PMID- 36534805
OWN - NLM
STAT- MEDLINE
DCOM- 20221221
LR  - 20230209
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 119
IP  - 52
DP  - 2022 Dec 27
TI  - Central tolerance promoted by cell chimerism.
PG  - e2214989119
LID - 10.1073/pnas.2214989119 [doi]
LID - e2214989119
AB  - Historically, successful allotransplantation was only achieved by utilizing 
      powerful immunosuppressive drugs that were exposing the patient to severe 
      opportunistic infections. The thymus of the transplant recipient renders such 
      therapy obligatory as it constitutively blocks self-reactive T cells while 
      allowing alloreactive T cells to mature and populate the periphery. In 1992, a 
      follow-up study revealed the presence of donor leukocytes in long-term transplant 
      survivors. The stable persistence of recipient and donor leukocytes in the 
      transplanted patient, referred to as "chimerism", was considered the reason why 
      in some cases it was even possible to stop immunosuppressive treatment without 
      damaging the transplanted organ. Unfortunately, it quickly became evident that 
      stable, persistent allogeneic chimerism was not easily achievable by design. 
      Recently, a novel approach has been identified to help address this clinical gap 
      in knowledge: Cotransplantation of a donor graft with a thymic organoid populated 
      with donor precursor cells generates stable, long-term chimerism in the 
      recipient. In humanized mice, the implantation of thymic organoids, populated 
      with human donor inducible pluripotent stem cell (iPSC)-derived thymic epithelial 
      cells (TECs) and the same donor CD34+ bone marrow precursors, induces tolerance 
      to human leukocyte antigen (HLA)-matched donor tissues/organs. This technology 
      will allow successful allotransplantation of cells/organs even between Major 
      Histocompatibility Complex (MHC)-noncompatible individuals and allow getting rid 
      of immunosuppressive treatments reducing recipient morbidity.
FAU - Zeleniak, Ann
AU  - Zeleniak A
AUID- ORCID: 0000-0002-7974-9617
AD  - Institute of Cellular Therapeutics, Allegheny Health Network, Pittsburgh, PA, 
      15212.
FAU - Trucco, Massimo
AU  - Trucco M
AD  - Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, PA, 
      15289.
LA  - eng
GR  - R01 AI123392/AI/NIAID NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20221219
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (Immunosuppressive Agents)
RN  - 0 (Histocompatibility Antigens)
SB  - IM
MH  - Humans
MH  - Mice
MH  - Animals
MH  - *Bone Marrow Transplantation
MH  - Follow-Up Studies
MH  - *Central Tolerance
MH  - Immune Tolerance
MH  - T-Lymphocytes
MH  - Immunosuppressive Agents
MH  - Histocompatibility Antigens
PMC - PMC9907097
OTO - NOTNLM
OT  - chimerism
OT  - thymic organoids
OT  - tolerance
COIS- The authors declare no competing interest.
EDAT- 2022/12/20 06:00
MHDA- 2022/12/22 06:00
PMCR- 2022/12/19
CRDT- 2022/12/19 15:12
PHST- 2022/12/19 15:12 [entrez]
PHST- 2022/12/20 06:00 [pubmed]
PHST- 2022/12/22 06:00 [medline]
PHST- 2022/12/19 00:00 [pmc-release]
AID - 202214989 [pii]
AID - 10.1073/pnas.2214989119 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2022 Dec 27;119(52):e2214989119. doi: 
      10.1073/pnas.2214989119. Epub 2022 Dec 19.