Phase I trial of donor-derived modified immune cell infusion in kidney transplantation
Open Access
- 23 March 2020
- journal article
- research article
- Published by American Society for Clinical Investigation in JCI Insight
- Vol. 130 (5), 2364-2376
- https://doi.org/10.1172/jci133595
Abstract
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.Keywords
Funding Information
- Federal Ministry for Economic Affairs and Technology, Berlin, Germany (03EFBBW056)
- TolerogenixX GmbH, Heidelberg, Germany (-)
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