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Landing on the Moon at Last! New Pathologic Landscapes In Renal Transplantation with Lymphocyte-depleting Anti-Rejection Protocols. Kim Solez, M.D. The Apollo moon landing of 1969 became the model for adventure and exploration for a generation. Calvin

Calvin R. R. Stiller, Stiller, M.D. M.D. A quarter century later in 1992 Cal Stiller called me about the first MMF biopsies: Kim, Kim, Its like landing on the moon! Like nothing you have ever seen before! Chair Chair Canadian Canadian Medical MedicalDiscoveries

Discoveries Fund Fund Awarded the Order of Canada Awarded the Order of Canada Established Established the theMulti-Organ Multi-OrganTransplant Transplant Service at UWO Service at UWO in in London, London, Ontario Ontario

Cal Stiller Directed Canadian Multicenter Trials of Cyclosporine Therapy in Renal Allografts in 1980s - A legendary figure in transplantation In 1978, Dr. Cal Stiller, who was attending a transplant meeting in Rome, tried without success to meet the scientist who had discovered a promising new antirejection drug, to discuss testing it in London. It was raining as Stiller finally found a cab in St. Peter's Square. Nearby, standing in the downpour, was a very wet Swiss scientist, Jean F. Borel, discoverer of cyclosporine. They shared the taxi and when the trip was over, it was decided London would be the site of clinical trials of the new agent that was to save countless lives around the world. Slide 5 Virtual Pathology Slide

http://www.telepathology.dcu.ie/vps02. php3 VPS Breast Needle Core Study (JMIR 2003) http:// www.medicine.uiowa.edu/pathology/ uarep_histopathology / Virtual slidebox of histopathology http://alf3.urz.unibas.ch/patho/pub/20 02-11.htm Human Pathology -- Volume 34, No. 10 (October 2003) -- pages 968-974 Katharina Glatz-Krieger , Dieter Glatz , Michael J. Mihatsch Virtual Slide: high quality demand, physical limitations and affordability.

http://vmic.unibas.ch Slide 6 The ScanScope System A Complete Virtual Microscopy System The First MMF Biopsies from the University of Wisconsin Cal Stiller was wrong at that moment in 1992. There was nothing unique about the morphologic changes seen under the influence of MMF. His impression otherwise was due to his unfamiliarity with kidney sections embedded in plastic as opposed to the usual paraffin embedding. Wrong at the time in 1992,

but presaging events of the present. However in a more general sense his words presaged an inevitable outcome of the development of new anti-rejection agents: Eventually there will be compounds or strategies used which will profoundly alter the pathologic landscape and the rules for diagnosis of rejection, and such a major morphologic development may usher in a new clinical era of antirejection therapy. And the situation now? So So are are we we there there yet? yet? Have

Have we we landed landed on on the the moon? moon? Recently Recently several several biopsies biopsies from from lymphocyte lymphocyte depleting depleting clinical clinical trails trails have have shown shown a a picture

picture of of predominant predominant infiltration infiltration by macrophage by cells cells of of macrophage monocyte monocyte lineage, lineage, behaving behaving like like rejection rejection clinically clinically but but fulfilling fulfilling none none of

of the the usual usual criteria criteria for for rejection rejection which which require require lymphocytes lymphocytes in in tubules tubules and and arteries. arteries. So So perhaps perhaps indeed indeed the the rules rules are

are changing! changing! For the details . You You must must be be patient! patient! Assumptions The The fluidity fluidity of of the the pathological pathological landscape landscape in in the

the transplanted transplanted kidney kidney seems seems to to have have been been consistently consistently underestimated, underestimated, the the psychological psychological "some "some things things never never change" change" mindset mindset of of human

human beings beings seems seems to to promote promote the the erroneous erroneous view view that that some some changes changes in in the the kidney kidney are are unidirectional unidirectional and and permanent

permanent until until the the end end of of time. time. Much Much persuasive persuasive evidence evidence argues argues against against this. this. Slides from Roz Mannon, Alan Kirk These pictures were taken by their pathologist, David Kleiner, on 15 Alemtuzumab patients. They received Alemtuzumab alone (n=6), with rapa (n=2), or Infliximab and rapa (n=4) or with DSG and rapa

(n=3). Slide 13 Methods All patients enrolled on Alemtuzumab (CAMPATH 1H) treatment All biopsies taken through day 100 BANFF 97 criteria used to grade rejections Infiltrates immuno-phenotyped using antibodies against CD3, CD4, CD8, CD20, CD45, CD45RO, CD68, HLA-DR, perforin, granzyme B Slide 14 Results - Biopsies 53 total biopsies (52 needle bx, 1 wedge) Adequacy: 32 adequate, 13 subopt, 8 inadeq Glomeruli: mean 15 (0-45) Arteries: mean 2 (0-7)

Slide 15 Clinical/Histological Rejection 12/15 patients had an episode of increased Cr to at least 1.5x baseline in the first 100 days Histologic correlation in 9 patients: 3 Borderline 1 Grade IA 3 Grade IB 1 Grade IIA 1 Grade IIB HLA-DR Immunostaining Progression Slide 16 Day 0 Day 21 Day 14

Progression of CD68 Infiltration in Alemtuzumab Treated Recipients Day 0 Day 21 Day 14 Day 22 Slide 17 Focal Macrophage Infiltrate Corresponds to Focal HLA-DR Expression CD68 HLA-DR

Slide 18 Slide 19 Composite of Campath Rejection vs. Non-Depletional Rejection CD3 AR Alem CD68 HLADR Slide 20 Practical Implications for Classification ? ? Routine

Routine staining staining for for CD68 CD68 Probably Probably no no formal formal change change in in classification classification until until experience experience with with this this new new type type of of rejection rejection

grows. grows. Sharing Sharing of of morphologic morphologic data data as as important important as as sharing sharing of of genomics genomics data. data.

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