PMID- 31996467
OWN - NLM
STAT- MEDLINE
DCOM- 20200925
LR  - 20240331
IS  - 1946-6242 (Electronic)
IS  - 1946-6234 (Print)
IS  - 1946-6234 (Linking)
VI  - 12
IP  - 528
DP  - 2020 Jan 29
TI  - Mixed chimerism and acceptance of kidney transplants after immunosuppressive drug 
      withdrawal.
LID - 10.1126/scitranslmed.aax8863 [doi]
LID - eaax8863
AB  - Preclinical studies have shown that persistent mixed chimerism is linked to 
      acceptance of organ allografts without immunosuppressive (IS) drugs. Mixed 
      chimerism refers to continued mixing of donor and recipient hematopoietic cells 
      in recipient tissues after transplantation of donor cells. To determine whether 
      persistent mixed chimerism and tolerance can be established in patients 
      undergoing living donor kidney transplantation, we infused allograft recipients 
      with donor T cells and hematopoietic progenitors after posttransplant lymphoid 
      irradiation. In 24 of 29 fully human leukocyte antigen (HLA)-matched patients who 
      had persistent mixed chimerism for at least 6 months, complete IS drug withdrawal 
      was achieved without subsequent evidence of rejection for at least 2 years. In 10 
      of 22 HLA haplotype-matched patients with persistent mixed chimerism for at least 
      12 months, reduction of IS drugs to tacrolimus monotherapy was achieved. 
      Withdrawal of tacrolimus during the second year resulted in loss of detectable 
      chimerism and subsequent rejection episodes, unless tacrolimus therapy was 
      reinstituted. Posttransplant immune reconstitution of naive B cells and B cell 
      precursors was more rapid than the reconstitution of naive T cells and thymic T 
      cell precursors. Robust chimerism was observed only among naive T and B cells but 
      not among memory T cells. No evidence of rejection was observed in all 
      surveillance graft biopsies obtained from mixed chimeric patients withdrawn from 
      IS drugs, and none developed graft-versus-host disease. In conclusion, persistent 
      mixed chimerism established in fully HLA- or haplotype-matched patients allowed 
      for complete or partial IS drug withdrawal without rejection.
CI  - Copyright (c) 2020 The Authors, some rights reserved; exclusive licensee American 
      Association for the Advancement of Science. No claim to original U.S. Government 
      Works.
FAU - Busque, Stephan
AU  - Busque S
AUID- ORCID: 0000-0003-1048-1621
AD  - Division of Abdominal Transplantation, Department of Surgery, Stanford University 
      School of Medicine, Stanford, CA 94305, USA.
FAU - Scandling, John D
AU  - Scandling JD
AD  - Division of Nephrology, Department of Medicine, Stanford University School of 
      Medicine, Stanford, CA 94305, USA.
FAU - Lowsky, Robert
AU  - Lowsky R
AUID- ORCID: 0000-0001-7924-2915
AD  - Division of Blood and Marrow Transplantation, Department of Medicine, Stanford 
      University School of Medicine, Stanford, CA 94305, USA.
FAU - Shizuru, Judith
AU  - Shizuru J
AUID- ORCID: 0000-0003-3246-4726
AD  - Division of Blood and Marrow Transplantation, Department of Medicine, Stanford 
      University School of Medicine, Stanford, CA 94305, USA.
FAU - Jensen, Kent
AU  - Jensen K
AUID- ORCID: 0000-0001-9721-4379
AD  - Division of Immunology and Rheumatology, Department of Medicine, Stanford 
      University School of Medicine, Stanford, CA 94305, USA.
FAU - Waters, Jeffrey
AU  - Waters J
AD  - Division of Immunology and Rheumatology, Department of Medicine, Stanford 
      University School of Medicine, Stanford, CA 94305, USA.
FAU - Wu, Hsin-Hsu
AU  - Wu HH
AUID- ORCID: 0000-0002-0028-7836
AD  - Division of Blood and Marrow Transplantation, Department of Medicine, Stanford 
      University School of Medicine, Stanford, CA 94305, USA.
AD  - Division of Immunology and Rheumatology, Department of Medicine, Stanford 
      University School of Medicine, Stanford, CA 94305, USA.
FAU - Sheehan, Kevin
AU  - Sheehan K
AUID- ORCID: 0000-0002-9778-3747
AD  - Division of Immunology and Rheumatology, Department of Medicine, Stanford 
      University School of Medicine, Stanford, CA 94305, USA.
FAU - Shori, Asha
AU  - Shori A
AUID- ORCID: 0000-0001-8447-362X
AD  - Division of Abdominal Transplantation, Department of Surgery, Stanford University 
      School of Medicine, Stanford, CA 94305, USA.
FAU - Choi, Okmi
AU  - Choi O
AUID- ORCID: 0000-0001-9786-7417
AD  - Department of Pathology, Stanford University School of Medicine, Stanford, CA 
      94305, USA.
FAU - Pham, Thomas
AU  - Pham T
AUID- ORCID: 0000-0001-7767-1978
AD  - Division of Abdominal Transplantation, Department of Surgery, Stanford University 
      School of Medicine, Stanford, CA 94305, USA.
FAU - Fernandez Vina, Marcelo A
AU  - Fernandez Vina MA
AUID- ORCID: 0000-0002-5707-2588
AD  - Department of Pathology, Stanford University School of Medicine, Stanford, CA 
      94305, USA.
FAU - Hoppe, Richard
AU  - Hoppe R
AUID- ORCID: 0000-0003-0125-0194
AD  - Department of Radiation Oncology, Stanford University School of Medicine, 
      Stanford, CA 94305, USA.
FAU - Tamaresis, John
AU  - Tamaresis J
AD  - Department of Biomedical Data Science, Stanford University School of Medicine, 
      Stanford, CA 94305, USA.
FAU - Lavori, Philip
AU  - Lavori P
AD  - Department of Biomedical Data Science, Stanford University School of Medicine, 
      Stanford, CA 94305, USA.
FAU - Engleman, Edgar G
AU  - Engleman EG
AUID- ORCID: 0000-0002-2096-9279
AD  - Department of Pathology, Stanford University School of Medicine, Stanford, CA 
      94305, USA.
FAU - Meyer, Everett
AU  - Meyer E
AUID- ORCID: 0000-0001-7953-853X
AD  - Division of Blood and Marrow Transplantation, Department of Medicine, Stanford 
      University School of Medicine, Stanford, CA 94305, USA.
FAU - Strober, Samuel
AU  - Strober S
AUID- ORCID: 0000-0002-1765-2326
AD  - Division of Immunology and Rheumatology, Department of Medicine, Stanford 
      University School of Medicine, Stanford, CA 94305, USA. sstrober@stanford.edu.
LA  - eng
GR  - P01 HL075462/HL/NHLBI NIH HHS/United States
GR  - P30 DK116074/DK/NIDDK NIH HHS/United States
GR  - R01 AI085024/AI/NIAID NIH HHS/United States
PT  - Journal Article
PL  - United States
TA  - Sci Transl Med
JT  - Science translational medicine
JID - 101505086
RN  - 0 (Immunosuppressive Agents)
RN  - 0 (Isoantigens)
RN  - WM0HAQ4WNM (Tacrolimus)
SB  - IM
MH  - Adult
MH  - B-Lymphocytes/immunology
MH  - *Chimerism
MH  - Female
MH  - Graft Survival/immunology
MH  - Haplotypes/genetics
MH  - Histocompatibility Testing
MH  - Humans
MH  - Immunosuppressive Agents/*pharmacology
MH  - Isoantigens/immunology
MH  - *Kidney Transplantation
MH  - Lymphocyte Culture Test, Mixed
MH  - Male
MH  - Middle Aged
MH  - Survival Analysis
MH  - T-Lymphocytes/immunology
MH  - Tacrolimus/pharmacology
MH  - Tissue Donors
MH  - Treatment Outcome
MH  - *Withholding Treatment
MH  - Young Adult
PMC - PMC8051148
MID - NIHMS1682356
COIS- Competing interests: S.S., R.L., and E.G.E. are cofounders of a cell therapy 
      company with a focus on organ transplantation, which provided no funding for the 
      study. A patent related to this work (Combined organ and hematopoietic cells for 
      transplantation tolerance of grafts) has been registered under U.S. Patent no. US 
      9,561,253 B2.
EDAT- 2020/01/31 06:00
MHDA- 2020/09/26 06:00
PMCR- 2021/04/16
CRDT- 2020/01/31 06:00
PHST- 2019/05/02 00:00 [received]
PHST- 2019/12/19 00:00 [accepted]
PHST- 2020/01/31 06:00 [entrez]
PHST- 2020/01/31 06:00 [pubmed]
PHST- 2020/09/26 06:00 [medline]
PHST- 2021/04/16 00:00 [pmc-release]
AID - 12/528/eaax8863 [pii]
AID - 10.1126/scitranslmed.aax8863 [doi]
PST - ppublish
SO  - Sci Transl Med. 2020 Jan 29;12(528):eaax8863. doi: 10.1126/scitranslmed.aax8863.