综述-50896_2011_Mazariegos_Immunosupp_withdrawal_liver_tx_next_steps
Immunosuppression Withdrawal After Liver Transplantation:What Are the Next Steps?
George V.Mazariegos
Achieving operational tolerance after liver transplantation remains a challenge for clinicians and scientists.Prospective immunosuppression withdrawal trials coupled with biomarker development and histologic assessment will be critical to the increasing applicability of drug-free transplantation from a sporadic event to a safely achieved,predictable state for increasing numbers of patients.
Keywords:Immunosuppression withdrawal,Liver transplantation,Operational tolerance.
(Transplantation2011;91:697–699)
T he achievement of operational tolerance defined as the absence of graft rejection without the use of immunosup-pression remains the goal of transplant research(1).Clini-cally,operational tolerance has been observed after liver transplantation(LT)in selected case reports or uncontrolled trials.Application of clinical regimens designed to prospec-tively achieve tolerance has not yet been applied to LT,and the safety and benefit of drug withdrawal have not been con-clusively demonstrated.Progress and challenges in the fol-lowing interrelated key areas are reviewed with respect to their effect on the state-of-the-art of immunosuppression withdrawal(IW)in LT.
DEMONSTRATING SAFETY AND EFFICACY All clinical interventions should balance benefit and risk.Despite concern over the risk of IW or the general appli-cability of IW to most patients,most clinicians intuitively understand that patients remain suboptimally managed with regard to immunosuppression and that subsets of patients suffer from excessive or at times inadequate immunosuppres-sion.The published clinical experience in drug withdrawal after LT includes IW for both elective and emergent indica-tions and after both deceased organ and live donor LT.In the aggregated data that have been well summarized(2),between 20%and25%of carefully selected patients may be success-fully withdrawn from immunosuppression for sustained pe-riods of time.Caveats to these conclusions include the fact that the majority of the published experience has not been carefully controlled and lacks histologic assessment of the liver graft before,during,or after IW.Reported incidence of acute rejection has varied in the literature but has been de-scribed as relatively easy to manage.Graft loss or chronic rejection after IW,although uncommon,has been reported.
Recently,a multicenter trial in IW after pediatric LT has been presented in preliminary form by Feng(3).Twelve of20 live donor pediatric liver recipients successfully underwent IW with follow-up of7to27months.This has been the im-petus for development of a larger prospective trial of IW after both deceased and live donor pediatric LT,planning for which is currently underway.Reprogramming the Immune System for Establishment of Tolerance(RISET),a multina-tional European project(https://www.wendangku.net/doc/e06222907.html,),is supporting a large prospective,multicenter European trial of IW in adult liver recipients.The Immune Tolerance Network(www. https://www.wendangku.net/doc/e06222907.html,)is sponsoring two clinical trials of IW: https://www.wendangku.net/doc/e06222907.html, NCT00105235uses Campath-1H as in-duction therapy in nonviral end-stage liver disease and NCT00135694includes patients with viral mediated end-stage liver disease in a randomized trial of IW(4).Trials of this type will first address the safety of IW but may also more conclusively demonstrate the benefit in reduced drug-related morbidities such as hypertension,renal dysfunction,or,in the case of hepatitis C virus-positive patients,reduced mor-bidity from recurrence of viral hepatitis.
Another tool to document the natural history of IW will be to prospectively enroll patients from multiple centers worldwide who are off immunosuppression into database registries that will document length of time off immunosup-pression,potentially identify clinical parameters that are pre-dictive of the ability to sustain operational tolerance,and identify potential subjects for concurrent or subsequent trials of biomarker assessment.Such efforts have begun with the establishment of the International Solid Organ Trans-
Children’s Hospital of Pittsburgh(CHP)Hillman Center for Pediatric
Transplantation,Pittsburgh,PA.
Address correspondence to:George V.Mazariegos,M.D.,F.A.C.S.,Hillman
Center for Pediatric Transplantation,Children’s Hospital of Pittsburgh,
One Children’s Hospital Drive,4401Penn Avenue,Faculty Pavilion,
Floor6,Pittsburgh,PA15224.
E-mail:george.mazariegos@https://www.wendangku.net/doc/e06222907.html,
G.V.M.conceived the design of the article,performed the literature review,
and authored the article in its entirety.
Received12April2010.Revision requested19May2010.
Accepted20December2010.
Copyright?2011by Lippincott Williams&Wilkins
ISSN0041-1337/11/9107-697
DOI:10.1097/TP.0b013e31820c85a3
Transplantation?Volume91,Number7,April15,https://www.wendangku.net/doc/e06222907.html,|697
plant Tolerance Registry(https://www.wendangku.net/doc/e06222907.html,)and
RISET.
MONITORING OF THE TOLERANT
PATIENT AND DEVELOPMENT OF
PREDICTIVE ASSAYS
Critical to the safe identification of the tolerant patient
and to more thorough investigation of patients undergoing
prospective trials will be the development of reproducible
biomarkers predictive of the tolerant state.Progress in this
regard has been recently reviewed(5,6)and is summarized in
Table1.The identification of specific gene transcription
products after adult LT that may be predictive of ability to
achieve operational tolerance is of particular interest(7).
Affymetrix microarray expression demonstrated??T-cell –related and natural killer cell–related pathways to be most
associated with the tolerant state.These profiles are undergo-
ing further prospective evaluation in the RISET trial.
The absence of donor-specific antibody(8)and the role
of regulatory T cells in the graft or in peripheral blood(9)of
tolerant subjects have also been proposed.Of note,bio-
marker investigations in these patients have also provided
supportive evidence to hypotheses that autoimmunity and
alloimmunity are interrelated phenomena rather than dis-
tinct processes.For example,CD4?CD25?Foxp3?regula-
tory T cells have been shown to demonstrate suppressive effects in autoimmunity and transplant models(10).Den-dritic cell-based therapies have also shown experimental evi-dence of promotion of transplant tolerance and in treatment of autoimmune disease(11).
HISTOPATHOLOGIC ASSESSMENT OF THE PATIENT UNDERGOING
DRUG WITHDRAWAL
The development of fibrosis in long-term survivors of LT has been well documented in both pediatric and adult populations,but the underlying causative factors are not clear.Protocolized biopsy assessment after LT has not been routinely practiced because of multiple concerns including safety,cost,and uncertainty of its utility in the patient with normal hepatocellular and canalicular enzymes.Although sample size is limited,certain common findings in the patient with normal liver function off immunosuppression have been recently published(12).In addition,the finding of fibrosis in live donor LT who were being withdrawn from immunosuppression prompted one group to reinstitute im-munosuppression when fibrosis progressed during IW(13).
A protocolized biopsy before IW and regular biopsy assess-ment during and after IW will help answer whether biopsy findings are immune mediated or related to other factors such as sampling,technical,or in cases of split liver or live
TABLE1.Potential biomarkers of liver transplant tolerance
Assay Description
Dendritic cells
pDC:mDC ratio TOL and PW patients exhibit a significantly higher incidence of circulating pDC relative to mDC mDC:pDC ratio Increased mDC:pDC ratio associates with late,but not early liver rejection
PD-L1:CD86ratio TOL patients expressed significantly higher PD-L1:CD86ratios on pDC
T-cell function
Immunoknow(Cylex)Recipients with a high Cylex immune response are more likely to develop cellular rejection than
those with a lower Cylex immune response
CD4?CD25hi Foxp3?High frequency during and after successful immunosuppressive drug withdrawal
V?1/??2T cell ratio Increased
V?24?V?11hi NKT Lower frequency of circulating V?24?V?11hi NKT in operationally tolerant living donor
transplant recipients
CD154?T cells Donor-specific,CD154?Tc memory cells are associated with rejection and increased
pretransplant CD154?Tc-memory cells response is associated with increased incidence of
rejection
Gene expression
Gene transcriptional profiling NK and??TCR?T cells predominate.Innate immune cells may play major roles in operational
tolerance
TNF?/IL-10polymorphisms Transplant recipients with low TNF-?and high/intermediate IL-10genetic profiles are more
likely to be maintained off or with minimal immunosuppression
Soluble factors
sHLA-G High serum levels is associated with normal liver function tests,whereas a decrease in levels is
rapidly followed by deterioration of liver function parameters
Donor-specific Ab Lack of donor-specific Ab in tolerant population
IL-17/IL-23IL-23and IL-17serum level increases during acute liver rejection episodes
Adapted from Curr Opin Organ Transplant2010;15:28.
TOL,operationally tolerant transplant recipients;PW,successful immunosuppression drug weaning;pDC,plasmacytoid dendritic cells;mDC,conven-tional myeloid dendritic cells;PD-L1,programmed death ligand-1;NK,natural killer cell;NKT,natural killer T cell;Tc,T-cytotoxic;TNF,tumor necrosis factor; IL,interleukin;Ab,antibody SHLA-G,soluble human leukocyte antigen-G.
698|https://www.wendangku.net/doc/e06222907.html, Transplantation?Volume91,Number7,April15,2011
donor segments,potentially related to microvascular isch-emia from the technical variant.
In summary,progress in achieving IW following trans-plantation will require concerted efforts in multiple areas. Prospective trials and registry efforts will help answer whether operational tolerance can be safely achieved and maintained and identify clinical characteristics,which may be favorable.Docu-mentation of proven benefit in reduction of drug-related mor-bidities will further shift the benefit-to-risk ratio toward IW. Finally,histopathological assesment of the graft during IW and the validation of proposed markers of tolerance will help trans-form the achievement from an uncertain proposition likened to predicting the weather(14)to a safe and worthwhile endeavor not only for the clinician,but most importantly for our patients.
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