Effect of aggressive prolonged diethylcarbamazine therapy on circulating antigen levels in bancroftian filariasis.

BACKGROUND: Single dose diethylcarbamazine (DEC) as used in control programmes is effectively microfilaricidal for periods of up to a year or more but has incomplete ability to kill Wuchereria bancrofti adult parasites. These regimens can be effective in breaking transmission by suppression of circulating microfilariae available to mosquito vectors. Whether prolonged or aggressive therapy with DEC has a significant effect on adult worms, which may live up to 12 years or more, and is important in the context of the treatment of individual patients, is still incompletely understood. METHODS: In order to investigate the adulticidal effect of aggressive therapy, DEC was given at 6 mg/kg/day for 12-day courses at 0, 6, 12, and 18 months and Og4C3 antigenaemia followed over two years in 38 CAg + Brazilians in a W. bancrofti endemic area. RESULTS: At two year follow-up, the median level of antigenaemia was 21% of the pre-treatment value. 92% of individuals had antigen levels < 50% of pretreatment values, but only 26% had completely cleared antigenaemia. The clearance rate at 24 months was only 12% (3/26) in the asymptomatic CAg + patients but 58% (7/12) in those with clinical manifestations of filariasis. The latter individuals cleared significantly more antigen (median of 0% pretreatment antigenaemia vs. 26%; P=0.02) than asymptomatic but infected individuals. CONCLUSION: Aggressive repeated therapy with DEC alone is ineffective in consistently eradicating adult W. bancrofti, especially in infected but asymptomatic individuals. Prolonged courses of combination therapy with other antifilarial drugs should be investigated for treatment of individual patients with the means to pursue aggressive personal medical care.

Biased TCR repertoire in infiltrating lesional T cells in human Bancroftian filariasis.

To investigate the hypothesis that T cells recognizing specific Ags localize to the site of disease activity in human bancroftian filariasis, we have compared the repertoire of TCR Vbeta gene segments in lesions vs blood in individual patients by RT-PCR ELISA. Vbeta14 and Vbeta24 were overrepresented (5% greater in tissue compared with PBMCs and/or tissue/PBMC ratios in the highest 5% of all tissue/PBMC ratios for all Vbetas for all subjects) in 50% and 40% of study subjects, respectively. Overrepresentation of these two Vbetas did not occur in any control subject. In comparing three patient groups, the proportion of individuals meeting at least one criterion for Vbeta14 overrepresentation was shown to increase in tandem with our current concepts of disease progression (asymptomatic filariasis = 25%; clinical filariasis with active infection = 60%; clinical filariasis without active infection = 71%). In 6 of the 10 individuals with Vbeta14 overrepresentation, Vbeta14 represented >20% of the entire lesional Vbeta repertoire. All but one of the 20 study subjects had at least one Vbeta gene segment that was overrepresented in tissue compared with PBMCs. Only a small number of Vbetas, usually three or less, were overrepresented in any single filariasis patient. However, in the same tissue, no differences between patient groups were found when IFN-gamma, TNF-alpha, IL-4, IL-5, and IL-12 mRNA expression were examined. Taken together, these findings suggest that, in principle, in essentially all patients, whether with subclinical or with clinical filariasis, distinct and limited T cell populations are concentrated in affected tissue.

T-lymphocytes from individuals with filarial inflammatory disease have increased transendothelial migration in vitro.

The in vitro transendothelial migration of circulating filarial antigen-specific T-cells was examined in Wuchereria banerofti infection. Circulating T-cells from individuals with filaria-induced lymphatic pathology (LP) had significantly greater migration through unstimulated HUVEC monolayers than did T-cells from asymptomatic infected (MF) individuals (P = 0.04). In contrast to the MF individuals where no effect was seen, transendothelial migration of 48-hr filarial antigen stimulated T-cells from LP individuals was significantly (P = 0.01) greater than migration of 48-hr media-stimulated T-cells. In six of seven patients examined, inhibition of the VLA-4/VCAM-1 pathway resulted in greater than 50% inhibition of transendothelial migration of T-cells.

Immunoregulation in onchocerciasis: persons with ocular inflammatory disease produce a Th2-like response to Onchocerca volvulus antigen.

To examine the role of specific cytokines in mediating the clinical manifestations of human onchocercal disease, microfilariae-positive Ghanaian subjects with inflammatory ocular disease were compared with microfilariae-positive subjects without ocular disease. Onchocerca volvulus antigen (OvAg)-stimulated peripheral blood mononuclear cells (PBMC) from subjects with disease produced significantly more interleukin (IL)-10 (with disease = 447.34 vs. without disease = 292.22 pg/mL; P < .01) and IL-5 (with disease = 33.36 vs. without disease = 27.26 pg/mL; P = .02). OvAg-stimulated IL-4 and interferon (IFN)-gamma levels were essentially undetectable in either group. When cytokine mRNA levels were measured by reverse transcriptase-polymerase chain reaction ELISA, persons with disease produced significantly more OvAg-stimulated IL-4, IL-5, and IL-10 mRNA (P = .03, < .01, .05, respectively). No difference in IFN-gamma mRNA production by either group was seen. Addition of neutralizing alpha IL-10 antibody to OvAg-stimulated PBMC increased TFN-gamma production to detectable levels in 20 of 24 persons.