PMID- 21384504
OWN - NLM
STAT- MEDLINE
DCOM- 20110624
LR  - 20220311
IS  - 1527-6473 (Electronic)
IS  - 1527-6465 (Linking)
VI  - 17
IP  - 3
DP  - 2011 Mar
TI  - Operational tolerance: past lessons and future prospects.
PG  - 222-32
LID - 10.1002/lt.22265 [doi]
AB  - Every liver transplant (LT) center has had patients who either self-discontinue 
      immunosuppressive (IS) therapy or are deliberately withdrawn due to a research 
      protocol or clinical concern (ie, lymphoproliferative disorder [LPD], 
      overwhelming infection). This is understandable because maintenance IS therapy, 
      particularly calcineurin inhibitors (CNI), is associated with significant cost, 
      side effects, and considerable long-term morbidity and mortality. Detrimental 
      effects of IS therapy include increased risk of cardiovascular disease, metabolic 
      syndrome, bone loss, opportunistic and community-acquired infections, and 
      malignancy. In fact, LT recipients have among the highest rates of chronic kidney 
      disease and associated mortality among all nonkidney solid organ recipients. This 
      mortality is only ameliorated by undergoing a curative kidney transplant, 
      usurping costs and valuable organ resources. The search for improved treatment 
      algorithms includes trial and error CNI dose minimization, the use of alternative 
      IS agents (antimetabolites, mammalian target of rapamycin [mTOR] inhibitors), or 
      even complete CNI withdrawal. Yet those who are successful in achieving such 
      operational tolerance (no immunosuppression and normal allograft function) are 
      considered lucky. The vast majority of recipients will fail this approach, 
      develop acute rejection or immune-mediated hepatitis, and require resumption of 
      IS therapy. As such, withdrawal of IS following LT is not standard-of-care, 
      leaving clinicians to currently maintain transplant patients on IS therapy for 
      life. Nonetheless, the long-term complications of all IS therapies highlight the 
      need for strategies to promote immunologic or operational tolerance. Clinically 
      applicable biomarker assays signifying the potential for tolerance as well as 
      tolerogenic IS conditioning are invariably needed if systematic, controlled 
      rather than "hit or miss" approaches to withdrawal are considered. This review 
      will provide an overview of the basic mechanisms of tolerance, particularly in 
      relation to LT, data from previous IS withdrawal protocols and biomarker studies 
      in tolerant recipients, and a discussion on the prospect of increasing the 
      clinical feasibility and success of withdrawal.
CI  - Copyright (c) 2011 American Association for the Study of Liver Diseases.
FAU - Levitsky, Josh
AU  - Levitsky J
AD  - Division of Hepatology and Comprehensive Transplant Center, Northwestern 
      University Feinberg School of Medicine, Chicago, IL 60611, USA. 
      j-levitsky@northwestern.edu
LA  - eng
PT  - Historical Article
PT  - Journal Article
PT  - Review
PL  - United States
TA  - Liver Transpl
JT  - Liver transplantation : official publication of the American Association for the 
      Study of Liver Diseases and the International Liver Transplantation Society
JID - 100909185
RN  - 0 (Immunosuppressive Agents)
SB  - IM
MH  - Animals
MH  - Drug Administration Schedule
MH  - Graft Rejection/history/immunology/*prevention & control
MH  - Graft Survival/*drug effects
MH  - History, 20th Century
MH  - History, 21st Century
MH  - Humans
MH  - Immunosuppressive Agents/*administration & dosage/adverse effects/history
MH  - Liver Transplantation/history/*immunology/trends
MH  - Patient Selection
MH  - Risk Assessment
MH  - Time Factors
MH  - Transplantation Tolerance/*drug effects
MH  - Treatment Outcome
EDAT- 2011/03/09 06:00
MHDA- 2011/06/28 06:00
CRDT- 2011/03/09 06:00
PHST- 2011/03/09 06:00 [entrez]
PHST- 2011/03/09 06:00 [pubmed]
PHST- 2011/06/28 06:00 [medline]
AID - 10.1002/lt.22265 [doi]
PST - ppublish
SO  - Liver Transpl. 2011 Mar;17(3):222-32. doi: 10.1002/lt.22265.