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 asymptomati c microfilaremic state (MF) in patients with lymphatic filariasis rema in undefined. MF patients have impaired filarial antigen (Ag)-specific lymphocyte proliferation and decreased frequencies (Fo) of Ag-specifi c T cells, and yet elevated serum IgE and antifilarial IgG4. To invest igate the mechanism of Ag-specific anergy in MF patients in contrast t o amicrofilaremic individuals with chronic lymphatic obstruction (CP), the Fo of Ag-specific lymphocytes from peripheral blood mononuclear c ells secreting either IL-4 or IFN-gamma were assessed by filter spot e nzyme-linked immunosorbent assay, and IL-10 and transforming growth fa ctor-beta (TGF-beta) mRNA transcript levels were assessed by a semiqua ntitative reverse transcriptase polymerase chain reaction technique. T he Fo of filaria-specific IL-4-secreting lymphocytes were equivalent i n both MF (geometric mean [GM] = 1:11,700) and CP (GM = 1:29,300 P = 0 .08), whereas the Fo of IFN-gamma-secreting lymphocytes were lower in MF (GM 1:39,300) than in CP (GM = 1:4,200, P < 0.01). When the ratio o f IL4/IFN-gamma (T helper type 2 [Th2]/Th1)-secreting cells was examin ed, MF subjects showed a predominant Th2 response (8:1) compared with a Th1 response in CP individuals (1:4). mRNA transcript levels of IL-1 0 were also significantly elevated in MF compared with CP individuals (P < 0.01). Further, IL-10 and TGF-beta were shown to have a role in m odulating the Ag-specific anergy among MF subjects, in that neutralizi ng anti-IL-10 or anti-TGF-beta significantly enhanced lymphocyte proli feration response (by 220-1,300%) to filarial Ags in MF individuals. T hese findings demonstrate that MF subjects respond to parasite antigen by producing a set of suppressive cytokines that may facilitate persi stence of the parasite within humans while producing little clinical d isease.