Changes in cellular response to mycobacterial antigens and cytokine production patterns in leprosy patients during multiple drug therapy

Abstract

Changes in Mycobacterium leprae-induced lymphoproliferative responses and mediator release by leprosy patients' lymphocytes were followed during multiple drug therapy (MDT). At the time of diagnosis, multibacillary (MB) patients who did not develop reactions responded to both sonicated M. leprae and synthetic disaccharide coupled to bovine serum albumin (ND-BSA) antigens, but those who would later develop reactions did not respond, even in the presence of added cytokines. The paucibacillary (PB) group initially had high responses to sonicated M. leprae but no response to ND-BSA, even in the presence of added cytokines. In the first year of treatment, the supernatants of PB patients' cell cultures contained factors that enhanced the phytohaemagglutinin (PHA) response of normal cells. In contrast, those MB patients who did not develop reactions at a later stage produced culture supernatants that were inhibitory. Interestingly, the MB patients who later developed reactions during treatment, and did not initially respond to M. leprae, produced supernatants containing enhancing factors, like those of the PB group. Later on in the treatment, all patients had the same patterns: when response to M. leprae decreased from its highest level, inhibitory factors were produced. Further studies revealed that the supernatants which inhibited the PHA response of normal cells contained the active form of transforming growth factor-beta 1, (TGF-beta 1), whatever the disease type or treatment status of the donor. These TGF-beta 1 levels correlated directly with the degree of inhibition. Similarly supernatants that neither inhibited nor enhanced PHA responses contained the highest levels of interleukin-10 (IL-10), while those from treated patients that enhanced contained the lowest levels of interleukin-4 (IL-4) and interferon-gamma (IFN-gamma). These cytokine correlations transcended the conventional disease classification, and imply that all patients pass through a sequence of patterns of immune response during treatment. These treatment-induced changes may explain occasional reports of response patterns at variance with the 'immunological spectrum' of leprosy.