Progetto Ematologia Romagna Rimini 8 aprile 2017 Immunologia e Tumori C’è futuro senza rigetto? M.Arpinati Istituto di Ematologia e Oncologia Medica “Seragnoli”
Outline of the talk Ø General mechanisms of alloreactivity Ø Alloreactivity in HSC transpantation Ø GVHD as a model to PREVENT alloreactivity Ø GVHD as a model to TREAT alloreactivity
The immunological barrier Medawar 1944 described it in skin transplants in mice Starzl 1967 performs first successful allo liver transplant Don Thomas 1968 performs first successufl BMT HOST IMMUNITY rejection T T DONOR IMMUNITY T GVHD T
Biology of the immunological barrier Mitchison1964 Billingham 1966 Thomson 1996 Schlomchick 1999 Ø Different antigens between host and donor Ø Functional APC presenting antigens Ø T lymphocytes.
Molecular basis of alloreactivity MHC match MHC mismatch T cell T cell APC APC mHA self peptides + mHA 1:10e6 clones 1:10e3 clones Holtan et al. Blood 2014
APC sense DANGER to activate T cells P Matzinger and R Steinman CD40 CD86 CD80 Anergic T cell T cell activation Immature APC TLR PAMP DAMP LN INFECTION, INFLAMMATION STEADY STATE
APC include DC and monocytes But also … HSC MONOBLAST DC PRECURSOR BONE MARROW B cells MONOCYTE CONVENTIONAL DC PLASMOCYTOID DC infiammazione PB CD34+ cells RESIDEN MACROPH MIGRATORY DC T DC AGES • E.g. LANGERHANS DC • DERMAL DC MIGRATORY DC • E.g. LANGERHANS DC • DERMAL DC LYMPH NODES PERIPHERAL TISSUES Non hematopoietic cells Stenger et al. Blood 2012
DIRECT ANT NTIGE GEN N PRESENT NTATION ON MHC donor DC rejection APC T recipient TCR donor IND NDIRECT ANT NTIGE GEN N PRESENT NTATION ON donor recipient DC rejection MHC APC TCR APOPTOTIC recipient BODIES Adapted from Wood et al. Transplantation 2012
T cell differentiation Wood et al Transplantation 2012
LYMPH-NODE ALLOGRAFT 1 HLA Graft cell 2 Host T Host APC IL-12 Donor APC GRAFT REJECTION TNF 3 Host CTL IL-2 IL-1 IFN γ Th1 4 Host B cell Th17 IL-17 Host M Φ
In SOLID ORGAN TRANSPLANTATION DONOR IMMUNITY HOST IMMUNITY In HSC TRANSPLANTATION HOST IMMUNITY DONOR IMMUNITY Institute “Seràgnoli”, Univ. of Bologna
Specificity of BMT I: Minor Histocompatibility Antigens (mHA) Miklos Blood 2005
Specificity of BMT II: DONOR vs RECIPIENT APC? DIRECT PRESENT NTATION ON IND NDIRECT PRESENT NTATION ON MHC recipient MHC T APC donor TCR APC TCR recipient APOPTOTIC BODIES donor acute GVHD chronic GVHD
Ruggeri 2002 Direct presentation drives ACUTE GVHD Schlomchick 1999 Matte 2004 Duffner 2004 MHC mismatch minor mismatch Zhang 2002 CD8+ CD4+ 100 100 100 80 80 80 % GVHD 60 60 60 40 40 40 20 20 20 60 40 48 30 20 24 control no host APC
donor APC maintain allo-reactive T cells in CHRONIC GVHD Balb B6 no GVHD T Balb B6 T 20 days B6 into Balb chimera GVHD Tivol 2005
Evidence in 100 p = 0.01 MONOCYTE humans 75 % aGVHD high mono (n= 19) 50 low mono (n=25) 25 0 0 250 500 750 1000 1250 1500 1750 days 100 CIRC. PLASMACYTOID DC 75 p=0.60 % aGVHD 50 100 high pDC (n= 22) p=0.86 25 75 % aGVHD CIRC. MYELOID DC low pDC (n= 22) 0 50 high mDC (n= 22) 0 250 500 750 1000 1250 1500 1750 days 25 days low mDC (n= 22) 0 0 250 500 750 1000 1250 1500 1750 days
39 p=0.008 no GVHD 7 8 72 4,1 chronic GVHD 4 33 p=0,006 0 treated 0 50 100 150 numbers CD86 MFI
Specifity of BMT III: HSC transplants should become tolerant T acute GVHD T T 3-6 months T T Homeostatic peripheral expansion T SC SC Thymic selection T 6 months-1 year tolerance thymus Adapted from de Kooning Blood 2016
However, the THYMUS … Ø Deteriorates with age Ø Is damaged by chemotherapy Ø Is damaged by acute GVHD thymectomised Zhao JI 2011
Chronic GVHD as an autoimmune syndrome Ø Clinical (mimicking autoimmune diseases) Ø Serological (autoantibodies) Ø Histological (fibrosis) Ø Immunological (B cell hyperplasia) Sociè and Ritz Blood 2014
Standard Prophylaxis of GVHD 0 +60 +90 +120 +150 +180 +30 calcineurin inhibitor MTX or MMF Ram BMT 2009
conditioning therapy tissues damage IL-6 IL-1 LPS TNF- α Target GVHD APC recip. IL-1 Mono TNF- α IL-12 cell.T CTL don. don. IL-17 NK IL-2 Th1 don . IFN- γ TNF- α Th17
Discovery-based prophylaxis: Modulating T cell function In vivo T depletion Partial T depletion Regulatory T cells Holtan Blood 2014
Full in vitro T cell depletion increases relapse As well as infections and graft failure
In vivo T depletion: ATG Kroger and Bonifazi NeJM 2016 Bacigalupo BBMT 2006 =ATG = no ATG all extensive FAMILY UNRELATED
In vivo T depletion: cyclophosphamide Luznik Sem Oncol 2012 Raiola BBMT 2013
Partial T depletion: alpha-beta T cells
TCD with modified T cell add back Greco, Bonini e Ciceri Front Immunol 2015
T regs prevent GVHD in HLA-haplo transplantation. Di Ianni et al. Blood 2011 fresh T reg cells CD34+ cells SC SC Conventional T cells 2 out 26 acute GVHD II 0 out of 26 chronic GVHD Effective GVHD prevention
Discovery-based prophylaxis: Modulating APC function Cells e.g. donor NK cells Antibodies e.g. Campath Drugs e.g. rapamycin bortezomib HDAC inhibitors Holtan Blood 2014
Bortezomib kills APC in vitro and prevents GVHD in vivo In Vivo In Vitro Koreth JCO 2012 Arpinati BMT 2008 * 100 % apoptosis 80 60 40 20 0 0 0,1 1 10 Velcade (ng/ml)
Vorinostat kills APC in vitro and prevents GVHD in vivo Acute GVHD IL-6 IL-12 In Vivo Choi Lancet Oncol 2014 vorinostat In Vitro Roger Blood 2011
Standard treatment of GVHD acute chronic steroids 1 mg/kg steroids 1-2 mg/kg steroid refractory (40-60%) van Lint MT Blood. 1998 Secondary treatment Mielcarek M Blood 2009 Flowers Blood 2014
Biologic treatment of GVHD
Lymph nodes Infuse T regs in GVHD? donor T cells T T T donor T regs donor APC peripheral tissues Adapted from Bruce R. Blazar et al Nature Reviews Immunology 12, 443-458 (June 2012)
Multiple donor regulatory T cell (Treg) infusions (T reg DLI) for severe refractory chronic Graft Versus Host Disease (GVHD) after allogeneic Hematopoietic Stem Cell Transplantation (HSCT). TREGeneration has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 643776
4 modi diversi di somministrarle Una infusione Lisbona 0 1 2 3 Una infusione Liegi Rapa e IL-2 per ESPANDERE le T reg 0 1 2 3 1 2 3 Una infusione di cellule ESPANSE IN VITRO Regensburg 0 1 2 3 Tre infusioni Bologna 0 1 2 3
Posi%ve ¡selec%on, ¡expansion ¡and ¡transplanta%on ¡ of ¡regulatory ¡T ¡cells ¡to ¡prevent ¡cellular ¡rejec%on ¡ and ¡to ¡induce ¡tolerance ¡ ¡in ¡solid ¡organ ¡ transplanta%on Treg Treg Treg Treg Treg Treg Treg Treg Treg Treg Infusione espansione ¡ PI: ¡RM ¡Lemoli/L ¡Catani ¡ ¡RF-‑2011-‑02346763 ¡ ¡
A jump to the future: CAR T-regs? CAR T regs CAR T regs Poly T regs Poly T regs
La fine del rigetto (GVHD)? SC DONATORE SC congela SC CAR-T T regs SC T regs CAR-T CAR-T SC CAR-T T regs T regs Cellule Anti-leucemia + staminali anti infezione se GVHD Se Ricaduta al trapianto
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