Reversible defect in antigen-induced lymphokine and gamma-interferon generation in cutaneous leishmaniasis

Abstract

Peripheral blood mononuclear cells from a patient with progressive Leishmania mexicana (LM) infection were examined for responses to mitogen and antigen before, during, and after successful treatment. Before therapy, his cells proliferated normally and secreted effective macrophage-activating lymphokines in response to concanavalin A (Con A) and Toxoplasma gondii antigen, but failed to show any response to LM antigen. At this time, suppressive humoral factors were not present, the intracellular antimicrobial activity of the patient's monocytes was intact, and once stimulated with normal lymphokines, his monocyte-derived macrophages readily killed his own infecting LM strain. One month after initial treatment, the patient's T cells showed variable but measurable responses to LM antigen, and by 6 mo, these responses were fully developed in proliferative and lymphokine-generating assays. The patient's lymphokines were examined for gamma-interferon (IFN-gamma) because a) a monoclonal anti-human IFN-gamma antibody abolished the capacity of lymphokines to activate normal macrophages to kill LM, and b) partially purified and recombinant IFN-gamma alone could induce macrophage leishmanicidal activity. The patient's pretreatment Con A- and T. gondii antigen-stimulated lymphocyte supernatants (which activated macrophages to kill LM) contained 2000 to 3000 U/ml of IFN-gamma, whereas his LM antigen lymphokine was devoid of activity (less than 10 U/ml). At 1 and 6 mo after therapy, however, the latter lymphokine showed 20 and 600 U/ml of IFN-gamma, respectively, paralleling the development of antigen-specific proliferation and active lymphokine generation and the clinical status of his infection. These results appear to support previous suggestions that the ability of T cells to secrete antigen-induced macrophage-activating lymphokines (particularly IFN-gamma) is a key cellular immune response to intracellular Leishmania infections.