Pathology In Lymphatic Filariasis Research Articles

Expansion of Parasite-Specific CD4+ and CD8+ T Cells Expressing IL-10 Superfamily Cytokine Members and Their Regulation in Human Lymphatic Filariasis

BackgroundLymphatic filariasis (LF) is known to be associated with an increased production of IL-10. The role of the other IL-10 family members in the pathogenesis of infection and/or disease is not known.Methodology/Principal FindingsWe examined the expression patterns of IL-10 family members – IL-19, IL-24 and IL-26 in LF. We demonstrate that both CD4+ and CD8+ T cells express IL-19, IL-24 and IL-26 and that the frequency of CD4+ T cells expressing IL-19 and IL-24 (as well as IL-10) is significantly increased at baseline and following filarial antigen stimulation in patients with LF in comparison to individuals with filarial lymphedema and uninfected individuals. This CD4+ T cell expression pattern was associated with increased production of IL-19 and IL-24 by filarial – antigen stimulated PBMC. Moreover, the frequency of CD4+ and CD8+ T cells expressing IL-26 was significantly increased following filarial antigen stimulation in filarial lymphedema individuals. Interestingly, IL-10 blockade resulted in diminished frequencies of IL-19+ and IL-24+ T cells, whereas the addition of recombinant IL-10 resulted in significantly increased frequency of IL-19+ and IL-24+ T cells as well as significantly up regulated IL-19 and IL-24 gene expression, suggesting that IL-10 regulates IL-19 and IL-24 expression in T cells. In addition, IL-1β and IL-23 blockade also induced a diminution in the frequency of IL-19+ and IL-24+ T cells, indicating a novel role for these cytokines in the induction of IL-19 and IL-24 expressing T cells. Finally, elimination of infection resulted in significantly decreased frequencies of antigen – specific CD4+ T cells expressing IL-10, IL-19 and IL-24.ConclusionsOur findings, therefore, suggest that IL-19 and IL-24 are associated with the regulation of immune responses in active filarial infection and potentially with protection against development of pathology, while IL-26 is predominantly associated with pathology in LF.

Macrofilaricidal Activity in Wuchereria bancrofti after 2 Weeks Treatment with a Combination of Rifampicin plus Doxycycline.

Infection with the filarial nematode Wuchereria bancrofti can lead to lymphedema, hydrocele, and elephantiasis. Since adult worms cause pathology in lymphatic filariasis (LF), it is imperative to discover macrofilaricidal drugs for the treatment of the infection. Endosymbiotic Wolbachia in filariae have emerged as a new target for antibiotics which can lead to macrofilaricidal effects. In Ghana, a pilot study was carried out with 39 LF-infected men; 12 were treated with 200 mg doxycycline/day for 4 weeks, 16 were treated with a combination of 200 mg doxycycline/day + 10 mg/kg/day rifampicin for 2 weeks, and 11 patients received placebo. Patients were monitored for Wolbachia and microfilaria loads, antigenaemia, and filarial dance sign (FDS). Both 4-week doxycycline and the 2-week combination treatment reduced Wolbachia load significantly. At 18 months posttreatment, four-week doxycycline resulted in 100% adult worm loss, and the 2-week combination treatment resulted in a 50% adult worm loss. In conclusion, this pilot study with a combination of 2-week doxycycline and rifampicin demonstrates moderate macrofilaricidal activity against W. bancrofti.

Doxycycline Reduces Plasma VEGF-C/sVEGFR-3 and Improves Pathology in Lymphatic Filariasis

Lymphatic filariasis is a disease of considerable socioeconomic burden in the tropics. Presently used antifilarial drugs are able to strongly reduce transmission and will thus ultimately lower the burden of morbidity associated with the infection, however, a chemotherapeutic principle that directly induces a halt or improvement in the progression of the morbidity in already infected individuals would constitute a major lead. In search of such a more-effective drug to complement the existing ones, in an area endemic for bancroftian filariasis in Ghana, 33 microfilaremic and 18 lymphedema patients took part in a double-blind, placebo-controlled trial of a 6-wk regimen of 200 mg/day doxycycline. Four months after doxycycline treatment, all patients received 150–200 μg/kg ivermectin and 400 mg albendazole. Patients were monitored for Wolbachia and microfilaria loads, antigenemia, filarial dance sign (FDS), dilation of supratesticular lymphatic vessels, and plasma levels of lymphangiogenic factors (vascular endothelial growth factor-C [VEGF-C] and soluble vascular endothelial growth factor receptor-3 [(s)VEGFR-3]). Lymphedema patients were additionally monitored for stage (grade) of lymphedema and the circumferences of affected legs. Wolbachia load, microfilaremia, antigenemia, and frequency of FDS were significantly reduced in microfilaremic patients up to 24 mo in the doxycycline group compared to the placebo group. The mean dilation of supratesticular lymphatic vessels in doxycycline-treated patients was reduced significantly at 24 mo, whereas there was no improvement in the placebo group. Preceding clinical improvement, at 12 mo, the mean plasma levels of VEGF-C and sVEGFR-3 decreased significantly in the doxycycline-treated patients to a level close to that of endemic normal values, whereas there was no significant reduction in the placebo patients. The extent of disease in lymphedema patients significantly improved following doxycycline, with the mean stage of lymphedema in the doxycycline-treated patients being significantly lower compared to placebo patients 12 mo after treatment. The reduction in the stages manifested as better skin texture, a reduction of deep folds, and fewer deep skin folds. In conclusion, a 6-wk regimen of antifilarial treatment with doxycycline against W. bancrofti showed a strong macrofilaricidal activity and reduction in plasma levels of VEGF-C/sVEGFR-3, the latter being associated with amelioration of supratesticular dilated lymphatic vessels and with an improvement of pathology in lymphatic filariasis patients.

New strategies to combat filariasis

Two of the major filarial infections, lymphatic filariasis (LF) and onchocerciasis, affect 150 million people, while 1 billion living in endemic areas are at risk of infection. Public health programs to control these infections have successfully existed for years and have evolved from activities driven by the WHO into global programs with public–private partnerships. Currently, these programs use yearly mass application of drugs that mainly kill the larval stages (the microfilariae), with the aim of preventing uptake by the transmitting insect vectors and thus, to block transmission and reduce the infections to such levels that in 15–30 years from now, they will no longer pose a public health problem. While the programs have been very successful in general, there are drawbacks such as coverage being too low within the population, reappearance of infection by migration of infected people into controlled areas, targeting of a stage (the microfilaria) that does not induce pathology in LF and thus lowers compliance, and the potential development of drug resistance, first indications of which have been clearly observed in onchocerciasis. In addition, even without drawbacks, program scopes are not the eradication of filarial infections, which is, however, an ultimate goal of control activities. There is therefore an unequivocal call for the development of higher efficient, complementary chemotherapeutical approaches that lead to a long-lasting reduction of the pathology-inducing worm stages; that is, microfilariae in onchocerciasis and adult worms in LF, or to a macrofilaricidal effect. The recent discovery that depletion of Wolbachia endosymbionts by tetracycline antibiotics leads to long-lasting sterility of adult female worms in onchocerciasis and a macrofilaricidal effect in LF fulfils these requirements. Successful regimens have already been published and agreed upon for use by expert panels. While these regimens are still too long for mass application, the antiwolbachial chemotherapy can currently be applied in the form of a suitable doxycycline regimen for 6 weeks for the treatment of individuals, and exploited in the future for the development of new drugs suitable for mass application. In addition, first data suggest that Wolbachia may also be major mediators of lymphangiogenesis and that their depletion is associated with reduction of lymph vessel-specific vascular endothelial growth factors and reduced lymph vessel size.

Lymphatic filariasis-specific immune responses in relation to lymphoedema grade and infection status. I. Cellular responses

The filariasis-specific cellular responsiveness was assessed in 109 adult individuals from a Wuchereria bancrofti-endemic area in north-east Tanzania. There were 9 study groups. Five groups of individuals were negative for microfilariae (mf) and specific circulating filarial antigen (CFA) and had leg lymphoedema of varying severity ranging from early to more advanced grades (pathology groups 1–5). Another group comprised individuals with mixed grades of lymphoedema and positive for mf and/or CFA (mixed pathology group). Three asymptomatic groups consisted of individuals without leg pathology but with different infection status: (i) CFA- and mf-negative individuals, (ii) CFA-positive but mf-negative individuals, and (iii) CFA- and mf-positive individuals. Peripheral blood mononuclear cells were collected and proliferative responsiveness and secretion of interleukin (IL)-4, IL-10 and gamma interferon (IFNγ) were measured upon stimulation with a Brugia pahangi antigen. No distinct differences in responses were observed between the 5 uninfected pathology groups. Instead, responses were associated with infection status, with generally higher proliferative activity and higher levels of IL-4 and IFNγ in uninfected as compared to infected individuals. High levels of IL-10 were observed in asymptomatic individuals without infection and in asymptomatic CFA-positive but mf-negative individuals. Asymptomatic individuals with mf had relatively low IL-10 levels. Groups presenting with chronic pathology generally had low levels of IL-10 independently of infection status. The findings thus give no immediate indication that the measured immunological parameters are related to progression of leg pathology. However, alternative interpretations are presented which suggest a possible role of immunological reactions in development of pathology in lymphatic filariasis.