Abstract
The agonistic anti-human CD3ε antibody (Ab), OKT3, has been used to control acute transplant rejection. The in vivo administration of OKT3 was previously shown to induce the partial depletion of T cells and unresponsiveness (anergy) in the remaining CD4+ T cells. However, this therapy is also associated with the systemic release of several cytokines, which leads to a series of adverse side effects. We established a novel anti-human CD3ε Ab, 20-2b2, which recognized a close, but different determinant on the CD3ε molecule from that recognized by OKT3. 20-2b2 was non-mitogenic for human CD4+ T cells, could inhibit the activation of T cells in vitro, and induced T cell anergy in in vivo experiments using humanized mice. Cytokine release in humanized mice induced by the administration of 20-2b2 was significantly less than that induced by OKT3. Our results indicated that the CD3ε molecule is still an attractive, effective, and useful target for the modulation of T cell responses. The establishment of other Abs that recognize CD3ε, even though the determinant recognized by those Abs may be close to or different from that recognized by OKT3, may represent a novel approach for the development of safer Ab therapies using anti-CD3 Abs, in addition to the modification of OKT3 in terms of the induction of cytokine production.
Highlights
T cells become fully activated when they recognize an antigen and receive signals through co-stimulatory molecules
The activation of T cells is known to be accompanied by the temporary down-modulation of the T cell receptor (TCR)/CD3 complex on the cell surface [1,2,3]
We previously demonstrated that inducing the down-modulation of the TCR/CD3 complex without stimulating T cells resulted in the modulation of T cell responses [8]
Summary
T cells become fully activated when they recognize an antigen and receive signals through co-stimulatory molecules. The activation of T cells is known to be accompanied by the temporary down-modulation of the T cell receptor (TCR)/CD3 complex on the cell surface [1,2,3] The manipulation of these events in the early stages of T cell activation, for example, by modifying antigenic determinants and/or by blocking the interaction between co-stimulatory molecules and ligands, has been shown to induce T cell unresponsiveness (anergy) [4,5,6,7]. In our previous study [9], we reported and characterized an Ab (Dow2) against mouse CD4+ T cells that was established based on its ability to induce the down-modulation of the TCR/CD3 complex and simultaneously not stimulate CD4+ T cells. Dow (rat IgG2a) recognized mouse CD3e, induced T cell anergy in vivo, and was more effective than the well-known agonistic anti-mouse CD3e Ab, 145-2C11, in terms of the induction of an immunosuppressive state. The mode of recognition by 20-2b2 differed from that of the well-studied agonistic anti-human CD3e Ab, OKT3. 20-2b2 could induce human CD4+ T cell anergy in vivo and was significantly less harmful in terms of cytokine induction in vivo
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