Immunopathology of T cell mediated rejection

Immunopathology of T cell mediated rejection Ibrahim Batal MD Columbia University College of Physicians & Surgeons New York, NY, USA

Overview Pathophysiology and grading of TCMR TCMR is still a significant diagnostic entity New look of TCMR

Rejection New MHC molecules (Allo-antigens) Rejection: TCMR, AMR, or both

AMR TCMR Nickeleit et al. Kidney Int 2007 Mengel et al. Am J Transplant 2009

Donor APC TCMR 1990s DCs Monocytes B Cells Cytotoxic or Helper T cell Recipient APC Helper T cell Cytotoxic T cell Abbas & Lichtman 2005

T cell activation CD40 CD40L Signal 1: Allo-Ag presentation Signal 2: Co-Stimulation signals Signal 3: Cytokine signals Clonal expansion IL2 Cytotoxic Perforin Granzyme Helper Cytokines Pollard et al. Trends Mol Med 2013

CD8 (Cytotoxic) CD4 (helper) CD4 (Helper) CD8 (Cytotoxic) CD8 (Cytotoxic) CD8 (Cytotoxic) Abbas & Lichtman 2005

Typical TCMR CD4 CD8

Solez et al. Kidney Int 1993 Racusen et al. Kidney Int 1999 Features of TCMR by Banff Classification (all assessed semi-quantitatively from 0 to 3) Established at 1991 meeting and further shaped in 1997 Intimal arteritis (v; 0-3) Tubulitis (t; 0-3) (no, mild, >25% arterial lumina, transmural or fibrinoid necrosis) (no, 1-5, 5-10, >10 or >2 disruptive tubulitis) Interstitial inflammation (i; 0-3) (nonscarred cortex) (<10%, 10-25%, 26-50%, >50%)

The Banff 97 Classification for TCMR Grade III (v3): arterial fibrinoid necrosis and/or transmural arteritis Grade IIB (v2): intimal arteritis occluding >25% of the luminal area Grade IIA (v1): milder intimal arteritis Grade IB: i >2 (>25% of non-scarred cortex) & severe tubulitis (t3) Grade IA: i >2 (>25% of non-scarred cortex) & mod tubulitis (t2) Racusen et al Kidney Int 1999

Other solid organs TCMR Interstitial inflammatory infiltrate and cytotoxic parenchymal injury

1R: 1 focus of myocyte damage 2R: 2 or more foci of myocyte damage 3R: diffuse inflammation and multiple foci of myocyte damage

Interstitial inflammation (portal tract) AND Cytotoxic injury to the bile duct and venules Combined score: grade of rejection: mild, moderate, severe

Cytotoxic injury to crypt: apoptotic bodies

TCMR Treatment Prevention: Potent induction and maintenance IS If TCMR occurs despite prophylaxis (CUMC): Corticosteroids (BL, 1A): low doses nonspecific immunosuppressive agents, which decrease T cell activation & block cytokine genes: inhibit IL-1, IL-2, IL-3, IL-6, IL-15, TNFα and INF-γ; High doses may be directly toxic to T cells Thymoglobulin (1B & above): Depletes lymphocytes

TCMR is not significant anymore With current potent IS regimens: Decrease in early TCMR (Meier-Kriesche et al. AJT 2004) TCMR is not associated with graft loss (Halloran et al. AJT 2013) Disappearance of TCMR transcript signal in the late post-transplant period (Halloran et al. JASN 2015) Early atcmr 1st year post-transplant (%) 60 40 20 0 55% 1995 2000 ~10% 2011 Meier-Kriesche et al. Am J Transplant 2004 Halloran et al. Am J Transplant 2013 Halloran et al. J Am Soc Nephrol 2015

TCMR is not significant anymore With current potent IS regimens: Decrease in early TCMR (later, more difficult to treat) TCMR is not associated with graft loss (HR: 1.79, Cr & egfr: NP) Disappearance of TCMR transcript signal in the late post-transplant period (Diagnostic for TCMR by > 2 pathologists; Banff criteria: iifta) Early atcmr 1st year post-transplant (%) 60 40 20 0 55% 1995 2000 ~10% 2011 Meier-Kriesche et al. Am J Transplant 2004 Halloran et al. Am J Transplant 2013 Halloran et al. J Am Soc Nephrol 2015

TCMR is still significant 1 18 pure TCMR and 14 non-inflamed controls (dysfunction biopsies) Patient never had C4d or DSA Late: 1582 +215 vs. 1114 +1336 days 41% of patients with TCMR showed no response to steroids Patients with TCMR had more deterioration in renal function at 2- year post-biopsy 2 years post-biopsy Rise of Cr above baseline (%) 80 * 60 40 20 0-20 -40 TCMR Controls Zhao et al. Transplantation 2016

TCMR is still significant 2 TCMR is a predictor for subsequent development of de novo DSA (Wiebe et al. AJT 2012) Tubulitis is an independent predictor for poor graft survival in patients with de novo DSA (Wiebe et al. AJT 2015) Wiebe et al. Am J Transplant 2012 Wiebe et al. Am J Transplant 2015

TCMR is still significant 1. Not all studies showed that TCMR is not important 2. TCMR may be a predictor for AMR and may also predict prognosis in patients with AMR 3. Change our classic appreciation of TCMR, adapt more liberal view

New concept of TCMR Changes: 1990s current time 1. Improvement of induction and maintenance immunosuppression 2. Expansion of donor pool

Induction Immunosuppression In USA 90% Signal 1 1. Induction (Basiliximab) therapy has Rituximab advanced a lot; 80% was not used in most patients in 1980s- 70% Signal 3 1990s 60% 50% 40% 30% 20% 10% IL2R antagonists Alemtuzumab (Campath) 0% 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 Courtesy of A Chandraker; modified

Azathioprine Maintenance immunosuppression Cyclosporine Tacrolimus (FK506) Mycophenolate Mofetil (MMF) Rapamycin (Sirolimus) Belatacept Tacrolimus 1990 1995 2000 Belatacept Rapamycin (mtori) MMF: anti-proliferation Zand. Semin Dial. 2005 Shrestha et al. Prog Transplant 2015 Karam et al. Crit Rev Eukaryot Gene Expr 2015

Expansion of donor pool ECD & DCD: prone to IFTA/chronic changes (solitary kidney) Extended Criteria Donor (ECD) Donation after Cardiac Death (DCD) Shrestha et al. Prog Transplant 2015

Decreased TCMR & more prominent IFTA 60 55% Early atcmr 1st year post-transplant (%) 40 20 Later TCMR ~10% 0 1995 2000 2011 Meier-Kriesche Hu et al. Am J Transplant 2004 http://srtr.transplant.hrsa.gov/annual_reports/2011/pdf/2011_srtr_adr.pdf iglietti et al. Transplantation 2015

Changing of TCMR Less fulminant TCMR, more scarring, and more inflammation in the areas of cortical scarring iifta So what is iifta and is it significant?

iifta is associated with graft loss Mengel et al: ti: i + iifta had similar proinflammatory transcription profile but worse prognosis than conventional TCMR Mannon et al: Patients with iatr/iifta had worse allograft survival than patients without iatr/iifta ti, which includes iifta, may potentially represent a broader spectrum of TCMR than what is currently recognized by Banff ti <25% ti >25% P<0.001 Mengel et al. Am J Transplant 2009 Mannon et al. Am J Transplant 2010

Phenotype of lymphocytic inflammation in iifta CD4 CD8

iifta is associated with graft loss 100 Confirmed that ti/iifta is associated with poor prognosis iifta include active inflammation with interaction between dendritic cells and proliferative lymphocytes Batal et al. J Am Soc Nephrol 2015 Graft survival (%) T cells proliferation index (%) 80 60 40 20 ti0-1 ti2-3 P<0.001 (log rank test) 0 0 500 1000 1500 2000 Post-biopsy time (days) 35 30 20 10 2 Low DC-SIGN P=0.014 High DC-SIGN

Summary TCMR is still an important diagnostic entity Current Banff classification is not optimal for TCMR (iifta is a classification problem) In addition to morphologic classifications, we need to invest more in pathophysiology of TCMR New therapies may be required to further control smoldering/chronic TCMR (iifta)