title: Interleukin-4-independent acceleration of cutaneous leishmaniasis in susceptible BALB/c mice following treatment with anti-CTLA4 antibody.
abstract: BALB/c mice are susceptible to progressive infection with Leishmania major due to the preferential development of CD4(+) T cells that secrete Th2 cytokines. Although Th2 cell development and susceptibility are disrupted by blockade of CD86 function early in infection, CD28-deficient BALB/c mice remain susceptible to leishmaniasis. We therefore examined whether the alternative CD86 ligand, CTLA4, contributes to the expression of susceptibility. BALB/c mice treated for 2 weeks of infection with anti-CTLA4 monoclonal antibody developed more rapidly progressive disease than sham-treated mice, whereas normally resistant C57BL/6 mice were unaffected. The draining lymph node cells of anti-CTLA4-treated BALB/c mice produced up to sixfold more interleukin-4 (IL-4) and IL-13 than control mice in the first 2 weeks of infection, but IFN-gamma synthesis was reciprocally decreased. Anti-CTLA4 treatment of BALB/c mice pretreated with neutralizing anti-IL-4 antibody or genetically deficient in IL-4 also caused significant worsening of leishmaniasis. Exacerbation in IL-4 KO mice was associated with increased IL-13 and decreased gamma interferon (IFN-gamma) and inducible nitric oxide synthase (iNOS) mRNA expression in vivo. These data indicate that anti-CTLA4 antibody induced earlier and more-polarized Th2 responses in susceptible BALB/c mice infected with L. major. The mechanism of disease worsening was partially IL-4 independent, indicating that increased IL-13 and/or decreased IFN-gamma production may have disrupted nitric oxide-based microbicidal responses. We conclude that CTLA4 significantly modulates Th2 development in murine leishmaniasis and that the Th2-polarizing effects of anti-CTLA4 treatment result in IL-4-independent exacerbation of disease.
authors.affiliation: Medical Research Service, Veterans Affairs Medical Center, and the Division of Geographic Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106-4983, USA. fxh10@po.cwru.edu
authors.forename: F P
authors.initials: FP
authors.lastname: Heinzel
authors.forename: R A
authors.initials: RA
authors.lastname: Maier
mesh_terms: D000069594:Abatacept; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000276:immunology*; D060908:CTLA-4 Antigen; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D004198:Disease Susceptibility; D005260:Female; D007113:Immunity, Innate; D018796:Immunoconjugates; D015847:Interleukin-4 / Q000276:immunology*; D018320:Leishmania major / Q000276:immunology; D016773:Leishmaniasis, Cutaneous / Q000276:immunology*; D008198:Lymph Nodes / Q000166:cytology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D016207:Cytokines; D018796:Immunoconjugates; D015847:Interleukin-4; D000069594:Abatacept