Fms-like tyrosine kinase 3-based immunoprophylaxis against infection is improved by adjuvant treatment with anti-interleukin-10 antibody.

Abstract

Fms-like tyrosine kinase 3 ligand (Flt3L) expands dendritic-cell populations in vivo and protects against microbial infection in healthy and immunocompromised hosts. Approaches for optimizing the protective effects of Flt3L in vivo are not well known.METHODS. BALB/c mice were treated for 9 days with 10 microg of recombinant (r) Flt3L with or without the addition of 250 microg of anti--interleukin (IL)-10 antibody on day 9. After Leishmania major infection, disease progression was determined by measuring cutaneous lesions. Production of IL-12 and interferon (IFN)- gamma were determined.RESULTS. Flt3L pretreatment increased the synthesis of CD40-inducible IL-12 p40 but not of bioactive p70. Coculture with anti--IL-10 antibody increased p70 production. Combined Flt3L and single-dose anti--IL-10 antibody pretreatment improved lesion cure rates from 40% to 87% relative to mice pretreated with rFlt3L only (P<.01, chi (2) test) and increased T helper 1 (Th1)--type cytokine production 4 weeks after infection but did not cure Rag-2-- and IFN- gamma -knockout BALB/c mice. Flt3L and anti-IL-10 antibody pretreatments increased frequencies of IL-12- and IFN- gamma -secreting cells 2 and 4 days after infection. Both natural killer and CD4(+) cells contributed to increased early IFN- gamma production.CONCLUSION. A single dose of anti--IL-10 antibody significantly improves Flt3L immunoprophylaxis against infection mediated by Th1-type adaptive responses.