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ligands on the APCs, plus CD40-CD154 (CD40L) interactions. Adhesion molecules, such as leukocyte function antigen (LFA)-1, LFA-3, and intercellular adhesion molecule (ICAM)-1, are also important in the initial binding of CTLs to APC and to tumor targets. The CTLs must receive the appropriate help before expansion can occur. Antigen-specific T-helper cells with T-helper 1 (TH1) activity must be coactivated by the APCs. Th1 cells release Th1 cytokines, such as interferon (IFN)-g and interleukin (IL)-12, which are also necessary for CTL activation, and interleukin-2 (IL-2), which is necessary for CTL expansion (Cheung and Rooney 2002). A tumor cell that induces the secretion of T-helper 2 (TH2) cytokines, such as IL-4 and IL-10, may promote antibody instead of CTL responses.

Because of the propensity for NB to undergo "spontaneous regression," many have implicated an endogenous anti-NB immune response. The recent discovery of a natural IgM anti-NB antibody in children suggests that innate immunity may have a potential role in surveillance against this tumor (Ollert et al. 1996). Besides IgM, lymphocytes of the innate immune system (NK,NKT, g/6-T cells) (Jameson et al. 2003) interact with tumors through unique activation and inhibitory receptors. The NK cells can lyse human NB in vitro and inhibit xenograft growth (Colucci et al. 2003; Cheung and Modak 2002). Spe cific ligands on tumor cells trigger activating or inhibitory receptors on NK cells (Schilbach et al. 2000). The NKT cells bear NK markers (CD161,CD122) and are thymus dependent, expressing CD 3 plus TCR (Kronenberg and Gapin 2002). They recognize a-galactosyl-ceramide as well as ganglioside GD3 presented on CD1d, a nonclassical major histocompatibility (MHC) molecule (Wu et al. 2003). These NKT cells are effective anti-tumor vehicles in preclinical cellular targeting strategies (Metelitsa et al. 2001; Smyth et al. 2002). Human g6T cells isolated from PBL and expanded with IL-2 in vitro also mediate effective cytotoxicity against NB cells (Schilbach et al. 2000; Carding and Egan 2002).

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