Rabbit antithymocyte globulin induces human lymphocyte activation, proliferation, and apoptosis in the absence of complement: an experimental study

Rabbit antithymocyte globulin (rATG) has become the first choice for induction therapy in HLA-presensitized patients undergoing organ transplantation. Meanwhile, complement inhibitors have been approved for preventing or treating antibody-mediated rejection in these patients. The biological effects of rATG on lymphocytes in cases of complement deficiency or significant inhibition are not yet clear. We measured lymphocyte activation, proliferation, and Apoptosis in response to rATG treatment in the absence of complement. T-cell subsets were analyzed transcriptomically features to rATG stimulation. Activation-related phenotypes on T cells were determined in patients after rATG administration. We found that rATG treatment led to lymphocyte activation and proliferation in vitro without the addition of complement. A dose-dependent Apoptosis in rATG-treated lymphocytes was detected, which was partially caspase-3-dependent but Fas/FasL-independent. T cells were more sensitive to rATG stimulation than were non-T cells. Both CD4⁺ T cells and CD8⁺ T cells upregulated a series of genes related to cell activation, cytokine production and Apoptosis to rATG stimulation. CD69 and CD25 levels in surviving T cells were increased in patients after rATG administration. These findings indicate that rATG can stimulate lymphocyte activation, proliferation, and Apoptosis in the absence of complement. Biologic effects of rATG other than complement-dependent cytotoxicity need to be concerned.