PROGRESSIVE DISEASE OR PROTECTIVE IMMUNITY TO LEISHMANIA-MAJOR INFECTION - THE RESULT OF A NETWORK OF STIMULATORY AND INHIBITORY INTERACTIONS

The study of experimental infection of inbred strains of mice with the intracellular protozoan parasite Leishmania major has contributed sig nificantly not only to our understanding of this fascinating host/para site relationship but also to that of many basic immunological phenome na. Much has been learned about the cognate interaction of antigen-spe cific T cells and antigen-presenting cells, about cytokine and T cell subset regulation, and the requirements for costimulation. Specificall y, the immune response to experimental L. major infection is the parad igm for polarized T helper cell (Th) 1 and Th2 differentiation. In thi s model system a Th1 response characterized by interleukin (IL)-2 and interferon (IFN)-gamma secretion leads to self-curing disease, whereas a Th2 response (IL-4, IL-10) leads to nonhealing disease. Numerous ma nipulations, including the injection of cytokines and of neutralizing anti-cytokine antibodies, cytokine transgene expression, and more rece ntly cytokine and cytokine receptor gene knockout studies, have all pr ovided intriguing new pieces to the still incomplete mosaic of our und erstanding of the immune response. Some of these findings were clearly unexpected and are still incompletely understood. For instance, based on earlier neutralizing anti-IL-4 monoclonal antibody injection studi es, IL-4 gene-disrupted BALB/c mice were expected to be unable to moun t the biased Th2 response typical of the IL-4(+/+) wild-type mice and to he able to control their lesions; quite unexpectedly, the BALB/c IL -4 knockout mice remain unable to heal their L. major infection. Based on these unexpected findings, we reexamine the literature in an attem pt to resolve this apparent paradox and to relate the large body of ex perimental findings in the mouse system to that which is known about n atural and experimental infections in the human.