BACKGROUND Preclinical experiments have shown that donor blood cells, modified in vitro by an alkylating agent (modified immune cells [MICs]), induced long-term specific immunosuppression against the allogeneic donor.METHODS In this phase I trial, patients received either 1.5 × 106 MICs per kg BW on day –2 (n = 3, group A), or 1.5 × 108 MICs per kg BW on day –2 (n = 3, group B) or day –7 (n = 4, group C) before living donor kidney transplantation in addition to post-transplantation immunosuppression. The primary outcome measure was the frequency of adverse events (AEs) until day 30 (study phase) with follow-up out to day 360.RESULTS MIC infusions were extremely well tolerated. During the study phase, 10 treated patients experienced a total of 69 AEs that were unlikely to be related or not related to MIC infusion. No donor-specific human leukocyte antigen Abs or rejection episodes were noted, even though the patients received up to 1.3 × 1010 donor mononuclear cells before transplantation. Group C patients with low immunosuppression during follow-up showed no in vitro reactivity against stimulatory donor blood cells on day 360, whereas reactivity against third-party cells was still preserved. Frequencies of CD19+CD24hiCD38hi transitional B lymphocytes (Bregs) increased from a median of 6% before MIC infusion to 20% on day 180, which was 19- and 68-fold higher, respectively, than in 2 independent cohorts of transplanted controls. The majority of Bregs produced the immunosuppressive cytokine IL-10. MIC-treated patients showed the Immune Tolerance Network operational tolerance signature.CONCLUSION MIC administration was safe and could be a future tool for the targeted induction of tolerogenic Bregs.TRIAL REGISTRATION EudraCT number: 2014-002086-30; ClinicalTrials.gov identifier: NCT02560220.FUNDING Federal Ministry for Economic Affairs and Technology, Berlin, Germany, and TolerogenixX GmbH, Heidelberg, Germany.
Christian Morath, Anita Schmitt, Christian Kleist, Volker Daniel, Gerhard Opelz, Caner Süsal, Eman Ibrahim, Florian Kälble, Claudius Speer, Christian Nusshag, Luiza Pego da Silva, Claudia Sommerer, Lei Wang, Ming Ni, Angela Hückelhoven-Krauss, David Czock, Uta Merle, Arianeb Mehrabi, Anja Sander, Matthes Hackbusch, Christoph Eckert, Rüdiger Waldherr, Paul Schnitzler, Carsten Müller-Tidow, Jörg D. Hoheisel, Shakhawan A. Mustafa, Mohamed S.S. Alhamdani, Andrea S. Bauer, Jochen Reiser, Martin Zeier, Michael Schmitt, Matthias Schaier, Peter Terness