Having identified two recombinant filarial proteins (Ov27 and OvD5B) that induced patient peripheral blood mononuclear cells to produce antigen-specific lgG4/lgE antibodies in vitro, we assessed the role these filarial antigens play in inducing antigen-specific isotype switching (γ4 and εiv) in the absence of T cells. Purified CD19⁺ sγ⁻/sε⁻ B cells were cultured with either of these antigens in the presence of anti-CD40 mAb and human IL-4. Both antigen and polyclonal signals delivered by IL-4 (or IL-13) were necessary for the induction of specific lgG4/lgE antibodies. To assess the role played by cytokines produced by B lymphocytes in antigen-driven selection of the γ4 or ε isotype, neutralizing anti-cytokine antibodies were used in vitro. While anti-IL-12 antibodies did not alter the antigen-specific lgG4/lgE production, anti-IL-6, anti-IL-13 and anti-tumor necrosis factor-α antibodies significantly inhibited the production of lgG4/lgE. Anti-IL-2 and anti-IL-10 antibodies appeared to down-regulate antigen-specific lgG4 antibodies without affecting antigen-specific IgE antibodies. Although anti-CD21 antibodies had no effect on specific IgE antibodies, they up-regulated specific lgG4 antibodies, a finding paralleled by anti-CD23 antibodies. These data suggest that certain filarial antigen-specific lgG4/lgE responses can be differentially regulated and that certain endogenously produced molecules from B cells—such as IL-2, IL-10, CD23 and CD21–play a significant role in the induction of specific isotypes of antigen-specific antibodies.