Preventing immunological rejection of transplanted organs without the need for long-term use of pharmacological immunosuppression is a primary objective in transplantation medicine. Reducing the need for immunosuppression would dramatically improve the outcome for transplant recipients and reduce health costs for society. The means to achieve this goal has not been realised with pharmacological or biological agents yet. Conditioning the immune response of solid organ transplant recipients towards allograft acceptance using cell-based therapies is now becoming technically feasible and clinically promising. The central focus of our proposed cooperative work programme is to produce distinct populations of haematopoietic regulatory cells and comparatively test their safety and efficacy in minimising pharmacological immunosuppression in solid organ transplantation. Preparations of regulatory T cells, macrophages and dendritic cells will be licensed for clinical manufacture in outstanding research facilities across Europe, and subsequently, these different tolerance-promoting cell types will be assessed in a single Phase I/II clinical study for safety, clinical practicality and efficacy. The therapeutic potential of these cells will be directly compared using one, single clinical protocol. In addition, we will study the tolerogenic characteristics of these regulatory cell types at in-depth molecular and functional levels. These integrative, but very focused, research plans are expected to result in the identification of the most promising regulatory cell products for further testing, and commercial exploitation: the final outcome is to identify a cell product which has genuine potential to induce operational tolerance if correctly applied in a Phase IIb clinical trial. This objective can only be accomplished by the cooperation of the most experienced researchers in this field across Europe, in alliance with SMEs devoted to cell therapy.