Quinze ans de greffe de tissus composites: quels ...

Quinze ans de greffe de tissus composites:

quels enseignements ? Fifteen years of composite grafts: what lessons

? Emmanuel Morelon

Service de Transplantation, Néphrologie et Immunologie Clinique INSERM U 1111

Hôpital Edouard Herriot, Lyon, France

Actualités néphrologiques Hôpital Necker 28 avril 2015

http://www.fondation-centaure.fr/fr/index.php

• Surgical and functional aspects

• Immunological aspects

– Acute rejection

– Chronic rejection

• Immunosuppression in VCA

Outline

CLINICAL COMPOSITE

TISSUE ALLOGRAFTS

• femoral diaphyses, knee-joints (1995)

• larynx + Thyroïd + Parathyroid (1998)

• 1 hand (1998)

• 2 hands (2000)

• abdominal wall (2001)

• face (2005)

• penis (2006)

• 2 arms (2008)

• 2 arms and face (2009)

• 2 legs (2011)

• Uterus (2011-2014)

The main indications for VCA

Unilateral or bilateral

Hand amputation

Severe facial

Disfigurement

Indications for face transplantation

Pomahac B, JPRAS 2011

Trauma

Burns

High-voltage injury

Malignancy

Congenital disease

IRHCTT-Upper extremity Follow-up: 3 months-16 years

Recipients from China: 12

8 unilateral upper extremity Tx

3 bilateral upper extremity Tx

1 palm; 1 thumb

IRHCCT

51 Recipients

25 single upper extremity Tx

26 bilateral upper extremity Tx

Upper extremity allotransplantation

28 partial or total face allotransplantations

IRHCTT-Face

Follow-up: 2 months-9 years

AMIENS-LYON 3

CHINA 1

PARIS 7

CLEVELAND 1

BALTIMORE 1

VALENCIA 1

SEVILLA 1

BARCELONA 1

BOSTON 5

BELGIUM 1

TURKEY 4

Pologne 1

27

27 FACIAL TRANSPLANTATIONS

ETIOLOGY

Trauma (primary)

Arterial malformation

Trauma (second)

2recklinghausen- 1burn

4 trauma(balistique)

Trauma (snd)

Trauma snd

Second ORN

Recklinghausen

Second trauma (shot gun)

3 burns

2 trauma (snd)

1 trauma

4 trauma

1 trauma

TOPOGRAPHY

2/3 inférior

2/3 inferior

Lateral

5: 2/3 inférior

2 full

2/3 inférior

2/3 inférior

2/3 inférior

2/3 inférior

Full

3 middle

2 full

1 full

1full

2 partial

2005

2012

2006

2007

2011

2008

2012

2010

2010

2010

2009

2011

2012

2012

2013

Lyon VCA Experience:

Bilateral Hand and Face Transplantation

Bilateral Hand Transplantation Face Transplantation

Patient #1 #2 #3 #4 #5 #6

#1 #2 #3

TR date 2000 2003 2007 2008 2009 2012 2005 2009 2012

Sex M M F M M M F M F

Age 33 21 27 29 21 40 38 27 52

Amputation date

1996 2000 2004 2003 2004 2007 2005 2008 2003

cause explosion crush Electro- cution

burn explosion crush Dog bite

explosion AVM

Amputation level

R: wrist

L: wrist

R: mid – forearm

L: distal forearm

R: mid-forearm

L: distal forearm

R: palm

L: wrist

R: distal forearm

L: wrist

R: mid-

forearm

L: mid-

forearm

Nose

Lips

Chin

mandible

lower lip

floor of the

mouth

chin

Maxilla Mandible

2/3 inf Face

Tongue



– Acute rejection



Outline

VCA: Surgery

Donor issue

Vascularized sentinel skin graft to

monitoring skin rejection

What are the results ?

Hand and face

patient and graft survival in the western countries

• Upper extremities alone (n= 76 limb uni or bilateral) – Patient survival: 100%

– Graft survival: 90.5%

• Face transplant alone – Patient survival 92 %: 2 death/26 (Spain, Paris)

– Death-censored graft survival: 100%

• Simultaneous face and hand transplantation (2 cases) – Patient survival: 50%

– Death-censored graft survival: • Face 100%

• Upper extremity 0%

Shores JT, PRS 2015

Graft survival

UPPER EXTREMITY: Graft removed

Early failure Late failure

Type of TR

Date

Post

TR

Cause of

graft loss

Type of

TR

Date of

amputation

Cause of graft

loss

1 bilateral hand

and face TR

D45 Sepsis

bleeding

Hand

TR

29 M Non

compliance

2 bilateral hand

and face TR

D5 Sepsis

necrosis

Hand

TR

275 days Intimal

hyperplasia

3 Bilateral hand

TR

D15 Necrosis

digital

phalanges

Hand

TR

771 days Chronic

rejection

4 Unilateral

hand TR

D3 Necrosis

ischemia

Hand

TR

12 years Non

compliance

Ongoing

rejection

episodes

Functional recovery and

cortical reorganization

Cortical reorganization in motor cortex

after graft of both hands

Pascal Giraux Angela Sirigu Fabien

Schneider & Jean-Michel Dubernard

Nat Neurosci. 2001 July;4(7):691-2.

Functional recovery will depend on

• Level of amputation

• Surgical skills and reparation

• Psychological strength of the recipient

• Rehabilitation program

– Complexity depends on

• Level of amputation

• Type of face reconstruction

Patient #1

Patient #2

Patient #3

Patient #4

Patient #5

A B

D E

C

Fig. 1

Petruzzo P et al Annals of surgery 2014

CRF Romans Ferrari

Aucun filament ressenti

Calibre 6.65

Calibre 4.56

Calibre 4.31

Calibre 3.61

Calibre 2.83

Left hand Right hand

Nerve recovery

At one year:

recuperation of protective sensibility is almost achieved

the Semmes– Weinstein test showed partial recovery of tactile sensitivity

that improved over time

Petruzzo P, Annals of surgery 2014

Intrinsic muscular recovery

Bernardon et al, Submitted

6.25

15.32

16.94

6.25

36.29

Hand transplantation

Functional recovery :Lyon experience

HTSS

Petruzzo P et al, Ann Surg 2015

Social rehabilitation

Patients are :

- Able to perform usual daily activities

- Able to find a job

- Well socially accepted

Amiens 2005

Cleveland USA 2008 Paris 2007

X’ian Chine 2006

MORPHOLOGIC RESULTS

Full face transplantation

Boston experience

Pomahac, NEJM 2012

ONE YEAR POST GRAFT

Sensitivity Recovery: Light Touch Sensation

by Semmes-Weinstein Test : Static Mono-filament

Month 4

N

A

,

N

A Month 6

6.65-4.56

Loss of

protective sensation

4.31-3.84

Diminished

protective sensation

3.61-3.22

Diminished

light touch

2.83-1.65)

Normal

NA NA

NA

NA

NA

NA NA

NA

NA

NA

NA NA

Week 2

Dubernard et al, NEJM 2007

Recovery of lip occlusion

Dubernard et al, NEJM 2007

Passive occlusion

Active occlusion

Fisher et al AJT 2015

Face outcome: speech

MASTICATION

DEGLUTITION

PHONATION

EXPRESSION

INTEGRATION

Restoration of the function



– Acute rejection



Outline

Episodes of skin acute rejection in

hand transplantation

In the first year after the transplantation 85% of the recipients

developed AR episodes

International registry on Hand

and Composite Tissue Transplantation

High Incidence of Acute Rejection in face

and hand transplantation: Lyon Experience

Early graft rejection Dubernard JM et al. Lancet 1999;2:1315 Kanitakis J et al. Transplantation 2000;69:1380

Petruzzo P et al. Clin Transplant 2003;17:455

YB D 50 CH D 63

Face Transplantation: Acute rejection

D17

M2

The Skin is the Main Target

of Acute Rejection

Kanitakis J et al Transplantation 2003

Tendons Bone Marrow Muscles

grade I grade II

grade III grade IV

Acute humoral rejection in Hand transplantation

Weissenbacher AM, Transplant Int 2013

C4d staining

CD20+ nodular

infiltrate

Grade 2 rejection 9 years after bilateral formearm transplantation

Antibody-mediated-rejection in Face

Transplantation of sensitized patient

Chandraker et al, AJT 2014

Pre-TR immunized patient

Positive Flow crossmath

Acute rejection:

differences between SOT and VCA

SOT

• Low frequency

• No clinical symptoms

• Graft dysfunction

• Diagnostic biological

markers

• Biopsy: invasive and

risky procedure

• T and B-cell mediated

VCA

• High frequency

• Erythema and oedema

• No graft dysfunction

• No biological marker

• Biopsy: non-risky

procedure

• T-cell mediated and B cell

mediated

What are the hallmarks of chronic rejection

in human VCA?

• Histological and clinic features of chronic rejection in a

VCA should include :

– vascular narrowing,

– loss of adnexa,

– skin and muscle atrophy,

– fibrosis of deep tissues,

– myointimal proliferation and nail changes (1 )

1

Cendales LC, AJT 2008

No evidence for chronic skin rejection in hand

and face transplant patients in triple IS therapy

Petruzzo P et al, AJT 2011

Consequences of immune mediated

injury in allograft damages

Tissue repair Immune-mediated injury

Alloimmune inflammation

Severity and frequency

Of AR episodes

Efficacy of IS Tissue regeneration +++

Tissue regeneration +/-

fibrosis/sequela

No fibrosis/no sequela

Consequences of immune

mediated injury in kidney allograft

Tissue healing

Interstitial Fibrosis Immune-mediated injury

Nankivell et al Transplantation 2004

Cellular rejection

Control of acute cellular rejection by standard

immunosuppression

34 36 38

10 mg/d Corticosteroids 60 mg/d 25 mg/d

Day 18

Cellcept 2-3 g per day

Tacrolimus 8-12 ngml

Month 3

Consequences of immune

mediated injury in VCA

Skin healing Immune-mediated injury

Cellular rejection Treatment of rejection

Grade 0

No fibrosis

A

Face Transplantation in Nov 27, 2009

IS: Thymo, Tacrolimus, Steroides, MMF

What would be the consequence of ongoing

cellular immune response in VCA ?

12 months post TR

4 episodes

of AR in the first year

Petruzzo et al

Transplantation in press

Severe complications after face transplantation

associated to EBV infection post transplantation

PTLD : 5 months post-transplantation (EBV D+/R-)

reduction of immunosuppression

Rituximab and R CHOP

EBV-associated post-transplant smooth muscle tumors in the liver

Conrad et al Transplant Infec Diseases 2013

High incidence of acute rejection after the reduction of immunosuppression

Petruzzo et al, Transplantation in press

Reduction of IS due to severe side effects led to T-cell mediated chronic rejection of the face

3 years post-transplant

Retraction of the facial graft Skin fibrosis

Petruzzo et al, Transplantation, in press

Does humoral response play a role in

chronic rejection in VCA ?

Transplant Vasculopathy in a Rat Hind-limb

Allotransplantation Model

Unadkat JV et al, Am J Transpl 2010

Transplant vasculopathy in clinical VCA

Kaufman, AJT, 2012

IS Minimization

Interosseous

arteries

Lyon experience (Petruzzo, AJT, 2011)

Protocol of minimization (low-dose tacrolimus monotherapy)

=> 4/5 CTA recipients developed DSA with MFI>2000

Schneeberger, Ann Surg, 2013

- transient

- - +

Development of DSA in VCA might depend on the level of IS

DSA

patient 2 : Transient anti-HLA class II antibodies in November 2009 (6 years post TR)

Distal arterial thrombosis in hand-transplant patient:

Lyon experience

Petruzzo et al, Ann Surg 2015

No detectable vasculopathy at 10 years post TR in:

Arteriography

High resolution US in radial artery

Date of TR: April 30, 2003

4th episode of skin acute rejection in October 2013 (non compliance)

Acute distal arterial thrombosis in June 2014 with finger necrosis

Distal phalanges amputation on July 17th, 2014

Distal arterial thrombosis in hand transplant patient:

Lyon experience

Arterial occlusion

No acute skin rejection, no DSA at the time of thrombosis

Challenge of Chronic rejection in VCA

• New tools for the diagnosis of vasculopathy

– Protocol deep skin biopsies

– High resolution ultrasound

– Intravascular ultrasound

• new probes to avoid arterial thrombosis

• Prevention:

– Sustained level of immunosuppression

– Patient education to improve observance

– Tolerance induction induced by mixed chimerism

Immunological challenges in VCA

Cell-mediated (parenchymal lesions)

Antibody-mediated (vascular lesions)

Acute erythema

Classical AR DSA+ C4d+

Chronic Skin atrophy

Graft vasculopathy

Graft inflammation

resistant to TTT

(X episodes of AR)

Fibrosis

DSA+/-

Vasculopathy

CL

INIC



– Acute rejection



Outline

Induction therapy in VCA



Hand Face

Tacrolimus, mycophenolate mofetil, steroids: 14 patients

Switch from tacrolimus to sirolimus: 8 patients

Switch from Tacrolimus to Belatacept: 1patient

Switch from MMF to Sirolimus: 5 patients

Steroid-free treatment: 4 patients

MMF-free treatment: 6 patients

Sirolimus, everolimus: 2 patients

Low dose Tacrolimus, Sirolimus, MMF: 1 patient

Hand: maintenance therapy

> 3 months



At 3 months

Steroids: 16 patients; 20 mg (7.5-60)

Tacrolimus:16 patients

Mycophenolate mofetil: 15 patients

In the follow-up:

Switch from tacrolimus to sirolimus: 2 patients

Steroid-free treatment: 4 patients

MMF withdrawal and sirolimus + tacrolimus: 1 patient

MMF withdrawal: 3 patients International registry on Hand


Face: maintenance therapy

> 3 months

Therapy of AR episodes

• IV Steroids: 65%

• ATG: 2.7%

• Campath-1: 4%

• Rituximab: 1.3%

• Increase in steroid oral dose: 45%

• Topical immunosuppressants: 95%

• Extracorporeal photochemotherapy: 2.7%

Immunosuppression side-effects

Hand Opportunistic infections

CMV reactivation: 10

Herpes virus: 3

Herpes zoster: 1

EBV infection: 1

Clostridium difficilis infection: 2

Cutaneous mycosis: 5

Bacterial infection: 14 (1 osteitis and 3 infections of graft connective tissues)

Malignancies:

Basal cell carcinoma of nose: 1

Post-transplant lymphoproliferative disease: 1

Metabolic complications:

Hyperglycemia: 19

Increased creatinine values: 9

End-stage renal disease (haemodialysis): 1

Cushing Syndrome: 1

Arterial hypertension: 5

Avascular necrosis of the hip: 1

Hyperparathyroidism: 1

Leukopenia: 2



Immunosuppression Side-effects:

Face Opportunistic infections

CMV reactivation: 2

Herpes virus: 5

EBV infection: 2

Cutaneous mycosis: 2

Bacterial infection: 12

- 2 facial cellulitis

- 1 pneumopathy

- 1 pneumonia with sepsis (acute ischaemia of grafted hands)

- 1 sepsis

Metabolic complications:

Hyperglycemia:3 (including 2 PTDM)

Increased creatinine values: 4

Arterial hypertension: 2

Increase in γ-GT values: 1

Neutropenia: 1

Malignancies:

Post-transplant lymphoproliferative disease: 1

Basal cell carcinoma of recipient face: 1

Uterus carcinoma: 1



Summary: The good

• Upper extremity alone, or face transplant alone:

– Very good patient and graft survival

• Upper extremity

– The restoration of motion, strength, and sensibility are fair

– Functional results are good, as well as quality of life evaluation

– Subjective and overall results are very good

• Most patients perform activities of daily living

• Improvement was seen to continue during the first three years, and

then tend to become stable

Summary: The bad

• Poor outcome in simultaneous hand and face or hand and leg

transplantation due to surgical complications or sepsis

• High rate of acute rejection episode

• Rate of chronic rejection still unknown but

– Graft vasculopathy is associated with graft loss and amputation

– Incidence of chronic rejection is higher in non-compliant patients

– Incidence of chronic rejection should increase with time

• Graft Half life still unknown

• Side effects of immunosuppression similar to that in organ transplantation

Conclusion

• Patient selection is critical on the basis of

– Medical

– Psychological

– Social factors

• Compliance with rehabilitation and immunosuppressive medication

is a key point for success

• Multidisciplinary teams are required to follow the patient on the long

term

• Next steps:

– to define new standardize tools for graft assessment and

psychological evaluation

– To progress in the diagnosis and treatment of graft vasculopathy

The Teams

AMIENS LYON

Bernard DEVAUCHELLE/ Sylvie TESTELIN

Sylvie TESTELIN ,surgeon

Cédric d’HAUTHUILLE ,surgeon

Sophie CREMADES, psychiatre

Giovanni de MARCO,neuroscience

Christophe MOURE , surgeon

Stephanie DAKPE , surgeon

Ghassan BITAR, surgeon

Benjamin GUICHARD, surgeon

Farid TAHA, surgeon

Sebastien GARSON,imaging

Anne-Sophie BRACQ-DORNER, anesthesiologist

Kamel CHEBOUBI, anesthesiologist

Gérard VILAIN, anesthesiologist

Jean TCHAOUSSOFF reanimation

BRUXELLES UCL

Benoit LENGELE , surgeon

LIONEL BADET/ Emmanuel MORELON

Aram Gazarian, surgeon

Jean –Luc BEZIAT, surgeon

Jean-Paul BOURGEOT, biologist

Félix BRUN, coordination

C Seulin, psychiatre

Jean Jacques COLPART, coordination ABM

Olivier THAUNAT, immunology

Jean KANITAKIS, dermatology

Maria Brunet, transplantology

Cécile Chauvet, transplantology

Fanny Buron, transplantology

Xavier MARTIN, transplantology

Mauricette MICHALLET, hématology

Denise MONGIN-LONG, Anesthésiologist

Palmina PETRUZZO, transplantology

Angela SIRIGU, neuroscience

Jean-Michel Dubernard, Transplantology

AD, August 2009, 14 months

after bilateral hand transplantation

« Dans nos ténèbres il n’y a pas une place pour la Beauté. Toute la place est pour la Beauté» René CHAR

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