Adjunctive immunotherapy of mycobacterial infections

In order to cope with the worldwide increase in the prevalence of multidrug-resistant tuberculosis and Mycobacterium avium complex (MAC) infections, a number of new antimycobacterial drugs have been or are being synthesized and developed. Development of new protocols for chemotherapy of refractory mycobacterioses is also sharing promise. In this context, one promising strategy is to devise regimens to treat patients with refractory mycobacterioses using ordinary antimycobacterial agents in combination with appropriate immunomodulators. This article deals with the following matters: an outline of the host immune response to mycobacterial pathogens, particularly in terms of mobilization of the cytokine network in response to mycobacterial infection, and adjunctive immunotherapy using (1) recombinant immunomodulating cytokines, (especially Th-1 and Th-1-like cytokines such as IFN-gamma, IL-2, IL-12, IL-18 and GM-CSF), (2) inhibitors of immunosuppressive cytokines (TGF-beta) and some proinflammatory tissue-damaging cytokines (TNF-alpha), and (3) immunomodulatory agents such as ATP and its analogs, imidazoquinoline, diethyldithiocarbamate, poloxamer, dibenzopyran, galactosylceramide, nonsteroidal anti-inflammatory drugs, Chinese traditional medicines, levamisole, synthesized mycobacterial oligoDNA, DNA vaccine expressing mycobacterial HSP65 or IL-12, and heat-killed Mycobacterium vaccae. Although adjunctive immunotherapy is fairly efficacious in treating intractable mycobacterioses, it still features serious problems and dilemmas, such as high cost, occasionally severe side effects, and, in many cases, only modest efficacy in potentiating host defense mechanisms against mycobacterial infections, primarily because of the induction of macrophage-deactivating cytokines during the course of long-term administration of adjunctive agents.