Adjunctive Immunotherapy for Drug-Resistant Tuberculosis

The fear of the epidemic of tuberculosis due to multi-drug resistant strains has prompted scientists to seek new drugs complementing conventional ones introduced in the early fifties. While new anti-tuberculosis drugs are being sought, immunotherapy in conjunction with the standard chemotherapy points to another potentially useful solution. The merit of such adjunctive immunotherapy in multi-drug resistance cases has been demonstrated in some clinical studies. As host immune defense is a critical factor in the pathogenicity of tuberculosis, immunotherapy should play an important role in disease prevention and cure.

Cytokine Therapy

Cytokines refer to an array of relatively low molecular weight, pharmacologically active proteins that are secreted by one cell and can alter either its own functions (autocrine effect) or those of adjacent cells (paracrine effect). Among the cytokine group are a large number of interleukins plus growth and colony-stimulating factors. Interleukin refers to a group of well-characterized cytokines that are produced by leukocytes and other cell types and are equipped with a wide spectrum of functional activities related to inflammatory and immune mechanisms. Cytokines such as TNF-alpha may enter the circulation and have a systemic effect. Cytokine therapy for multi-drug resistant tuberculosis has produced some successes (ref. 1):

IFN-gamma aerosol: rapid sputum smear conversion but no cultural conversion
IFN-gamma subcutaneous: 2 cures. 1 improvement, 2 unchanged
IL-2 intradermal: rapid reduction in sputum smears with clinical improvement

Thalidomide Therapy

The anti-inflammatory and immunomodulatory effects of thalidomide have led scientists to explore its clinical therapeutic values. Thalidomide is now being considered as a potential treatment for tuberculosis. Thalidomide affects cytokine production and T lymphocyte proliferation. It appears that thalidomide suppresses TNF-alpha production by macrophages and thereby reduces inflammatory response. Thalidomide elevates the IFN-gamma level and modulates several other cytokines as well, noteworthily, IL-2 and IL-12. Thalidomide costimulates T lymphocytes, with greater effect on CD8+ than CD4+ T cells. This finding is important since CD8+ T cells have been shown contributory to the protective immune response to tuberculosis infection. The clinical application of thalidomide as part of standard tuberculosis therapy is inconclusive amid variability among reports. However, thalidomide has been shown to be an effective adjuvant for tuberculosis patients complicated with severe inflammatory reaction or wasting conditions.

Reference:

(1) S.M. Holland. 2000. Adjunctive Immunotherapy (Interferon - g) for Difficult-to-Treat Infections Including Mycobacterial Disease. http://www.intermune.com/library/html/library.html