PMID- 22399264
OWN - NLM
STAT- MEDLINE
DCOM- 20120709
LR  - 20240410
IS  - 1946-6242 (Electronic)
IS  - 1946-6234 (Print)
IS  - 1946-6234 (Linking)
VI  - 4
IP  - 124
DP  - 2012 Mar 7
TI  - Chimerism and tolerance without GVHD or engraftment syndrome in HLA-mismatched 
      combined kidney and hematopoietic stem cell transplantation.
PG  - 124ra28
LID - 10.1126/scitranslmed.3003509 [doi]
AB  - The toxicity of chronic immunosuppressive agents required for organ transplant 
      maintenance has prompted investigators to pursue approaches to induce immune 
      tolerance. We developed an approach using a bioengineered mobilized cellular 
      product enriched for hematopoietic stem cells (HSCs) and tolerogenic graft 
      facilitating cells (FCs) combined with nonmyeloablative conditioning; this 
      approach resulted in engraftment, durable chimerism, and tolerance induction in 
      recipients with highly mismatched related and unrelated donors. Eight recipients 
      of human leukocyte antigen (HLA)-mismatched kidney and FC/HSC transplants 
      underwent conditioning with fludarabine, 200-centigray total body irradiation, 
      and cyclophosphamide followed by posttransplant immunosuppression with tacrolimus 
      and mycophenolate mofetil. Subjects ranged in age from 29 to 56 years. HLA match 
      ranged from five of six loci with related donors to one of six loci with 
      unrelated donors. The absolute neutrophil counts reached a nadir about 1 week 
      after transplant, with recovery by 2 weeks. Multilineage chimerism at 1 month 
      ranged from 6 to 100%. The conditioning was well tolerated, with outpatient 
      management after postoperative day 2. Two subjects exhibited transient chimerism 
      and were maintained on low-dose tacrolimus monotherapy. One subject developed 
      viral sepsis 2 months after transplant and experienced renal artery thrombosis. 
      Five subjects experienced durable chimerism, demonstrated immunocompetence and 
      donor-specific tolerance by in vitro proliferative assays, and were successfully 
      weaned off all immunosuppression 1 year after transplant. None of the recipients 
      produced anti-donor antibody or exhibited engraftment syndrome or 
      graft-versus-host disease. These results suggest that manipulation of a mobilized 
      stem cell graft and nonmyeloablative conditioning represents a safe, practical, 
      and reproducible means of inducing durable chimerism and donor-specific tolerance 
      in solid organ transplant recipients.
FAU - Leventhal, Joseph
AU  - Leventhal J
AD  - Comprehensive Transplant Center, Northwestern Memorial Hospital, Chicago, IL 
      60611, USA.
FAU - Abecassis, Michael
AU  - Abecassis M
FAU - Miller, Joshua
AU  - Miller J
FAU - Gallon, Lorenzo
AU  - Gallon L
FAU - Ravindra, Kadiyala
AU  - Ravindra K
FAU - Tollerud, David J
AU  - Tollerud DJ
FAU - King, Bradley
AU  - King B
FAU - Elliott, Mary Jane
AU  - Elliott MJ
FAU - Herzig, Geoffrey
AU  - Herzig G
FAU - Herzig, Roger
AU  - Herzig R
FAU - Ildstad, Suzanne T
AU  - Ildstad ST
LA  - eng
GR  - R01 DK025243/DK/NIDDK NIH HHS/United States
GR  - R01 DK069766/DK/NIDDK NIH HHS/United States
GR  - UL1 RR025741/RR/NCRR NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
PL  - United States
TA  - Sci Transl Med
JT  - Science translational medicine
JID - 101505086
RN  - 0 (HLA Antigens)
RN  - 0 (Immunosuppressive Agents)
RN  - HU9DX48N0T (Mycophenolic Acid)
RN  - WM0HAQ4WNM (Tacrolimus)
SB  - IM
CIN - Sci Transl Med. 2012 Mar 7;4(124):124fs5. PMID: 22399262
CIN - Am J Transplant. 2012 Jul;12(7):1667-9. PMID: 22702487
CIN - Am J Kidney Dis. 2012 Oct;60(4):521-3. PMID: 22809762
MH  - Adult
MH  - Graft vs Host Disease/immunology
MH  - HLA Antigens/*immunology
MH  - Hematopoietic Stem Cell Transplantation/*methods
MH  - Humans
MH  - Immune Tolerance/*immunology
MH  - Immunosuppressive Agents/therapeutic use
MH  - Kidney Transplantation/*immunology
MH  - Male
MH  - Middle Aged
MH  - Mycophenolic Acid/analogs & derivatives/therapeutic use
MH  - Tacrolimus/therapeutic use
PMC - PMC3610325
MID - NIHMS452051
EDAT- 2012/03/09 06:00
MHDA- 2012/07/10 06:00
PMCR- 2013/03/28
CRDT- 2012/03/09 06:00
PHST- 2012/03/09 06:00 [entrez]
PHST- 2012/03/09 06:00 [pubmed]
PHST- 2012/07/10 06:00 [medline]
PHST- 2013/03/28 00:00 [pmc-release]
AID - 4/124/124ra28 [pii]
AID - 10.1126/scitranslmed.3003509 [doi]
PST - ppublish
SO  - Sci Transl Med. 2012 Mar 7;4(124):124ra28. doi: 10.1126/scitranslmed.3003509.