Finally, CTLA4Ig graduates to the clinic.

require two signals for full activation, but the mechanisms of how these signals function have been only recently elucidated (1). The first signal is provided by the T-cell receptor after interacting with the MHC/antigenic peptide complex. This so-called “signal one” confers antigen specificity to the immune response but alone is insufficient for full T-cell activation. Indeed, T cells receiving only signal one are rendered anergic (unresponsive to antigenic rechallenge, with inhibition of proliferation and cytokine production) in vitro (2). The second signal, or “costimulatory signal,” is provided by interactions between specific receptors on the T cell and their respective ligands on antigen-presenting cells (APCs). The CD28/CD152–B7-1/B7-2 T-cell costimulatory pathway is a unique and complex pathway that regulates T-cell activation (recently reviewed in refs. 3 and 4) (Figure 1). Interaction of CD28, constitutively expressed on T cells, with the B7 family of molecules (B7-1 and B7-2), expressed on APCs, provides a second “positive” signal that results in full T-cell activation, including cytokine production, clonal expansion, and prevention of anergy. In addition, CD28 signaling appears to be important in prevention of cell death and promotion of cell survival, presumably by upregulation of T-cell expression of bcl-xl genes (5). Once activated, T cells express another costimulatory molecule (CD152, or CTLA4) that is homologous to CD28, has a higher affinity to B7-1 and B7-2, and functions to provide a “negative” signal that inhibits cytokine production and arrests cell cycle progression (6–8). The importance of CTLA4 as a negative regulatory T-cell costimulatory molecule in the physiologic termination of T-cell responses (9) is highlighted by the observation that CTLA4 gene knockout mice develop massive lymphoproliferation and early death (10, 11). Furthermore, recent evidence suggests that CTLA4 negative signaling pathway may be required for the induction of acquired tolerance (12, 13). Indeed, it has been hypothesized that CTLA4 may function as a “master switch” for peripheral T-cell tolerance in vivo (14). Several years before the regulatory function of CTLA4 was elucidated, Linsley et al. first described the creation of a new immunomodulatory agent that consists of the extracellular domain of the soluble CTLA4 receptor fused to the heavy chain of human IgG1 (6). Other similar agents have been subsequently described, including a murine form of CTLA4Ig, and several hundred articles have been published describing the immunomodulatory functions of CTLA4Ig in several experimental animal models of transplant