Allograft rejection and immunosuppression are two major issues in transplantation medicine. The specific targeting of alloreactive T cells, the initiators and promoters of allograft rejection, would be a promising strategy to reduce unwanted T-cell responses and side effects of lifelong immunosuppression. The novel humanized monoclonal antibody GZ-alphabetaTCR, specific for the human alphabetaT-cell receptor, was tested in vitro and in vivo for its specificity and efficacy to modulate the alphabetaT-cell compartment. GZ-alphabetaTCR moderately induced apoptosis in resting alphabetaT cells in vitro, an effect considerably amplified in activated T cells. A single dose of GZ-alphabetaTCR significantly reduced human CD45(+)CD3(+) T cells in vivo, with a preferential modulation of CD4(+) alphabetaT cells. Importantly, naive T cells, the T-cell subset from which alloreactivity emanates, were significantly reduced. Simultaneously, a significant, compensatory increase of gammadelta T cells was observed in vitro and in vivo in both humanized mouse models examined. GZ-alphabetaTCR did not induce cytokines and was well tolerated. Thus, specificity and high efficacy make GZ-alphabetaTCR a powerful tool to selectively eliminate putatively detrimental T-cell subsets, a major goal in transplantation medicine. At the same time, GZ-alphabetaTCR spares gammadelta and natural killer cells, thus leaving the recipient's immune system competent for cell-mediated immunoregulation and cell-mediated immunity.