Local Suppression of T Cell Responses by Arginase-Induced L-Arginine Depletion in Nonhealing Leishmaniasis

The balance between T helper (Th) 1 and Th2 cell responses is a major determinant of the outcome of experimental leishmaniasis, but polarized Th1 or Th2 responses are not sufficient to account for healing or nonhealing. Here we show that high arginase activity, a hallmark of nonhealing disease, is primarily expressed locally at the site of pathology. The high arginase activity causes local depletion of L-arginine, which impairs the capacity of T cells in the lesion to proliferate and to produce interferon-γ, while T cells in the local draining lymph nodes respond normally. Healing, induced by chemotherapy, resulted in control of arginase activity and reversal of local immunosuppression. Moreover, competitive inhibition of arginase as well as supplementation with L-arginine restored T cell effector functions and reduced pathology and parasite growth at the site of lesions. These results demonstrate that in nonhealing leishmaniasis, arginase-induced L-arginine depletion results in impaired T cell responses. Our results identify a novel mechanism in leishmaniasis that contributes to the failure to heal persistent lesions and suggest new approaches to therapy

Age-Related Alteration of Arginase Activity Impacts on Severity of Leishmaniasis

It is well documented that ageing alters many aspects of immune responses; however, a causal relation between impaired immune functions in ageing individuals and the response to infection has not been established. Experimental leishmaniasis is an excellent model to analyse protective and pathological immune responses. Leishmania parasites are obligate intracellular pathogens and invade mainly macrophages, which have dual function: they can kill the parasites or promote their growth. We have recently shown that arginase, an enzyme induced in infected macrophages, is a key factor for parasite survival. Here, we show that ageing reduces the expression levels of arginase in macrophages, resulting in more efficient control of parasite growth. Our results suggest that age-related differences in the metabolism of arginase in macrophages might contribute to the higher susceptibility of children to leishmaniasis

The Immunoregulatory Potential of L-Arginine Metabolism

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Cytokine production.

<p>Groups of young (6–8 weeks) and older (12 months) BALB/c mice were infected with 2×10⁶<i>L. major</i> promastigotes in one hind footpad. Four weeks post infection, the popliteal lymph nodes were harvested and restimulated with <i>L. major</i> parasites. The supernatant were harvested and tested for their content of cytokines by ELISA. The data represent the cytokine concentration±standard error of the mean and data show the results of three independent experiments are represented.</p

Age distribution of visceral and cutaneous leishmaniasis.

<p>The age distribution of patients suffering from visceral (n = 37, circle) or cutaneous (n = 91, triangle) leishmaniasis was determined in endemic areas of Ethiopia.</p

Higher arginase activity at the site of pathology correlates with exacerbation of disease.

<p>Groups of young (6–8 weeks) and older (12 months) BALB/c mice were infected with 2×10⁶<i>L. major</i> promastigotes in one hind footpad. Four weeks post infection, the infected footpads were harvested and the level of arginase activity was determined by enzymatic assay (a) or western blot (b). (c) Groups of pre-pubertal mice (3–4 weeks), adult (10 weeks) or older (40 weeks) BALB/c mice were infected with 2×10⁶<i>L. major</i> promastigotes in one hind footpad and the lesion development was monitored by measuring the increase in footpad thickness at regular intervals; the error bars represent standard error of the mean (left panel); 4 weeks post infection, the infected footpads were harvested and the parasite load (upper right panel) and arginase activity (lower right panel) were measured. (d) BALB/c mice were infected with 2×10⁶<i>L. major</i> promastigotes in one hind footpad. Four weeks post infection, the infected footpads were harvested and arginase activity was determined both in the footpads and in the amastigotes purified from the footpads. The horizontal bar represents the average value and data show the results of one representative experiment out of three independent experiments.</p

Severity of experimental leishmaniasis is increased in young BALB/c mice.

<p>Groups of young (6–8 weeks) and older (12 months) BALB/c mice were infected with 2×10⁶<i>L. major</i> promastigotes in one hind footpad. (a) The lesion development was monitored by measuring the increase in footpad thickness at regular intervals; the error bars represent standard error of the mean; (b) the parasite load was determined by limiting dilution assay 4 weeks post infection; the horizontal bar represents the average value. Data show the results of one representative experiment out of six independent experiments.</p