[The cytokine network and development of immune-based intervention in mycobacterial infection]

Cell-mediated immunity, which is activated through the macrophage-cytokine-CD4 helper T cell axis, plays a key role in host defense against mycobacterial infection. In the process, protection in the host is a local event focused on granulomatous lesions that may lead to tissue damage including caseous necrosis, cavity formation, fibrosis, and consequently respiratory failure and marked deformity. The immune response to tuberculosis is a double-edged sword that may contribute to both clearance of infection and tissue damage. In experimental mouse models, immune-based intervention by interleukin (IL) 12 replacement therapy showed antimycobacterial activity in established infection but simultaneously induced both local and systemic toxicities, such as augmentation of granulomatous inflammation and damage to muscles, liver, and blood. Intermittent combination therapy including antimicrobial chemotherapy (rifamycins) and cytokine (IL-12) immune therapy resulted in maximal defense and minimal inflammation without toxicities. Although observations in mice cannot necessarily be extrapolated directly to humans, there has been a continuing hope that immune-based intervention and combination therapy, available in potentially unlimited quantities by biotechnology, albeit at considerable expense, would have a major impact on treatment of infectious diseases caused by drug-resistant microorganisms. In addition, the understanding of host defense mechanisms facilitates development of new vaccines for mycobacterial diseases.