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 CD4+ effector (Th1) cells, a process that is aberrant in highly susceptible BALB strains. We sought to establish whether vaccination strategies using whole parasite lysates or a characterized immunodominant antigen, the Leishmania homolog of mammalian receptor for activated protein kinase C (LACK), would be capable of protecting subsequently infected BALB mice if given within a cytokine milieu capable of biasing the immune response toward Th1 cells. When given with neutralizing antibody to IL-4, but not when given alone, subcutaneously administered soluble Leishmania antigens mediated substantial protection to BALB/c mice against subsequent infection with parasites as assessed by size of the local lesion, enhanced Th1-type immune responses, and decreased parasite burdens. Similarly, when given with recombinant IL-12, LACK conferred substantial protection to cohorts of BALB.B, BALB/c, and BALB.K mice that was associated with reduction in serum IgE levels, consistent with effects on IL-4 production. Thus altering the cytokine milieu during administration of vaccine antigens by neutralizing IL-4 induced powerful Th1 recall responses during infection that were capable of mediating substantial levels of protection.
Wakil
A E
AE
Department of Medicine, University of California San Francisco 94143-0654, USA.
Wang
Z E
ZE
Locksley
R M
RM
D000818:Animals; D000906:Antibodies / Q000276:immunology; D000953:Antigens, Protozoan / Q000276:immunology*; D005260:Female; D016056:Immunodominant Epitopes; D018664:Interleukin-12 / Q000276:immunology; D015847:Interleukin-4 / Q000276:immunology*; D018320:Leishmania major / Q000276:immunology*; D016773:Leishmaniasis, Cutaneous / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008815:Mice, Inbred Strains; D015800:Protozoan Proteins / Q000276:immunology*; D011994:Recombinant Proteins / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology; D014611:Vaccination
D000906:Antibodies; D000953:Antigens, Protozoan; D016056:Immunodominant Epitopes; D015800:Protozoan Proteins; D011994:Recombinant Proteins; C093139:LACK antigen, Leishmania; D018664:Interleukin-12; D015847:Interleukin-4