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Infection and Immunity, April 2003, p. 2244-2246, Vol. 71, No. 4
0019-9567/03/$08.00+0 DOI: 10.1128/IAI.71.4.2244-2246.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.
Immunologie des Leishmanioses,1 Service d'Epidémiologie, Institut Pasteur,2 Institut Guyanais de Dermatologie Tropicale, E.A. 2188, Centre Hospitalier Andrée Rosemon,3 Institut d'Enseignement Supérieur de la Guyane, Université Antilles-Guyane, Cayenne, French Guiana4
Received 1 October 2002/ Returned for modification 19 November 2002/ Accepted 9 January 2003
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), and Th2, which produces IL-4, IL-5, IL-10, and IL-13, made it possible to characterize the CD4+ T cells involved in the pathological processes of various diseases (1, 8). In the murine model of infection with L. major, development of CD4+ Th1 and Th2 cells conferred resistance and susceptibility to infection, respectively (12). Although peripheral T-cell responses in human leishmaniasis involve a mixture of Th1 and Th2 cells (11), the Th responses elicited at the lesion site are not yet fully elucidated. In localized cutaneous leishmaniasis (LCL) caused by L. braziliensis or L. major, Th1 cytokines (IL-2 and IFN-
) predominate over Th2 cytokines (IL-4) (4, 7, 10, 15). IL-4, used as a marker of Th2 response, has been detected indisputably only in cases of diffuse and mucocutaneous leishmaniasis, which are the more severe forms of American cutaneous leishmaniasis (4, 10). Recent data from our laboratory on patients with cutaneous leishmaniasis due to L. guyanensis showed, however, that Th2 cytokines, and particularly IL-13, are produced locally at the site of infection (3). Since Louzir et al. (7), analyzing the local response in patients infected with L. major, noted that IL-4 was detected in an early stage of lesion evolution, we therefore hypothesized that Th2 cytokines, and particularly IL-13, that were found in LCL lesions could play a transient immunoregulatory role in early infection. To address this issue, we studied the association between intralesional cytokine expression and disease evolution in patients with leishmaniasis due to L. guyanensis.
First, the ratio of Th2 (IL-4 and/or IL-13 mRNA expression) to Th1 (IFN-
mRNA expression) cytokines was analyzed in biopsy samples from 76 patients with active LCL due to L. guyanensis by semiquantitative RT-PCR as previously described (3). We found a predominance of Th2 cytokines (ratio, >1) in 39 biopsy samples labeled as Th2 biopsies, a predominance of Th1 response (ratio, <1) in 28 samples labeled as Th1 biopsies, and equivalent Th2 and Th1 cytokine expression in nine samples (ratio, 1).
When we analyzed the correlation between Th1 and Th2 responses with the clinical data, we found no correlation between Th responses and the number of lesions, location of lesions, or presence of adenopathy or lymphadenitis. However, the Th responses correlated with the number of days required for development of lesions. As shown in Fig. 1, the duration of development of lesions was statistically shorter (P < 0.0001) in Th2 biopsies (median, 25.5 days) than in Th1 biopsies (median, 67.5 days). For biopsies that developed equivalent Th1 and Th2 responses, the time of development of lesions was intermediate (30 days) between that in Th1 biopsies and that in Th2 biopsies. Thus, in patients with LCL due to L. guyanensis, a Th2 response transiently predominated during the early phase of infection and was followed by the development of a Th1 response during the late course of lesion development.
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production that can activate macrophages harboring parasites to make them microbicidal (14, 16). Indeed, the level of IFN-
was negatively associated with the number of parasites within Th1 lesions (Table 1). However, Th2 cytokines counter the activation of macrophages triggered by IFN-
(6, 13). Thus, we postulated that the increase in the number of parasites during Th2 cell development is a consequence of Th2 cytokine deactivation. However, and as shown in Table 1, there was no association between the number of parasites within lesions and the level of any cytokine in Th2 biopsies, even if IL-13, found in LCL due to L. guyanensis, is the cytokine responsible for the inability of specific T cells to respond to IL-12 by inhibiting the IL-12 receptor ß2 expression on these cells (3). Nonetheless, we cannot rule out the possibility that Th2 cytokines other than IL-4, IL-10, and IL-13, which act on nitric oxide production, influence parasite growth. The possible role of a well-known deactivating factor, such as transforming growth factor beta, is under investigation.
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In conclusion, we demonstrated that a Th2 response precedes the development of a Th1 response at the local site of infection in LCL patients. The exact role of this Th2 response in the development of the disease is not yet well understood, but it might be involved in the development of an effective Th1 immune response. Therefore, the precocious treatment of patients might need reconsideration, since the development of Th2 responses during early phases of Leishmania infection might lead to the development of recall immunity. The early treatment might, therefore, prevent the consequent development of a Th1 response capable of inducing protection against reinfection. To address this issue, epidemiological studies are strongly suggested.
| ACKNOWLEDGMENTS |
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The study was supported by grants from the Institut Pasteur and the French Ministry of Research
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