PANCREAS SESSION

REPORT

2011 BANFF CONFERENCE

GUIDELINES FOR THE DIAGNOSIS OF ANTIBODY MEDIATED

REJECTION IN PANCREAS ALLOGRAFTS –

UPDATED BANFF GRADING SCHEMA

Cinthia B. Drachenberg, Jose R. Torrealba, Brian J. Nankivell, Erika B.

Rangel,Ingeborg M.Bajema, Dae Un Kim, Lois Arend,

Erica R. Bracamonte, JonathanS.Bromberg, Jan A.Bruijn,

Diego Cantarovich, Jeremy R.Chapman, Alton B.Farris, Lillian Gaber,

Julio C. Goldberg, Abdolreza Haririan, Eva Honsová,Samy S. Iskandar,

David K. Klassen, Edward Kraus, Fritz Lower,

Jon Odorico, Jean L. Olson, Anuja Mittalhenkle,

Raghava Munivenkatappa,

Steven Paraskevas, John C. Papadimitriou, Parmjeet Randhawa,

Finn P. Reinholt, Karine Renaudin, P.Revelo, Phillip Ruiz, Milagros D.

Samaniego, Ron Shapiro, Robert J. Stratta,

David E.R. Sutherland, Megan L.Troxell, Luděk Voska,

Surya V. Seshan,Lorraine C. Racusen and Stephen T. Bartlett

Am J Transplant In Press

Co-chairs

• Ed Kraus

• Brian Nankivell

PROGRAM

• Ugo Boggi

• Christian Margreiter

• Phillip Ruiz

• Erika Rangel

• Dae Un Kim

• John Papadimitriou

• Erika Bracamonte

Percutaneous biopsy (graft accessibility)

PROGRAM

• Ugo Boggi (Pisa, Italy)

• Christian Margreiter

• Phillip Ruiz

• Erika Rangel

• Dae Un Kim

Percutaneous biopsy (graft accessibility)

Percutaneous biopsy (graft accessibility)

PROGRAM

• Ugo Boggi (Pisa, Italy)

• Christian Margreiter (Innsbruck,

Austria)

• Phillip Ruiz

• Erika Rangel

• Dae Un Kim

PROGRAM

• Ugo Boggi (Pisa, Italy)

• Christian Margreiter (Innsbruck, Austria)

• Phillip Ruiz (Miami, USA)

• Erika Rangel

• Dae Un Kim

Summary• Cardinal features of T1DR demonstrated in several patients by:

– clinical features (loss of insulin secretion and diabetes

symptoms in the presence of normal pancreas transplant

exocrine function)

– biochemical autoantibody assays

– pancreas transplant biopsy (isletitis)

– autoreactive T cells, possibly representing memory responses

• T1DR observed in ~5% of SPK recipients, despite

immunosuppression

• Its frequency is not dissimilar from that of chronic rejection.

• T1DR may occur even after several years of secretory function

• The immunosuppression used does not restore self-tolerance

β CELL FAILURE

• ACMR and AMR leading to graft fibrosis

with secondary damage to islets

• Death of the β cells (preservation of the

exocrine pancreatic component)

Banff Pancreas Allograft Rejection Grading Schema

- Update

7. ISLET PATHOLOGY

-Recurrence of autoimmune DM (insulitis and/or selective ß cell loss)

- Islet amyloid (amylin) deposition

Islet Amyloid deposition: Type 2 DM related changes

Islet amyloid deposition limits the viability of human islet grafts but not

porcine islet grafts K. J. Potter, A. Abedini, P. Marek, A. M. et al

Proc Natl Acad Sci U S A. 2010 March 2; 107(9): 4305–4310

PROGRAM

• Ugo Boggi (Pisa, Italy)

• Christian Margreiter

• Phillip Ruiz

• Erika Rangel (San Paulo, Brazil)

• Dae Un Kim (New Jersey, USA)

C4d staining in pancreas interacinar

capillaries

Immunohistochemical (A) and Immunofluorescence (B) methods.

C4d in Pancreas: IHC vs IF

• Both adequate for clinical purposes

• IF typically more diffuse and with stronger

staining (10-50%)

• Focal C4d often correlate with DSA.

Threshold for positivity ≥5%.

• The results of this analysis will be

prepared for publication under the

leadership of Surya Seshan

PROGRAM (Cont.)

• John Papadimitriou (Maryland,

USA)

• Erika Bracamonte (Arizona, USA)

Predominance of Histological Features in Stereotypical ACMR and AMR

ACMR AMR

Septal infiltrates +++ - to +

Eosinophils + to +++ - to +

Neutrophils - to ++ +/- to +++

T- Lymphocytes ++ to +++ +/- to +

Macrophages ++ ++++

Venulitis ++ -

Ductitis ++ -

Acinar cell injury +/- to ++ +++

Acinar inflammation - to +++ + to +++

Acinitis (mononuclear infiltrates within the

basement membrane of individual acini)

+ to +++ - to +/-

Interacinar Capillaritis - to +/- + to +++

Intimal arteritis + +

Necrotizing vasculitis / thrombosis - to + +++

Confluent hemorrhagic necrosis - to ++ - to ++++

Active transplant arteriopathy + +

Pancreas Allograft Rejection

• Acute T-cell mediated rejection

• Acute antibody mediated rejection

• (Mixed forms)

Acute T-cell mediated rejection

Septal inflammation

– Veins (venulitis)

– Ducts (ductitis)

– Arteries (intimal arteritis,

transmural arteritis)

Acinar inflammation

– Acinitis

– Acinar cell damage

Venulitis

Acinitis

Septal inflammation Intimal arteritis

Islet

Islet

Septal area

Septal area

CD3

CD68

Antibody Mediated Rejection in the

Pancreas

CD68

CD3

Mild acute AMR: The lobular architecture is preserved but there

are interacinar infiltrates predominantly composed of

macrophages (CD68 stain on the right).

BANFF GUIDELINES FOR THE DIAGNOSIS OF

ANTIBODY MEDIATED REJECTION

1. Confirmed circulating donor specific antibody (DSA)

2. Morphological evidence of tissue injury

3. C4d positivity in interacinar capillaries

- Acute AMR (all 3 diagnostic components present).

- Suspicious of acute AMR (2 diagnostic components present).

- Not sufficient for diagnosis of AMR (1 diagnostic component present). Heightened clinical vigilance recommended.

PROGRAM (Cont.)

• John Papadimitriou (Maryland, USA)

• Erika Bracamonte (Arizona, USA)

Reproducibility Study• Fair to moderate agreement for major

diagnostic categories (k>0.2)

No Rejection or

Indeterminate vs. Acute

Cellular Rejection

k = 0.55

Grade of Acute Cellular

Rejectionk = 0.32

Chronic Active Cellular

Rejectionk = 0.31

Antibody Mediated

Rejectionk = 0.41

Morphologic Feature

• Necrotizing arteritis

• Active septal inflammation• Acinar inflammation

• Perineural inflammation

• Intimal arteritis

• Venulitis

• Acinar cell injury

• Chronic allograft arteriopathy

• Ductitis

• Capillaritis

0.65

0.610.42

0.40

0.35

0.32

0.30

0.29

0.27

0.17

Kappa AgreementReproducibility Study

Kappa Agreement

Aims for Banff 2013 • Evaluation of protocol biopsies

• Correlation of rejection related findings in

duodenal cuff and pancreas parenchyma

• Detailed evaluation of the incidence and

characteristics of recurrent Type I and II

DM

• Development of an official Banff lesion

scoring system in combination with the

preparation of a didactic training set in

preparation for further reproducibility

studies. (MI lesions, special stains)

Aims for Banff 2013 (cont)

• Wideworld Survey to evaluate clinical

practices with respect to biopsy

performance and pathological practices

– C4d staining

– Protocol biopsies

– Characterization of chronic active AMR