THE ROLE OF TNF-ALPHA IN T-CELL-MEDIATED INFLAMMATION DEPENDS ON THE TH1 TH2 CYTOKINE BALANCE/

The role of tumour necrosis factor-alpha (TNF-alpha) in tuberculosis i s paradoxical because although there is much evidence for a protective role, there is also evidence that it plays a part in the tissue damag e that characterizes human disease. We have shown previously that TNF- alpha frequently induces necrosis when injected into sites undergoing delayed-type hypersensitivity (DTH) responses to mycobacterial antigen . This is dependent on CD4(+) T cells. However the presence of this se nsitivity to TNF-alpha-induced necrosis depended on the immunization p rotocol. We have tested the hypothesis that sensitivity to TNF-alpha d epends on the cytokine profile of the induced T-cell response. All sub cutaneous doses of mycobacterial immunogen used (10(7) to 10(9) organi sms) primed spleen cells so that they secreted interferon-gamma (IFN-g amma) and interleukin-2 (IL-2) when cultured in vitro with soluble ant igen. However priming for production of IL-4 was dose dependent as in other systems, and was produced at all times from 7 to 30 days after i mmunization with 10(9) organisms. Time-course studies over 30 days sho wed that sensitivity to TNF-alpha was found in DTH sites of animals pr imed for IL-4 and IFN-gamma production, but not in animals primed only for the Th1 cytokines, We suggest therefore that the paradoxical role of TNF-alpha can be resolved. In 'pure' Th1 responses it may act as a n additional macrophage-activating factor. In mixed Th1 + Th2 or Th0 r esponses it may cause tissue damage. This mixed pattern is characteris tic of tuberculosis, and of the late stage of many chronic infections where elimination of the infecting organism is failing, and chronic ti ssue damage is seen.