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-Deficient Mice in Chronic Leishmaniasis Reveal a Protective Role for IL-13 Receptor Signaling1
*
Max-Planck-Institute for Immunobiology, Freiburg, Germany;
Novartis Pharma Ltd., Basel, Switzerland;
Department of Pathology, University Freiburg, Freiburg, Germany;
§
Institute for Clinical Microbiology and Immunology, University Erlangen, Erlangen, Germany; and
¶
Department of Immunology, University of Cape Town, Cape Town, South Africa
IL-4 receptor 
-chain-deficient (IL-4R-/-) mice
were generated by homologous and site-specific recombination, using the
Cre/loxP system in BALB/c-derived embryonic stem cells. In vitro
analysis of cells from these mice revealed impaired IL-4- and
IL-13-mediated functions, demonstrating that the IL-4R-chain is an
essential component of both the IL-4 and the IL-13 receptor. Whereas
Leishmania major-infected BALB/c mice developed fatal
progressive disease with type 2 Ab responses within 3 mo, both
IL-4R-/- and IL-4-/- BALB/c mice
contained infection with reduced footpad swelling, parasite load,
moderate histopathology, and type 1 Ab responses during this time
period. Conclusively, these results demonstrate an IL-4-dependent
mechanism of susceptibility in BALB/c mice. Nevertheless, in contrast
to mutant mice, infected C57BL/6 mice healed completely within 3 mo,
indicating that additional factors are necessary for subsequent healing
and elimination of the pathogen. During the further course of
infection, IL-4R-/- mice developed progressive disease
with massive footpad swelling. Lesions became ulcerative and necrotic
with subsequent destruction of connective tissue and bones, as well as
dissemination into organs and consequent mortality within the monitored
6 mo of chronic infection. In striking contrast, IL-4-/-
mice maintained control of infection on a moderate level, but were
unable to clear the pathogen. The distinct phenotypes of the BALB/c
embryonic stem cell-derived IL-4-/- and
IL-4R-/- mouse strains identify previously unsuspected
mechanisms for maintaining host immunity to chronic infection with
L. major, mediated by a functional IL-13
receptor.
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S. L. Constant, C. Dong, D. D. Yang, M. Wysk, R. J. Davis, and R. A. Flavell JNK1 Is Required for T Cell-Mediated Immunity Against Leishmania major Infection J. Immunol., September 1, 2000; 165(5): 2671 - 2676. [Abstract] [Full Text] [PDF]
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