REGULATOR AND EFFECTOR FUNCTIONS OF T-CELL SUBSETS IN HUMAN LEISHMANIA INFECTIONS

Because of an increasing number of patients suffering from Leishmania infections and because of the serious consequences of these infections more thorough knowledge of the host factors responsible for resistanc e and susceptibility to the diseases is needed. In murine models of Le ishmania infections the cytokine production by CD4(+) T cells has been identified as a major factor in determining the outcome of the infect ion. In these models Th1 cells producing IFN-gamma provide protection against the infection whereas Th2 cells producing IL-4 and IL-10 aggra vate the disease. The fatal outcome of Leishmania infections in humans with defects in T-cell functions illustrates that these cells are fun damental in the defence against Leishmania in humans also. However, as for many other infectious diseases (meningococcal disease and other s epticaemic conditions, pneumonia, viral hepatitis, schistosomiasis) th e immune reactions to Leishmania parasites in humans can be associated with both protection and pathogenesis. Many individuals without previ ous exposure to Leishmania parasites have T cells which can respond to Leishmania antigens. These cells have the potential to generate eithe r Th1 or Th2 like responses. During infection with Leishmania parasite s humans develop specific T-cell recognition of well-characterized par asite antigens. T cells producing disease-exacerbating factors such as IL-4 in response to Leishmania antigen stimulation have been identifi ed in humans as well as in mice. Both Th1 like and Th2 like cells reco gnizing Leishmania antigens can be expanded during infection. At the p olyclonal level Th1 like responses to Leishmania antigens are found in individuals who have had self-healing or asymptomatic infections. Fac tors secreted by such Leishmania specific Th1 like cells can induce ki lling of intracellular parasites in infected macrophages. In individua ls who have been cured from uncontrollable disseminating disease both Th1 and Th2 like responses can be detected. A restriction in the antig en recognition to particular protein fractions could not be demonstrat ed in the Th1 or Th2 like responses. These findings suggest an associa tion between the pattern of cytokines produced by parasite specific T cells and the clinical course of the infection similar to the one seen in mice. In the murine model the cytokine pattern present in the anim al at the time of infection can determine whether a Th1- or a Th2 resp onse will develop. In vitro studies on human and murine cells have con firmed that certain cytokines (e.g. IFN-gamma, IL-12) will favour matu ration of Th1 responses whereas others (e.g. IL-4, IL-10) support Th2 development. If similar immunoregulatory mechanisms operate in mouse a nd man, design of vaccines against human leishmaniasis should aim at i ntroducing powerful Th1 like responses. Importantly, once generation o f either Th1 or Th2 has started, the immune response seems to be locke d in this pattern, even when it is harmful to the host. Therefore new vaccines against leishmaniasis should be designed in a way that they g enerate controlled Th1 like primary responses.