In the creation of stable tolerance to MHC-incompatible allografts, reducing the large mass of donor-reactive cells via apoptosis is often required. Apoptosis induction by immunotoxins targeting surface molecules specifically presented on donor-reactive cytopathic T effector (T(eff)) cells is a promising strategy. Traditionally, the toxin moieties are bacterial exotoxins or plant-derived ribosome-inactivating proteins (RIPs) with large molecular size and strong immunogenicity, hence causing the problems of tissue penetration, host immune reaction and quick clearance. We have identified a novel class of small molecule RIPs (<10 kD) from the seeds of the plant Luffa cylindrica. The smallest member of this family, Luffin P1, has a molecular weight of 5226.8 Da, yet possessing a highly potent inhibitory activity on cell-free protein synthesis with IC50 of 0.88 nM. We now report a recombinant hIL-2-Luffin P1 immunotoxin, which strongly inhibited T-cell proliferation in mixed lymphocyte reaction and ConA response with IC50 of 1.8-10 nM. In vivo, hIL-2-Luffin P1 significantly prolonged the survival of major MHC-mismatched skin and kidney allografts in animal models. Thus, we demonstrate for the first time the efficacy of the smallest immunotoxin that could be further combined with other pharmacological and immunological reagents for synergistic control of pathogenic lymphocytes in immune-mediated diseases.