Cytokine Control of Parasite-specific Anergy in Human Lymphatic Filariasis Preferential Induction of a Regulatory T Helper Type 2 Lymphocyte Subset

The immunological mechanisms involved in maintenance of an asymptomatic microfilaremic state (MF) in patients with lymphatic filariasis remain undefined. MF patients have impaired filarial antigen ( Ag)-specific lymphocyte proliferation and decreased frequencies (Fo) of Ag-specific T cells, and yet elevated serum IgE and antifilarial IgG4. To investigate the mechanism of Ag-specific anergy in MF patients in contrast to amicrofilaremic individuals with chronic lymphatic obstruction (CP), the Fo Ag-specific lymphocytes from peripheral blood mononuclear cells secreting either IL-4 or IFN- g were assessed by filter spot enzyme-linked immunosorbent assay, and IL-10 and transforming growth factor-ß (TGF-ß) mRNA transcript levels were assessed by a semiquantitative reverse transcriptase polymerase chain reaction technique. The Fo of filariaspecific IL-4-secreting lymphocytes were equivalent in both MF (geometric mean [GM] = 1:11,700) and CP (GM = 1:29,300 P =0.08), whereas the Fo of IFN- g -secreting lymphocytes were lower in MF (GM = 139,300) than in CP (GM = 1:4,200, P < 0.01). When the ratio of IL-4/IFN- g (T helper type 2 [ Th2]/Th1 )-secreting cells was examined, MF subjects showed a predominant Th2 response (8:1) compared with a Th1 response in CP individuals (1:4). mRNA transcript levels of IL-10 were also significantly elevated in MF compared with CP individuals (P < 0.01). Further, IL-10 and TGF-ß were shown to have a role in modulating the Ag-specific anergy at neutralizing anti-IL-10 or anti- TGF-ß significantly enhanced lymphocyte proliferation response (by 220-1,300%) to filarial Ags in MF individuals. These findings demonstrate that MF subjects respond to parasite antigen by producing a set of suppressive cytokines that may facilitate persistence of the parasite within humans while producing little clinical disease. ( J. Clin. Invest. 1993. 92:1667-1673.) Key words: lymphatic filariasis • tolerance • T helper subsets • IL-10 • ELISPO