Presentation by Dr. Cinthia Drachenberg summarizing the pancreas sessions from 2011 Eleventh Banff Conference on Allograft Pathology, June -10, 2011 in Paris, France.

1. PANCREAS SESSION
REPORT
2011 BANFF CONFERENCE

2. 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

3. Co-chairs
• Ed Kraus
• Brian Nankivell

4. PROGRAM
• Ugo Boggi
• Christian Margreiter
• Phillip Ruiz
• Erika Rangel
• Dae Un Kim
• John Papadimitriou
• Erika Bracamonte

5. Percutaneous biopsy (graft accessibility)

6. PROGRAM
• Ugo Boggi (Pisa, Italy)
• Christian Margreiter
• Phillip Ruiz
• Erika Rangel
• Dae Un Kim

7. Percutaneous biopsy (graft accessibility)

8. Percutaneous biopsy (graft accessibility)

9. PROGRAM
• Ugo Boggi (Pisa, Italy)
• Christian Margreiter (Innsbruck,
Austria)
• Phillip Ruiz
• Erika Rangel
• Dae Un Kim

12. PROGRAM
• Ugo Boggi (Pisa, Italy)
• Christian Margreiter (Innsbruck, Austria)
• Phillip Ruiz (Miami, USA)
• Erika Rangel
• Dae Un Kim

13. 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

14. 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)

15. 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

16. Islet Amyloid deposition: Type 2 DM related changes

17. 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

18. PROGRAM
• Ugo Boggi (Pisa, Italy)
• Christian Margreiter
• Phillip Ruiz
• Erika Rangel (San Paulo, Brazil)
• Dae Un Kim (New Jersey, USA)

19. C4d staining in pancreas interacinar
capillaries
Immunohistochemical (A) and Immunofluorescence (B) methods.

20. 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

21. PROGRAM (Cont.)
• John Papadimitriou (Maryland,
USA)
• Erika Bracamonte (Arizona, USA)

22. 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 + to +++ - to +/-
basement membrane of individual acini)
Interacinar Capillaritis - to +/- + to +++
Intimal arteritis + +
Necrotizing vasculitis / thrombosis - to + +++
Confluent hemorrhagic necrosis - to ++ - to ++++
Active transplant arteriopathy + +

23. Pancreas Allograft Rejection
• Acute T-cell mediated rejection
• Acute antibody mediated rejection
• (Mixed forms)

24. Acute T-cell mediated rejection
Septal inflammation
– Veins (venulitis)
– Ducts (ductitis)
– Arteries (intimal arteritis,
transmural arteritis)
Acinar inflammation
– Acinitis
– Acinar cell damage

25. Venulitis
Acinitis
Septal inflammation Intimal arteritis

26. Septal area
Islet
CD3
Septal area
Islet
CD68

27. Antibody Mediated Rejection in the
Pancreas

29. CD68
CD3

30. Mild acute AMR: The lobular architecture is preserved but there
are interacinar infiltrates predominantly composed of
macrophages (CD68 stain on the right).

31. 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.

32. PROGRAM (Cont.)
• John Papadimitriou (Maryland, USA)
• Erika Bracamonte (Arizona, USA)

33. Reproducibility Study
• Fair to moderate agreement for major
diagnostic categories (k>0.2)
No Rejection or
Indeterminate vs. Acute k = 0.55
Cellular Rejection
Grade of Acute Cellular
k = 0.32
Rejection
Chronic Active Cellular
k = 0.31
Rejection
Antibody Mediated
k = 0.41
Rejection

34. Reproducibility Study
Kappa Agreement
Morphologic Feature Kappa Agreement
• Necrotizing arteritis 0.65
• Active septal inflammation 0.61
• Acinar inflammation 0.42
• Perineural inflammation 0.40
• Intimal arteritis 0.35
• Venulitis 0.32
• Acinar cell injury 0.30
• Chronic allograft arteriopathy 0.29
• Ductitis 0.27
• Capillaritis 0.17

35. 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)

36. 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