T cells drive adaptive immune responses that can turn out pathogenic when directed against your own body tissues and organs causing autoimmune diseases. On the other hand, T cells are the main cellular component driving acute organ rejection after transplantation. Therefore different strategies to deplete/inactivate T cells have been pursued to treat patients either suffering from autoimmime diseases or requiring organ transplantation. While non-immunolglobulin drugs are efficient to cause T cell cytotoxicity, they fail to be specific and they also affect other cells. In an attempt to achieve cell specificity and cause solely T cell neutralization, immunoglobulin strategies using antibodies against the specific T cell molecule CD3e were developed three decades ago and since then have been used successfully to control acute organ rejection in transplanted patients. Moreover, promising results have been obtained in clinical trials studying the efficacy of anti-CD3e antibodies against several autoimmune diseases where T cells are pathogenic. However, anti-CD3e showed early on to produce adverse secondary effects in patients that were related with the systemic release of cytokines associated with a transient T cell activation response observed after the first dose of the antibody and that included fever, chills, diarrhea, vomits, respiratory, circulatory, and neurological problems. The release of cytokines was a consequence of the undesired activation of T cells that escaped depletion by anti-CD3E antibodies. Therefore, many efforts have been placed to avoid cytokine release by T cells when treated with anti-CD3e antibodies; rendering modified immunoglobnlins engineered to minimize their capacity to activate T cells. Still last generation of anti-CD3e antibodies developed are somewhat stimulatory and when tested in clinical trials have been shown to cause adverse side effects in patients including fever, headache, diarrhea and rashes.