science and art of immunsuppression after liver ... · declining renal function as common problem...

Science and Art of Immunsuppression

after Liver Transplantation

Hans J. SchlittDepartment of Surgery

University of Regensburg

Is there the Optimal Immunsuppression ?

No, because:

Different underlying diseases

Different comorbidities

Different risk factors

Different individ. sensitiviy to side effects

Different requirement for immunosuppression

Is there the Optimal Immunsuppression ?

No, because:

Different underlying diseases

Different comorbidities

Different risk factors

Different individ. sensitiviy to side effects

Different requirement for immunosuppression

therefore: „Optimal“ immunosuppression is individualized immunosuppression

„Optimized“ Immunosuppression after LTx

Specific aspects of immunosuppression:

● Clinically bad patient (high MELD score)

● Impaired renal function (periop. and long-term)

● Tumor risk (Recurrence and de novo)

New drugs for immunosuppression

Protocols aiming at tolerance induction

More and more:Marginal recipients and donors

associated with renal dysfunction

• MELD score-based liver allocation selects forrecipients with renal dysfunction prior to LTx

• Extended donor criteria (for livers and kidneys) associated with increased rates of renal dysfunction after kidney and liver transplantation

Declining renal function as common problem in non-renal transplant patients

Ojo AO et al. N Engl J Med 2003; 349:931-40.

Heart-lung

0.35

0.30

0.25

0.20

0.15

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0.05

0.10

Time since transplantation (months)

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ive

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re Intestine Liver

LungHeart

12 24 36 48 60 72 84 96 108 1200

• Prospective, multi-centre study ofde novo liver recipients (12-month follow-up)

• To determine whether reduced or delayed TAC with 2 g MMF during the first month post-transplant reduces nephrotoxicity without compromising graft survival

Mayer AD et al. American Transplant Congress 2007, San Francisco. Abstract 637.

ReSpECT studyObjective

ReSpECT studyDesign


TxStandard-dose TAC (> 10 ng/ml) + corticosteroids

2 g MMF + reduced-dose TAC (≤ 8 ng/ml) + corticosteroids

2 g MMF + reduced-dose TAC (≤ 8 ng/ml) delayed to day 5 + corticosteroids + daclizumab

ReSpECT studyInterim analyses

• 525 patients randomised– Interim analysis at 6 months– 485 patients included in analysis

• Received at least one dose of assigned immunosuppression and had at least one calculated creatinine clearance


2 g MMF and delayed reduced TAC improves renal function

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ine

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-35

-30

-25

-20

-15

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-5

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p = 0.002

p = 0.337

Standard TAC2 g MMF + reduced TAC2 g MMF + delayed reduced TAC


0

10

20

30

40

Pat

ient

s w

ith B

PAR

(%)

Standard TAC2 g MMF + reduced TAC2 g MMF + delayed reduced TAC

2 g MMF and delayed reduced TAC results in low rates of BPAR

Immunosuppression in Clinically Very Bad Patients (MELD score↑↑)

i.e. dystrophic patient, hepato-renal syndrome, high risk of infection, probably marginal donor organ

Principle strategies:

● low immunsuppression generally sufficient

● avoid or delay CNI (nephrotoxicity)

● Initial antibody-based induction therapy (eg.: anti-CD25)

● low dose steroids

„Bottom-up“ Immunosuppression after LTx

● Anti-CD25 antibody (d 0, d 4)

● Mycophenolate 2 g/d

● Steroids, initially 1 mg/kg/d (tapered over 6 weeks)

● CNI (ciclosporin) only introduced in histologically proven rejection

prerequisite: low „threshold“ for biopsies

„Bottom-up“ Immunosuppression after LTx

● Anti-CD25 antibody (d 0, d 4)

● Mycophenolate 2 g/d

● Steroids, initially 1 mg/kg/d (tapered over 6 weeks)

● CNI (ciclosporin) only introduced in histologically proven rejection

prerequisite: low „threshold“ for biopsies

Regensburg experience in high MELD patients (n=15): only about 1/3 of patients require CNIs (!!)

Plan for Prospective Study

“Bottom-up” Immunosuppression in Patients with after Liver Transplantation with high MELD

(BUILT study)

e.g. IL-2R antibody inductionMycophenolate

Low-dose steroids

Introduction of CNI or mTOR-inhibitor only when and if required

“Bottom-up” Immunosuppression in Patients with after Liver Transplantation with high MELD

(BUILT study)

e.g. IL-2R antibody inductionMycophenolate

Low-dose steroids

Introduction of CNI or mTOR-inhibitor only when and if required

planned BMBF application for multicentric clinical trial (Deadline: 30.10.09)

Plan for Prospective Study

Further Perspectives

CNI-free “bottom-up” immunosuppression as basisfor immunregulatory cell therapy

e.g.,

CD4+CD25+ cells

Monocyte-derived cells (MdC, TAIC, STIC)

Mesenchymal stem cells (MSC)

Infection

HPV (Skin cancer)

EBV (PTLD)

HCV (HCC)

ImmuneSystem

Malignancy(Tx Recipients)

Tumor Cell Growth

Angiogenesis

MetastasisAll immuno-suppressive

drugs

CancerCancer-FreeIS

Geissler and SchlittCurr Opin Transplantation Dec, 2004

Immunosuppression and Cancer

DNA Repair

Infection

HPV (Skin cancer)

EBV (PTLD)

HCV (HCC)

ImmuneSystem

Malignancy(Tx Recipients)

Tumor Cell Growth

Angiogenesis

Metastasis

All immuno-suppressive

drugs

mTORi

mTORi

mTORi

mTORi

CNI

CNI +

CNI

+

Cancer

Cancer-Free

ISCNI

mTORi mTORimTORi

Immunosuppression and Cancer

Rapamycin Rapamycin EffectEffect: : „„ProofProof of Principleof Principle““

•• 15/15 15/15 patientspatients afterafter 3 3 months months RAPA RAPA therapytherapy no Kaposino Kaposi´́s s sarcomasarcoma

•• Remission Remission provenproven histologicallyhistologically (6 (6 monthmonth))

•• KaposiKaposi´́s s sarcomasarcoma cellscells: VEGF, Akt, p70S6 : VEGF, Akt, p70S6 expressionexpression increasedincreased

•• all all KTx with KTx with good good functionfunction

•• no no graft rejectiongraft rejection

Histologic Diagnosis Confirmation

HCC Diagnosis

LTx (deceased donor or living-related) • Start center-specific immunosuppressive protocol• Protocol should not include mTOR inhibitor

Sirolimus-Containing IS

mTORi-Free ISRandomization

Disease-Free Survival*

4-6 weeks (mTOR inhibitor-free)

Basic Protocol SiLVER Study

Arm 1 Arm 2

* The end-point analysis will be performed 5 years after all patients are enrolled (with yearly interim analyses)

New Substances for Immunosuppression

FK778:analogue of the active metabolites of leflunomide (Astellas), inhibits the de-novosynthesis of pyrimidines resulting in suppression of T and B cell proliferation, smoothmuscle cell proliferation was inhibited; phase III kidney trials,

JAK3 inhibitor:antiproliferative agent (CP-690,550, Pfizer), delayed rejection+prolong kidney allograft survival as monotherapy in non-human primate models, non-reversible anemia

AEB071 :Protein kinase C-inhibitor (Novartis), phase I+II

Anti-IL15 fusion receptor protein mutant: IL-15/Fc

Humanized CD11a (antiLFA1) antibody: Efalizumab

Second generation CTLA4Ig: Belatacept/LEA29Y (BMS), clinical trials phase II and III, selective T-cell-costimulation-blocking agent (CD80/CD86)

Science and Art of Immunsuppression after LTxTake Home Messages

There is not the optimal immunosuppression

„Optimal“ immunosuppression is individualizedimmunosuppression ( → studies !!)

Some of the Current Problems: - Management of immunosuppression in patients with high MELD

(low / CNI-free immunsuppression !!)- Avoidance of long-term side effects (e.g. nephrotoxicity) and tumor

development / recurrence in HCC- Hepatitis C

Some new substances in the pipeline

Development of „tolerance promoting“ therapeutic protocols(LTx as a good model for pilot trials)

science and art of immunsuppression after liver ... · declining renal function as common problem...

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