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Infection and Immunity, December 1999, p. 6454-6460, Vol. 67, No. 12
0019-9567/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Interleukin-4-Independent Acceleration of Cutaneous Leishmaniasis in Susceptible BALB/c Mice following Treatment with Anti-CTLA4 Antibody

Frederick P. Heinzel* and Richard A. Maier Jr.

Medical Research Service, Veterans Affairs Medical Center, and the Division of Geographic Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106-4983

Received 9 March 1999/Returned for modification 26 April 1999/Accepted 13 September 1999

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.

* Corresponding author. Mailing address: Geographic Medicine W-137, Case Western Reserve University School of Medicine, 2109 Adelbert Rd., Cleveland, OH 44106. Phone: (216) 368-1859. Fax: (216) 368-4825. E-mail: fxh10{at}po.cwru.edu.

Infection and Immunity, December 1999, p. 6454-6460, Vol. 67, No. 12
0019-9567/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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