title: LeIF: a recombinant Leishmania protein that induces an IL-12-mediated Th1 cytokine profile.
abstract: We have evaluated the ability of the Leishmania protein LeIF to influence the Th1/Th2 cytokine responses and the generation of LeIF-specific T cell clones in the absence of adjuvant. We characterized LeIF-specific T cell responses in Leishmania major-infected and uninfected BALB/c mice. These mice develop a strong Th2 response during infection with L. major. When lymph node cells from infected BALB/c mice were stimulated in vitro with LeIF, only IFN-gamma (and no detectable IL-4) was found in the culture supernatant. In addition, LeIF down-regulated Leishmania Ag-specific IL-4 production by lymph node cells from infected BALB/c mice. Subsequently, Th responses were evaluated in naive BALB/c mice following immunization with LeIF. T cell clones derived from mice immunized with LeIF preferentially secreted IFN-gamma. Finally, to understand the basis for the preferential Th1 cytokine bias observed with LeIF, the ability of LeIF to influence the early cytokine profile was evaluated in splenocytes of SCID mice. We found that LeIF stimulated fresh spleen cells from naive SCID mice to secrete IFN-gamma by IL-12/IL-18-dependent mechanisms. The N-terminal half of the molecule (amino acid residues 1-226) maintained the ability to stimulate IFN-gamma from splenocytes of SCID mice. Finally, we also demonstrated that LeIF was able to provide partial protection of BALB/c mice against L. major. Thus, our results suggest the potential of LeIF as a Th1-type adjuvant and as a therapeutic and prophylactic vaccine Ag for leishmaniasis when used with other leishmanial Ags.
authors.affiliation: Corixa Corporation, Seattle, WA 98104, USA. Skeiky@Corixa.Com
authors.forename: Y A
authors.initials: YA
authors.lastname: Skeiky
authors.forename: M
authors.initials: M
authors.lastname: Kennedy
authors.forename: D
authors.initials: D
authors.lastname: Kaufman
authors.forename: M M
authors.initials: MM
authors.lastname: Borges
authors.forename: J A
authors.initials: JA
authors.lastname: Guderian
authors.forename: J K
authors.initials: JK
authors.lastname: Scholler
authors.forename: P J
authors.initials: PJ
authors.lastname: Ovendale
authors.forename: K S
authors.initials: KS
authors.lastname: Picha
authors.forename: P J
authors.initials: PJ
authors.lastname: Morrissey
authors.forename: K H
authors.initials: KH
authors.lastname: Grabstein
authors.forename: A
authors.initials: A
authors.lastname: Campos-Neto
authors.forename: S G
authors.initials: SG
authors.lastname: Reed
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000595:Amino Acid Sequence; D000818:Animals; D000953:Antigens, Protozoan / Q000494:pharmacology; D002999:Clone Cells; D003001:Cloning, Molecular; D015536:Down-Regulation / Q000276:immunology; D005260:Female; D007371:Interferon-gamma / Q000096:biosynthesis; D018664:Interleukin-12 / Q000502:physiology*; D020382:Interleukin-18 / Q000502:physiology; D015847:Interleukin-4 / Q000096:biosynthesis; D018320:Leishmania major / Q000235:genetics / Q000276:immunology*; D016773:Leishmaniasis, Cutaneous / Q000276:immunology / Q000517:prevention & control; D008198:Lymph Nodes / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D016513:Mice, SCID; D008969:Molecular Sequence Data; D010448:Peptide Initiation Factors / Q000235:genetics / Q000276:immunology / Q000494:pharmacology*; D015800:Protozoan Proteins / Q000235:genetics / Q000276:immunology / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000494:pharmacology*; D017386:Sequence Homology, Amino Acid; D013154:Spleen / Q000166:cytology / Q000276:immunology; D018417:Th1 Cells / Q000378:metabolism*
chemical_list: D000276:Adjuvants, Immunologic; D000953:Antigens, Protozoan; D020382:Interleukin-18; C092810:LeIF protein, Leishmania; D010448:Peptide Initiation Factors; D015800:Protozoan Proteins; D011994:Recombinant Proteins; D018664:Interleukin-12; D015847:Interleukin-4; D007371:Interferon-gamma