© 2003 American Thoracic Society
Immunotherapy for TuberculosisWave of the Future or Tilting at Windmills?Departments of Microbiology, Immunology, and Medicine Center for Pulmonary and Infectious Disease Control University of Texas Health Center Tyler, Texas
Protective immunity against Mycobacterium tuberculosis is believed to be mediated by T-lymphocytes that produce the type 1 (Th1) helper T cell cytokines IFN-
The reduced systemic Th1 response in tuberculosis provides a rationale for using IL-2 as an immunotherapeutic adjunct to treat tuberculosis. IL-2 strongly induces IFN- In this issue of AJRCCM (pp. 185–191), Johnson and colleagues report the results of the first large-scale randomized trial of cytokine therapy for tuberculosis (9). Of 110 human immunodeficiency virus–seronegative patients with pulmonary tuberculosis treated with a standard four-drug regimen, 55 patients also received twice-daily injections of IL-2. Although IL-2 was well tolerated, it did not increase the rate of sputum culture conversion after 1 and 2 months of antituberculosis therapy, which were the primary study endpoints. Contrary to expectations, the time to culture conversion was prolonged and the quantitative sputum bacillary counts were slightly higher at all time points in persons receiving IL-2, suggesting that IL-2 may have detrimental effects on bacillary clearance. The percentage of CD4+ cells expressing the IL-2 receptor, CD25, was increased in patients receiving IL-2. A subpopulation of CD4+CD25+ cells are immunosuppressive T regulatory cells, which require IL-2 for survival in vitro (10). It is intriguing to speculate that IL-2 increases the number of T regulatory cells, which in turn downregulates the immune response, reducing the rate of bacillary elimination. Similar mechanisms may underlie the finding that IL-2 increases the CD4 cell count in patients infected with human immunodeficiency virus, but attenuates the immune response to immunization (11). Johnson and colleagues' important study supports the belief that therapy with a single cytokine during the initial phase of therapy is unlikely to significantly improve outcome in unselected patients with drug-susceptible tuberculosis. This belief is based on several factors. First, treatment regimens for drug-susceptible tuberculosis are so effective that it is difficult to significantly increase cure rates by any modality. Second, cytokines stimulate T cells and natural killer cells to kill intracellular M. tuberculosis, but most organisms are extracellular during the initial phase of therapy. Third, compared with the effect of antituberculosis drugs, the immune response has a minor impact on mycobacterial elimination during the early phase of therapy. For example, the concentration of viable organisms in sputum fell at similar rates in persons with drug-susceptible tuberculosis, regardless of the presence of coinfection with human immunodeficiency virus (12).
I believe that there are three major potential uses for immunotherapy in tuberculosis patients. First, in patients with multidrug-resistant tuberculosis, current therapy is suboptimal, and adjunctive immunomodulation may facilitate initial bacillary clearance and increase cure rates. Immunotherapeutic strategies could include administration of Th1 cytokines such as IL-2 or IFN- The second potential use for immunotherapy is to shorten the duration of treatment for drug-susceptible tuberculosis, reducing cost and increasing treatment completion rates. A distinctive role for immunotherapy could be to kill slowly replicating or "dormant" organisms more effectively than current antituberculosis agents, perhaps by administering immunotherapy after the initial phase of treatment. However, a more sophisticated understanding of the biology of slowly replicating M. tuberculosis is necessary to develop such a strategy.
The third use for immunotherapy is to downregulate the host inflammatory response, which can cause substantial morbidity during the early phase of antituberculosis therapy, usually in patients with severe disease. These problems are likely to be due to cytokine production, as the highest local and systemic levels of Th1 cytokines are found in patients with the most severe tuberculosis (14, 15). In these individuals, targeted strategies to reduce the inflammatory response, such as antibodies to IFN- Administration of cytokines or cytokine antagonists alters only one aspect of a complex immune response. An alternative approach is to provide a stimulus that generates a multifaceted response favoring bacillary elimination. Administration of the environmental mycobacterium M. vaccae has been postulated to enhance the Th1 response and suppress the Th2 response, but adjunctive immunotherapy with M. vaccae in tuberculosis patients has not yielded conclusive evidence of clinical benefits in controlled trials (16). Other strategies could include administering Toll-like receptor agonists that boost the innate immune response to infection, a cocktail of immunogenic peptides that stimulate protective T cell responses, or a DNA construct encoding these immunogenic peptides. During the past decade, we have seen explosive growth in our knowledge of the pathogenesis of disease due to M. tuberculosis, coupled with an improved understanding of the mechanisms that mediate protective immunity. During the next decade, I hope that this information will be used to turn the promise of immunotherapy into reality. Johnson and colleagues have fought one of the first battles, but the war remains to be won. FOOTNOTES Conflict of Interest Statement: P.F.B. has no declared conflict of interest. REFERENCES
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and interleukin (IL)-2 (
, may have significant benefits, similar to those achieved with corticosteroids, but with reduced risk of immunosuppression. 
