune-mediated thrombocytopenia (18) but is now widely used in treating a range of neurological, hematological, immunological, dermatological, and rheumatological immune and inflammatory disorders (29). Recently, the use of JNJ-7706621 IVIg as an anti-infectious agent in viral and bacterial infections has been reviewed (4), and it has been demonstrated that IVIg given in combination with ampicillin is protective against pneumococcal pneumonia (10). In this study, we investigated the capacity of hdIVIg to influence the course of infection in a murine model of TB. MATERIALS AND METHODS Mice. C57BL/6, BALB/c, and nude (BALB/c nu/nu) mice aged 8 to 12 weeks were obtained from breeding colonies maintained under specific pathogen-free conditions in the Division of Biological Services, National Institute for Medical Research. Experiments were carried out in the United Kingdom according to the Home Office Animals Scientific Act of 1986. Bacterial cultures. (H37Rv) was grown in 7H9 Middlebrook medium supplemented with 0.05% Tween 80 and 10% Middlebrook ADC enrichment (Difco Laboratories, Surrey, United Kingdom) at 37C for 14 days, aliquoted, and stored at ?80C. Aliquots were thawed and diluted in phosphate-buffered.