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Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, Keppel Street, London, United Kingdom
CTLA-4 has recently been shown to act as a negative regulator of T
cell activation. Here we provide evidence that blockade of CTLA-4 can
result in enhanced host resistance to an intracellular pathogen. The
administration of anti-CTLA-4 mAb 4F10 to BALB/c mice, 1 day
following infection with Leishmania donovani, enhanced
the frequency of IFN-
and IL-4 producing cells in both spleen and
liver, and dramatically accelerated the development of a hepatic
granulomatous response. The expression of mRNA for the CXC chemokine
IP-10 was also elevated above that seen in control Ab treated mice,
and was directly correlated with the frequency of IFN- producing
cells. In contrast, macrophage inflammatory protein-1
(MIP-1) and
monocyte chemotactic protein-1 (MCP-1) mRNA levels were unaffected by
anti-CTLA-4 treatment, suggesting that CTLA-4 blockade may exert
selective effects on chemokine expression. These changes in tissue
response and cytokine/chemokine production were accompanied by a 50 to
75% reduction of parasite load in the spleen and liver of
anti-CTLA-4-treated animals compared to controls. Furthermore,
administration of anti-CTLA-4 mAb 15 days after L.
donovani infection, when parasite burden is increasing in both
organs, also resulted in enhanced resistance. Thus, these studies
indicate a potent immunomodulatory and potentially therapeutic role for
interventions targeted at CTLA-4.
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