Fp. Heinzel et Ra. Maier, Interleukin-4-independent acceleration of cutaneous leishmaniasis in susceptible BALB/c mice following treatment with anti-CTLA4 antibody, INFEC IMMUN, 67(12), 1999, pp. 6454-6460
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.