title: Interleukin-4 (IL-4) and IL-10 collude in vaccine failure for novel exacerbatory antigens in murine Leishmania major infection.
abstract: Leishmaniasis affects 12 million people but there are no vaccines in routine use. Recently, we used DNA vaccination in a susceptible BALB/c high-dose model of infection to screen 100 novel Leishmania major genes as vaccine candidates. In addition to finding novel protective antigens, we identified several antigens that reproducibly exacerbated disease. Here we examined the immune response to two of these antigens, lmd29 and 584C, that were originally identified in an expressed sequence tag cDNA sequencing project. We show that, in addition to exacerbating disease in susceptible BALB/c mice, these antigens retain a propensity to exacerbate disease in resistant C57BL/6 mice. This ability to exacerbate disease was lost when susceptible BALB/c mice were rendered resistant by disruption of the genes encoding interleukin-4 (IL-4) alone, IL-4/IL-13, or IL-4, IL-5, IL-9, and IL-13. Failure to exacerbate disease was associated with reduced IL-5 and IL-10 production in IL-4 knockout mice. Treatment of lmd29-vaccinated mice with anti-IL-10 receptor antibody prior to challenge infection converted exacerbation in wild-type BALB/c mice into highly significant antigen-specific protection. These studies demonstrate that some highly immunogenic antigens of L. major, while having an intrinsic capacity to exacerbate disease in the context of otherwise T helper 1-promoting DNA vaccine delivery, can be rendered protective by the removal of functional IL-10.
authors.affiliation: Cambridge Institute for Medical Research, Wellcome Trust/MRC Building, Addenbrooke's Hospital, Hills Rd., Cambridge CB2 2XY, United Kingdom.
authors.forename: Mark T M
authors.initials: MT
authors.lastname: Roberts
authors.forename: Carmel B
authors.initials: CB
authors.lastname: Stober
authors.forename: Andrew N
authors.initials: AN
authors.lastname: McKenzie
authors.forename: Jenefer M
authors.initials: JM
authors.lastname: Blackwell
mesh_terms: D000818:Animals; D000906:Antibodies / Q000276:immunology; D000953:Antigens, Protozoan / Q000235:genetics / Q000276:immunology* / Q000502:physiology; D018450:Disease Progression; D004198:Disease Susceptibility; D005260:Female; D016753:Interleukin-10 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015847:Interleukin-4 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D018320:Leishmania major / Q000276:immunology* / Q000472:pathogenicity*; D016773:Leishmaniasis, Cutaneous / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016052:Protozoan Vaccines / Q000276:immunology*; D018123:Receptors, Interleukin / Q000037:antagonists & inhibitors; D053701:Receptors, Interleukin-10; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism; D013997:Time Factors; D017211:Treatment Failure
chemical_list: D000906:Antibodies; D000953:Antigens, Protozoan; D016052:Protozoan Vaccines; D018123:Receptors, Interleukin; D053701:Receptors, Interleukin-10; D016753:Interleukin-10; D015847:Interleukin-4