Cellular immune responses in tuberculosis: Protection and immunopathology

Tuberculosis (TB) patients relapse if treatment is not continued for 6 months, because chemotherapy fails to convert the patients' response from the necrotising pattern characteristic of the disease (Koch phenomenon), to the non-necrotising bactericidal function required for immunity. We need to understand the nature of these two immunological states, and we need to learn how to convert one to the other. Recent data indicate that protection requires a Type 1 cell-mediated response. Cytokine TNF alpha is also required, and yet there is evidence to implicate TNF alpha in the pathology of the disease. This paradoxical dual role of TNF alpha may provide the key to understanding TB. TNF alpha causes no tissue damage if injected into an inflammatory site mediated by a ''pure'' Th1 response. In such sites, it acts as an additional macrophage-activating factor. In sharp contrast, TNF alpha is toxic if injected into inflammatory sites mediated by mixed Th1+Th2 (?Th0) T cell responses. DTH response sites in mice with progressive pulmonary TB are also TNF alpha-sensitive. Moreover if the immunological state accompanying progressive disease (mixed Th1/Th2 and TNF alpha-sensitivity) is deliberately primed in mice before they are infected, they are rendered more susceptible to pulmonary TB than unimmunised control animals. This reminds us of earlier work showing that preimmunised guinea-pigs (so as to have the Koch phenomenon) are more, rather than less, susceptible to deep infection. This state of increased susceptibility to TB can be induced by using a saprophytic environmental mycobacterium. Similarly the same organism can be used to vaccinate (by evoking a ''pure'' Th1 pattern with a dose that is 100-fold lower) or to partially treat established disease in man and mice. Therefore epitopes that are common to M. tuberculosis and to a fast-growing saprophyte (likely to include heat shock proteins) can play key roles in protection and immunopathology. This may explain the effect of contact with environmental species on the variable efficacy of BCG. Thus, it seems that these crucially important common epitopes do not evoke the Koch phenomenon, and in fact skin-test responsiveness to these is lost during progressive TB, while antigen extracts of M. tuberculosis still cause necrosis. This raises questions as to why the common epitopes are handled differently, and an important fact, it means that they are safe to use in human immunotherapy trials.