PMID- 31990685
OWN - NLM
STAT- MEDLINE
DCOM- 20210126
LR  - 20210126
IS  - 1558-8238 (Electronic)
IS  - 0021-9738 (Print)
IS  - 0021-9738 (Linking)
VI  - 130
IP  - 5
DP  - 2020 May 1
TI  - Phase I trial of donor-derived modified immune cell infusion in kidney 
      transplantation.
PG  - 2364-2376
LID - 133595 [pii]
LID - 10.1172/JCI133595 [doi]
AB  - BACKGROUNDPreclinical 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.METHODSIn this phase I 
      trial, patients received either 1.5 x 106 MICs per kg BW on day -2 (n = 3, group 
      A), or 1.5 x 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.RESULTSMIC 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 
      x 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.CONCLUSIONMIC administration 
      was safe and could be a future tool for the targeted induction of tolerogenic 
      Bregs.TRIAL REGISTRATIONEudraCT number: 2014-002086-30; ClinicalTrials.gov 
      identifier: NCT02560220.FUNDINGFederal Ministry for Economic Affairs and 
      Technology, Berlin, Germany, and TolerogenixX GmbH, Heidelberg, Germany.
FAU - Morath, Christian
AU  - Morath C
AD  - Department of Nephrology, Heidelberg University Hospital, Heidelberg, Germany.
AD  - TolerogenixX GmbH, Heidelberg, Germany.
FAU - Schmitt, Anita
AU  - Schmitt A
AD  - TolerogenixX GmbH, Heidelberg, Germany.
AD  - Department of Hematology, Oncology and Rheumatology.
FAU - Kleist, Christian
AU  - Kleist C
AD  - Transplantation Immunology, Institute of Immunology.
AD  - Department of Nuclear Medicine.
FAU - Daniel, Volker
AU  - Daniel V
AD  - Transplantation Immunology, Institute of Immunology.
FAU - Opelz, Gerhard
AU  - Opelz G
AD  - Transplantation Immunology, Institute of Immunology.
FAU - Susal, Caner
AU  - Susal C
AD  - Transplantation Immunology, Institute of Immunology.
FAU - Ibrahim, Eman
AU  - Ibrahim E
AD  - Transplantation Immunology, Institute of Immunology.
FAU - Kalble, Florian
AU  - Kalble F
AD  - Department of Nephrology, Heidelberg University Hospital, Heidelberg, Germany.
FAU - Speer, Claudius
AU  - Speer C
AD  - Department of Nephrology, Heidelberg University Hospital, Heidelberg, Germany.
FAU - Nusshag, Christian
AU  - Nusshag C
AD  - Department of Nephrology, Heidelberg University Hospital, Heidelberg, Germany.
FAU - Pego da Silva, Luiza
AU  - Pego da Silva L
AD  - Department of Nephrology, Heidelberg University Hospital, Heidelberg, Germany.
AD  - TolerogenixX GmbH, Heidelberg, Germany.
FAU - Sommerer, Claudia
AU  - Sommerer C
AD  - Department of Nephrology, Heidelberg University Hospital, Heidelberg, Germany.
FAU - Wang, Lei
AU  - Wang L
AD  - TolerogenixX GmbH, Heidelberg, Germany.
AD  - Department of Hematology, Oncology and Rheumatology.
FAU - Ni, Ming
AU  - Ni M
AD  - Department of Hematology, Oncology and Rheumatology.
FAU - Huckelhoven-Krauss, Angela
AU  - Huckelhoven-Krauss A
AD  - Department of Hematology, Oncology and Rheumatology.
FAU - Czock, David
AU  - Czock D
AD  - Department of Clinical Pharmacology and Pharmacoepidemiology.
FAU - Merle, Uta
AU  - Merle U
AD  - Department of Gastroenterology.
FAU - Mehrabi, Arianeb
AU  - Mehrabi A
AD  - Department of General, Visceral and Transplantation Surgery.
FAU - Sander, Anja
AU  - Sander A
AD  - Institute of Medical Biometry and Informatics.
FAU - Hackbusch, Matthes
AU  - Hackbusch M
AD  - Institute of Medical Biometry and Informatics.
FAU - Eckert, Christoph
AU  - Eckert C
AD  - Institute of Pathology, and.
FAU - Waldherr, Rudiger
AU  - Waldherr R
AD  - Institute of Pathology, and.
FAU - Schnitzler, Paul
AU  - Schnitzler P
AD  - Virology, Center for Infectious Diseases, Heidelberg University Hospital, 
      Heidelberg, Germany.
FAU - Muller-Tidow, Carsten
AU  - Muller-Tidow C
AD  - Department of Hematology, Oncology and Rheumatology.
FAU - Hoheisel, Jorg D
AU  - Hoheisel JD
AD  - Division of Functional Genome Analysis, DKFZ, Heidelberg, Germany.
FAU - Mustafa, Shakhawan A
AU  - Mustafa SA
AD  - Division of Functional Genome Analysis, DKFZ, Heidelberg, Germany.
AD  - Kurdistan Institution for Strategic Studies and Scientific Research, Kurdistan 
      Region, Iraq.
FAU - Alhamdani, Mohamed Ss
AU  - Alhamdani MS
AD  - Division of Functional Genome Analysis, DKFZ, Heidelberg, Germany.
FAU - Bauer, Andrea S
AU  - Bauer AS
AD  - Division of Functional Genome Analysis, DKFZ, Heidelberg, Germany.
FAU - Reiser, Jochen
AU  - Reiser J
AD  - Department of Medicine, Rush Medical College, Rush University, Chicago, Illinois, 
      USA.
FAU - Zeier, Martin
AU  - Zeier M
AD  - Department of Nephrology, Heidelberg University Hospital, Heidelberg, Germany.
FAU - Schmitt, Michael
AU  - Schmitt M
AD  - Department of Hematology, Oncology and Rheumatology.
FAU - Schaier, Matthias
AU  - Schaier M
AD  - Department of Nephrology, Heidelberg University Hospital, Heidelberg, Germany.
AD  - TolerogenixX GmbH, Heidelberg, Germany.
FAU - Terness, Peter
AU  - Terness P
AD  - Transplantation Immunology, Institute of Immunology.
LA  - eng
SI  - ClinicalTrials.gov/NCT02560220
SI  - EudraCT/2014-002086-30
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - J Clin Invest
JT  - The Journal of clinical investigation
JID - 7802877
RN  - 0 (Immunosuppressive Agents)
SB  - IM
CIN - J Clin Invest. 2020 May 1;130(5):2189-2191. PMID: 32250338
MH  - Allografts
MH  - Female
MH  - Follow-Up Studies
MH  - Humans
MH  - Immunosuppressive Agents/*administration & dosage
MH  - *Kidney Transplantation
MH  - *Leukocyte Transfusion
MH  - Male
MH  - *Tissue Donors
PMC - PMC7190926
OTO - NOTNLM
OT  - Clinical Trials
OT  - Tolerance
OT  - Transplantation
COIS- Conflict of interest: CM, A. Schmitt, CK, GO, MZ, M. Schmitt, M. Schaier, and PT, 
      together with the University of Heidelberg, are cofounders of TolerogenixX GmbH, 
      a biotechnology company that holds licenses for modified immune cell (MIC) 
      treatment. CK, GO, and PT hold a patent for MIC treatment ("Immunosuppressive 
      blood cells and methods of producing the same." Patent no. WO 2010/000730, EP 
      2318020). CM, A. Schmitt, CK, VD, GO, C. Susal, MZ, M. Schmitt, M. Schaier, and 
      PT filed a patent application for MIC treatment ("MIC therapy for specific 
      immunosuppression in transplantation." Patent no. PCT/EP2019/062857). JR is 
      cofounder and shareholder of Trisaq, a biopharmaceutical company that develops 
      novel therapies for kidney diseases.
EDAT- 2020/01/29 06:00
MHDA- 2021/01/27 06:00
PMCR- 2020/08/01
CRDT- 2020/01/29 06:00
PHST- 2019/09/23 00:00 [received]
PHST- 2020/01/22 00:00 [accepted]
PHST- 2020/01/29 06:00 [pubmed]
PHST- 2021/01/27 06:00 [medline]
PHST- 2020/01/29 06:00 [entrez]
PHST- 2020/08/01 00:00 [pmc-release]
AID - 133595 [pii]
AID - 10.1172/JCI133595 [doi]
PST - ppublish
SO  - J Clin Invest. 2020 May 1;130(5):2364-2376. doi: 10.1172/JCI133595.