LEISHMANIA-MAJOR - TARGETING IL-4 IN SUCCESSFUL IMMUNOMODULATION OF MURINE INFECTION

Protection against Leishmania major infection among inbred strains of mice is dependent upon successful expansion and activation of type 1 C D4(+) effector (Th1) cells, a process that is aberrant in highly susce ptible BALE strains. We sought, to establish whether vaccination strat egies using whole parasite lysates or a characterized immunodominant a ntigen, the Leishmania homolog of mammalian receptor for activated pro tein kinase C (LACK), would be capable of protecting subsequently infe cted BALE mice if given within a cytokine milieu capable of biasing th e immune response toward Th1 cells. When given with neutralizing antib ody to IL-4, but not when given alone, subcutaneously administered sol uble Leishmania antigens mediated substantial protection to BALB/c mic e against subsequent infection with parasites as assessed by size of t he local lesion, enhanced Th1-type immune responses, and decreased par asite burdens. Similarly, when given with recombinant IL-12, LACK conf erred substantial protection to cohorts of BALB.B, BALB/c, and BALB.K mice that was associated with reduction in serum IgE levels, consisten t with effects on IL-4 production. Thus altering the cytokine milieu d uring administration of vaccine antigens by neutralizing IL-4 induced powerful Th1 recall responses during infection that were capable of me diating substantial levels of protection. (C) 1996 Academic Press, Inc .