Interleukin-4-independent acceleration of cutaneous leishmaniasis in susceptible BALB/c mice following treatment with anti-CTLA4 antibody

BALB/c mice are susceptible to progressive infection with Leishmania major due to the preferential development of CD4(+) T cells that secrete Th2 cyto kines. Although Th2 fell development and susceptibility are disrupted by bl ockade of CD86 function early in infection, CD28-deficient BALB/c mice rema in susceptible to leishmaniasis. We therefore examined whether the alternat ive CD86 ligand, CTLA4, contributes to the expression of susceptibility. BA LB/c mice treated for 2 weeks of infection with anti-CTLA4 monoclonal antib ody developed more rapidly progressive disease than sham-treated mice, wher eas normally resistant C57BL/6 mice were unaffected. The draining lymph nod e cells of anti-CTLA4-treated BALB/c mice produced up to sixfold more inter leukin-4 (IL-4) and IL-13 than control mice in the first 2 weeks of infecti on, but IFN-gamma synthesis was reciprocally decreased. Anti-CTLA4 treatmen t of BALB/c mice pretreated with neutralizing anti-IL-4 antibody or genetic ally deficient in IL-4 also caused significant worsening of leishmaniasis, Exacerbation in IL-4 KO mice was associated with increased IL-13 and decrea sed gamma interferon (IFN-gamma) and inducible nitric oxide synthase (iNOS) mRNA expression in vivo. These data indicate that anti-CTLA4 antibody indu ced earlier and more-polarized Th2 responses in susceptible BALB/c mice inf ected with L. major. The mechanism of disease worsening was partially IL-4 independent, indicating that increased IL-13 and/or decreased IFN-gamma pro duction may have disrupted nitric oxide-based microbicidal responses. We co nclude that CTLA4 significantly modulates Th2 development in murine leishma niasis and that the Th2-polarizing effects of anti-CTLA4 treatment result i n IL-1-independent exacerbation of disease.