E possibile creare un ambiente tollerogenico dopo il trapianto d organo utilizzando cellule staminali come se fossero farmaci?
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1 E possibile creare un ambiente tollerogenico dopo il trapianto d organo utilizzando cellule staminali come se fossero farmaci? Giuseppe Remuzzi 1 Infections & Transplantation Varese, 18 maggio 2017
2 LONG TERM GRAFT SURVIVAL AFTER RENAL TRANSPLANTATION HAS NOT SIGNIFICANTLY IMPROVED IN THE PERIOD Projected median half-life (years) Deceased donor years of transplant No rejection * within 1 year post-tx Rejection* 10.9 OPNT/SRTR 2012 Annual Data Report
3 THE PROMISE OF NOVEL IMMUNOSUPPRESSIVE AGENTS Basiliximab (chimeric monoclonal antibody against IL-2 R) CAMPATH-1H (humanized anti-cd52 antibody - T and B cells depletion) Belatacept (IgG/CTLA4 fusion protein selective blocker of T cell activation) Mycophenolate (specific suppressor of T and B lymphocytes) Daclizumab (humanized monoclonal antibody against IL-2 R) Sirolimus Everolimus (m-tor T cell proliferation inhibitor) Kidney Tx (Lancet) Kidney Tx (Nashan et al., Lancet) Kidney Tx (Vincenti et al., N Engl J Med) Kidney Tx (Calne et al., Lancet) Kidney Tx (Kahan et al., Lancet) Heart Tx (Eisen et al., N Engl J Med) Kidney Tx (Vincenti et al., N Engl J Med)
4 THE SPECIAL PROBLEM OF MEMORY IFN-γ Activated CD8 + memory - Calcineurin inhibitors - Hydrocortisone - Azathioprine - MMF - Basiliximab - Sirolimus, everolimus - Alemtuzumab* IFN-γ blockade (in vitro) partial partial no partial partial stimulation stimulation * Campath-1 Jones et al., Transplantation, 2006 Page et al., Curr OpOrgan Transplant, 2009 Memory T cells contribute to allograft rejection through: - Activation endothelial cells - Help naïve CD8, CD4 T cells and B cells 4
5 COSTIMULATON BLOCKADE-RESISTANT REJECTION Belatacept APC Naïve CD28 + T cells Memory CD28 - T cells APC CD80/86 CD28 CD80/86 MHC TCR TCR MHC CD8 + CD8 + Antigen-experienced T cells, in particular CD8 + Tcells, lose CD28 expression and became memory T cells with increased capability of mounting a rapid response upon antigen rechallenge independent of CD80/86-CD28 costimulation 5 Traitanou et al., Am J Transpl, 2014
6 BELATACEPT-RESISTANT REJECTION - CD28 - CD8 + T CELLS CD8 + TCR TNFα INFγ IL-15 Effector-memory phenotype 6
7 BELATACEPT-RESISTANT REJECTION - CD57 + CD4 + T CELLS CD28 - CD57 + T cells Granzyme B TCR CD57 CD4 Granzyme B Infiltrate the allograft during rejection May carry allograft-specific memory by antigen cross-reactivity This cell subset pre-transplant correlates with costimulation blockade-resistant rejection posttransplant L-selectin P-selectin 7 Endothelial cell Direct endothelial damage Espinosa et al., Am J Transpl, 2016
8 Belatacept 1,420-11,300 euro per month depending on treatment phase 8
9 9 Casiraghi et al, Curr Opin Organ Transpl, 2010
10 Primi anni 50
11 BCR Cell activation B cells T cells Proliferation Ig release Cell activation Cytotoxicity Proliferation NK cells MSC Expansion T reg Inhibition Differentiation Maturation DC Memory T cells 11 Nauta et al, Blood, 2007
12 AUTOLOGOUS MSC PROLONG HEART TRANSPLANT SURVIVAL MEDIATED BY CD4 + CD25 + Foxp3 + REGULATORY T CELLS B6 MSC infusion (0.5 x 10 6 cells) B6 recipient mice B6C # % surviving allografts vv v Recipient MSC # Donor MSC no cell infusion >100 days after transplant % CD4 + CD25 + Foxp3 + cells # Naive P<0.05 Tolerant 12 Casiraghi et al, J Immunol, 2008
13 AUTOLOGOUS BONE MARROW-DERIVED MSC TO INDUCE TOLERANCE IN LIVING-DONOR KIDNEY TRANSPLANT RECIPIENTS Bergamo IRCCS, Mario Negri Institute (coordinator/immunomonitoring) Azienda Ospedaliera Papa Giovanni XXIII U.S.C. Chirurgia pediatrica Kidney Tx U.S.C. Ematologia Bone marrow explants Laboratorio Terapie Cellulari G. Lanzani MSC preparation according to European GMP U.S.C. Nefrologia pre- and post-transplant patient monitoring and follow-up 13
14 14 Timing is important
15 Memory T cells Regulatory T cells Mesenchymal stem cells Timing of MSC infusion? 7 days post transplant coincides with the start of homeostatic proliferation induced by lymphopenia 15
16 Phase a: 2 patients Kidney Tx Low CsA + Low MMF Recipient MSC* Time post Tx (days) MP L-RATG (0.5 mg/kg) Basiliximab (20 mg) MSC in-vitro expanded for 2 passages * Dose: 2 x 10 6 /kg i.v. 16 Perico, Casiraghi et al, Clin J Am Soc Nephrol, 2011
17 Serum creatinine (mg/dl) Patient #1 D.D MSC infusion start MP pulses no biopsy (BT>12 min) Serum creatinine (mg/dl) Patient #2 G.U MSC infusion Biopsy start MP pulses day months Perico, Casiraghi et al, Clin J Am Soc Nephrol, 2011
18 GRAFT INFILTRATING CELLS (day +15) (cells/field) Patient #2: G.U. Controls acute rejection (n=3) CD4 + T cells ± 35 CD8 + T cells ± 35 CD20 + B cells ± 16 CD68 + macrophages ± 2 granulocytes ± 1.2 Complement C ± 0.3 Values are mean of 30 fields 18 Perico et al., CJASN, 2011
19 MSC INFILTRATE THE GRAFT (day +15) CD105 + CD44 + cells (cells/3 mm 2 ) Patient #2: G.U. Controls Acute rejection: 15 day post-tx 17 0 Native control kidneys (n=4) 1.5 ± 2.6 A high number of CD105 + CD44 + MSC was found into the kidney graft biospy of MSC infused patient 19 Perico, Casiraghi et al, Clin J Am Soc Nephrol, 2011
20 American Journal of Transplantation, 2011 Acute Renal Endothelial Injury During Marrow Recovery in a Cohort of Combined Kidney and Bone Marrow Allografts A.B. Farris et al. 20
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24 PRE-TRANSPLANT INFUSION OF MSC IN SENSITIZED MICE % survival B6 recipient mice Untreated day +2* Balb/c kidney Tx day >60 Days post-transplant 5 animals for each group Balb/c donor splenocyte (1,000,000/mouse i.v.) autologous MSC (500,000/mouse i.v.) * day+7 in mice is unfeasible because of graft loss for acute rejection in all recipient mice 24 Casiraghi et al, Am J Transplant, 2012
25 LOCALIZATION OF MSC DICTATES THEIR IMMUNE OR PROINFLAMMATORY EFFECTS IN KIDNEY TRANSPLANTATION IN MICE (cells/mm 2 ) PKH 26 + MSC kidney spleen MSC day ± 4.0* 58.9 ± 20.9* MSC day ± ± 107 * P<0.05 vs MSC day-1 C3 deposition Treg induction GFPfoxp3 MSC day -1 MSC day +2 MSC day -1 MSC day CD4 Casiraghi et al., Am J Transpl. 2012
26 IS BASILIXIMAB PERMISSIVE FOR T REG MEDIATED TOLERANCE? Basiliximab CD4 CD25 Foxp3 T regs 26
27 ANTI-CD25 ANTIBODY ABROGATES TOLERANCE (BY DEPLETING TREGs) Balb/c splenocytes C57 recipient mice Balb/c kidney 100 MSC, day -7 and day -1 MSC, day -7 and day -1 + anti-cd25 mab no-msc infusion double MSC infusion +3 days % graft survival Depleting anti-cd25 mab (500 µg, i.p.) >60 days after transplantation 27 Casiraghi et al, Am J Transpl. 2012
28 Phase b: 2 patients Kidney Tx Low CsA + Low MMF Recipient MSC* Time post Tx (days) MP L-RATG (0.5 mg/kg) 28 * Dose: 2 x 10 6 /kg i.v.
29 Patient #3 C.M. MSC infusion Serum creatinine (mg/dl) day Protocol biopsy months Perico, Casiraghi et al, Transplant Int, 2013
30 Patient #4 D.A. MSC infusion Kidney Tx Serum creatinine (mg/dl) MP pulses 5.0 Biopsy days months 30 Perico, Casiraghi et al, Transplant Int 2013
31 31
32 GRAFT INFILTRATING CELLS (day +17) (cells/field) Patient #4: D.A. Controls acute rejection (n=3) CD4 + T cells ± 35 CD8 + T cells ± 35 CD20 + B cells ± 16 CD68 + macrophages ± 2 granulocytes ± 1.2 Values are mean of 30 fields 32 Perico et al., CJASN, 2011
33 EFFECT OF INDUCTION REGIMEN WITH OR WITHOUT BASILIXIMAB ON FoxP3 + T CELL PROFILE % on CD CD4 + FoxP3 + pre-tx days post transplant Pt #1 DD Pt #3 CM with Basiliximab without Basiliximab Pt #2 GU Pt #4 DA Control Bas/RATG (n=6) Control RATG alone (n=6) 33 Perico, Casiraghi et al,transplant Int, 2013
34 THE HIGH RATIO OF Treg/Tmemory COULD FAVOUR A STATE OF IMMUNE REGULATION Treg/memory CD8 + T cells (ratio) Pre-tx 6mo 1 yr 2 yrs 3 yrs 4yrs 5yrs 6 yrstime post-tx 34 Patient #1 Patient #2 Patient #3 Patient #4 Bas+LowRATG and maintenance therapy alone (N = 6) Casiraghi, Personal communication, 2015
35 LONG-LASTING COMPLETE AND DONOR-SPECIFIC SUPPRESSION OF CD8 + T CELL CYTOTOXICITY Cell mediated lympholysis vs donor % of specific lysis pt # pt #3 % of specific lysis pt # Years of transplant pt # Years of transplant Bas+Low RATG and maintenance therapy alone (N = 6)
36 Naive B cells (cells/μl) CD19 + IgD + CD27 - Transitional B cells (cells/μl) CD19 + CD24 high CD38 high yrs 3 yrs 4 yrs 5 yrs 6 yrs 0 2 yrs 3 yrs 4 yrs 5 yrs 6 yrs Patient #1 Patient #2 Patient #3 Patient #4 Controls (N = 6) * P<0.05 vs pre-tx 36 Spontaneous operational tolerance to kidney allograft is associated with elevated number of naïve and transitional B cells with regulatory properties suggesting a critical role for these B cells subsets in the regulation of alloimmune response Newell et al., J Clin invest, 2010
37 Patient #3 C.M. MSC infusion Serum creatinine (mg/dl) day Protocol biopsy months Perico, Casiraghi et al, Transplant Int, 2013
38 38
39 RENAL GRAFT FUNCTION IN MSC-TREATED PATIENTS GFR slope (ml/min/1.73 m 2 /year) Patients 1 2 Last follow-up (range 5-8 years) Engraftment syndrome 3 4 CTR (n=6, median) Acute rejection Measured GFR by iohexol plasma clearance 39 Casiraghi, Personal communication, 2017
40 IMMUNOSUPPRESSIVE DRUG TAPERING IN PATIENT #3 OVER 5 YEAR FOLLOW-UP Kidney Tx Low MMF mg/day mg/day Recipient MSC* Low CsA - total dose (mg/day) - trough levels (ng/ml) <10 9/9/ < Time post Tx (days) (years) 6 MP L-RATG (0.5 mg/kg) 40 * Dose: 2 x 10 6 /kg i.v.
41 DONOR HLA-SPECIFIC ANTIBODIES Patients pre-tx 1 st year 2 nd year 3 rd year 5 th year 1 2 NEG NEG NEG NEG NEG NEG NEG NEG NEG NEG 3 4 NEG NEG NEG NEG NEG NEG NEG NEG NEG NEG CTR (n=6) NEG NEG 5 NEG 1 POS NEG 3 NEG 3 POS By Luminex Threshold for DSA positivity: Mean Fluorescence Intensity > Casiraghi, Personal communication, 2017
42 RENAL GRAFT FUNCTION IN MSC-TREATED PATIENTS Δ mgfr (ml/min/1.73m 2 ) MSC: mgfr slope (n=4) ml/min/1.73 m 2 /year Controls: mgfr slope (n=6) ml/min/1.73m 2 /year Time post-tx (years) Values are median of individual GFR slopes Measured GFR by iohexol plasma clearance 42 Casiraghi, Personal communication, 2017
43 LIVING TRANSPLANT RECIPIENTS 2 * Kidney Tx Bas Bas MSC Engraftment syndrome: YES Acute graft rejection: IL-2 dependent Treg expansion NO MSC Kidney Tx Engraftment syndrome: NO 2 * Acute graft rejection: YES (1) IL-2 dependent Treg expansion 2 43 * Ongoing MSC Bas Kidney Tx Bas Time post Tx (days) Engraftment syndrome: NO Acute graft rejection: NO IL-2 dependent Treg expansion? * On top of RATG (0.5 mg/kg for 7 days)
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46 THIRD-PARTY BONE MARROW-DERIVED MSC TO INDUCE TOLERANCE IN LIVER TRANSPLANT RECIPIENTS Bergamo IRCCS, Mario Negri Institute (coordinator/immunomonitoring) Azienda Ospedaliera Papa Giovanni XXIII U.O. Chirurgia III (Liver Tx) U.O. Ematologia (Bone marrow explants) Laboratorio Terapie Cellulari G. Lanzani (MSC preparation according to European GMP) Bologna Azienda Ospedaliera Policlinico S. Orsola-Malpighi U.O. Chirurgia Generale e Trapianto (Liver Tx) 46
47 Phase 1: A pilot explorative study Liver Tx Tac + Low MMF Third party MSC* -4/-2 h Time post Tx (days) MP L-RATG (0.5 mg/kg) * Dose: 1-2 x 10 6 /kg i.v. 47 Group 1: MSC (n = 10) Group 2: Control (n = 10) - safety - immuno-mechanisms
48 201 7 MSC were infused on days post liver transplant No side effect of MSC infusion The immunosuppression weaning in MSC recipients was not successful
49 REGISTERED CLINICAL TRIALS OF MSCs IN SOLID ORGAN TRANSPLANTATION MSC after renal or liver Tx (Liege, Belgium) MSC and subclinical kidney graft rejection (Leiden, Netherlands) MSC in liver Tx (Regensburg, Germany) MSC in kidney Tx (Chandigarh, India) MSC for kidney acute rejection with donors after cardiac death (Fujian, China,) Induction therapy with MSC for kidney allograft MSC + Standard CNI (n = 53) MSC + Low CNI (n = 52) MSC groups n = 105 Control groups n = 51 Endpoint: acute graft rejection Riella et al., JAMA, 2012 Casiraghi et al., Nat Rev Nephrol, 2016
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52 INDUCTION THERAPY WITH AUTOLOGOUS MESENCHYMAL STEM CELLS IN LIVING-RELATED KIDNEY TRANSPLANT MSC + Standard CNI (n = 53) Kidney Tx Standard CNI + MMF + ST 0 4d MSC 12d MSC Low CNI + MMF + ST MSC + Low CNI (n = 52) 0 4d MSC 12d MSC Anti-IL-2 R-Ab + Standard CNI (n = 51) Standard CNI + MMF + ST 0 4d 12d Time post Tx Anti-IL-2 R-Ab MSC: Bone Marrow MSC (1-2 x 10 6 /kg) Anti-IL-2 R-Ab 52 Tan et al., J Am Med Assoc, 2012
53 LOWER FREQUENCY OF ACUTE REJECTION EPISODES IN MSC-TREATED PATIENTS THAN IN THOSE GIVEN INDUCTION THERAPY WITHANTI-IL-2 R-Ab 30 P < Biopsie-proven acute rejection (%)* P < MSC + Standard CNI MSC + Low CNI Anti-IL-2 R-Ab + Standard CNI 53 * At 6 months Tan et al., J Am Med Assoc, 2012
54 NO DIFFERENCE IN ACUTE REJECTION INCIDENCE AMONG GROUPS AT 12 MONTHS POST TRANSPLANTATION MSC + Standard CNI MSC + Low-dose CNI Anti-IL2R Ab + Standard CNI Acute rejection (%) At 6 months post-tx 7.5 * 7.7 ** 21.6 At 12 months post-tx *p<0.040, **p<0.046 vs. Anti-IL2R Ab + standard CNI Tan et al., JAMA,
55 CMV DONOR/RECIPIENT STATUS MSC + Standard CNI (n=53) MSC + Low-dose CNI (n=52) Anti-IL2R Ab + Standard CNI (n=51) CMV status D+/R D-/R Tan et al., JAMA,
56 A CMV SEROSURVEY ON 8,190 SERUM SAMPLES IN SHANGHAI (June May 2008) CMV seroprevalence (%) 63% 85% 97% 97% 56 >3-5 >10-15 >20-25 Age groups (years) >40 Fang et al., Clin Vaccine Immunol 2009
57 TAN S STUDY COHORT CMV negative Tx recipients Age range (yrs) Estimated screened individuals on waiting list with CMV negative living donors * * Based on 3% CMV negative individuals in the Eastern China population (Shanghai) of comparable age range (Fang et al., Clin Vaccine Immunol 2009) 57
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59 These slides belong to Giuseppe Remuzzi, M.D. Mario Negri Institute for Pharmacological Research, Bergamo, Italy. Using these slides is only authorized when mentioning the source 59
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