Table 2 –

Preclinical and clinical studies of donor apoptotic cell infusion prior to transplantation

Reference	Model	Treatment	Outcomes
Rodent models
Kaneko et al 200357	Heart allograft Mouse	Treatment: ECDI-treated donor DC infusion 7 days prior to transplantation without other IS Methods: Bone-marrow derived DC cultured with GM-CSF and IL-4, pulsed with donor cell lysate and ECDI Control: Control donor DCs or no treatment	Median survival approximately 10 days in control groups vs >25 days in ECDI-DC infusion group (exact values not reported; p < 0.01)
Wang et al 200647	Heart allograft Mouse	Treatment: Apoptotic donor splenocyte infusion 7 days prior to transplantation without other IS Methods: Donor splenocytes with apoptosis induced by UV-B irradiation Control: Necrotic donor splenocytes or no treatment	Median survival approximately 20 days in control groups vs 40 days in apoptotic donor splenocyte infusion group (exact values not reported, p = 0.0001)
Luo et al 200858	Islet allograft Mouse	Treatment: ECDI-treated donor splenocyte infusion 7 days prior and 1 day after transplantation without other IS Methods: Donor splenocytes with apoptosis induced by ECDI Control: Multiple groups, primary comparator no treatment	Median survival 20 days in control groups vs >100 days in ECDI-splenocyte infusion group (p < 0.0036)
Martin et al 201059	Sex-mismatched skin allograft Mouse	Treatment: ECDI-treated recipient splenocyte infusion 7 days prior and 0 days after transplantation without other IS Methods: Recipient splenocytes ECDI-cross-linked to Y chromosomal CD4 antigen Control: Alternative non-CD4 Ag ECDI-cross linked to recipient splenocytes, or no treatment	Median survival approximately 20 days in control groups vs >100 days in ECDI-splenocyte infusion group (p < 0.001)
Kheradmand et al 201156	Islet allograft Mouse	Treament: ECDI-donor splenocyte infusion 7 days prior and 1 day after transplantation without other IS Methods: Donor splenocytes with apoptosis induced by ECDI Control: No infusion	Median survival <20 days in control group vs >150 days in ECDI-splenocyte infusion group (p value not reported)
Kheradmand et al 201252	Islet allograft Mouse	Treatment: ECDI-donor splenocyte infusion 7 days prior and 1 day after transplantation ± anti-CD20 antibody or macrophage depletion or CD11c depletion Methods: Donor splenocytes with apoptosis induced by ECDI, macrophage depletion with lipo-clodronate Control: No infusions	Median survival <10 days in control group vs <20 days in ECDI-splenocyte infusion plus CD11c depletion group vs >100 days in ECDI-splenocyte (p = 0.008) ± anti-CD20 ± macrophage depletion groups
Chen et al 201262	Heart allograft Mouse	Treatment: ECDI-donor splenocyte infusions 7 days prior and 1 day after; ± 7 / 14 days after transplantation; ± rapamycin from 1 day prior to 8 days posttransplant Methods: Donor splenocytes with apoptosis induced by ECDI Control: No infusions	Mean survival 9 days in control vs 45 days in 2 infusion group (p = 0.0005) vs 85 days in 4 infusion group (p = 0.012) vs >150 days in 2 infusion group with rapamycin (p = 0.0018)
Wang et al 201373	Islet xenograft Rat >Mouse	Treatment: ECDI-donor splenocyte infusions 7 days prior and 1 day after transplantation plus depleting anti-CD20 antibody Methods: Donor splenocytes with apoptosis induced by ECDI Control: No infusions	Median survival approximately <20 days in control vs >40 days in ECDI-splenocyte infusion group (p = 0.0026; exact values not reported). Indefinite graft survival when combined with anti-CD20 Ab
Bryant et al 201463	Heart allograft Mouse	Treatment: ECDI-donor splenocytes infusions 7 days prior and 1 day after transplantation without other IS Methods: Donor splenocytes with apoptosis induced by ECDI Control: No infusion	Median survival approximately 10 days in control vs >20 days in ECDI-splenocyte infusion group (p < 0.05, exact values not reported)
Wang et al 201571	Islet allograft Mouse	Treatment: ECDI-donor splenocytes infusions 7 days prior and 1 day after transplantation without other IS Methods: Donor splenocytes with apoptosis induced by ECDI, or recipient splenocytes ECDI-coupled to donor splenocyte lysate Control: Multiple groups, primary comparator no infusion or recipient splenocytes infusions 7 days prior and 1 day after transplantation	Median survival approximately <20 days in control vs >100 days for either donor or antigen-pulsed recipient ECDI-splenocyte infusion (p = 0.0017)
Lai et al 201754	Heart allograft Mouse	Treatment: ECDI-donor splenocytes infusions 7 days prior and 1 day after transplantation ± α1-antitrypsin from 1 day prior to 8 days after transplantation Methods: Donor splenocytes with apoptosis induced by ECDI Control: No infusion	Mean survival 7 days in control vs 42 days in ECDI-splenocyte infusion group (p = 0.0006) vs >90 days in ECDI-splenocyte infusion plus α1-antitrypsin infusion group (p = 0.0005)
Ding et al 201855	Skin allograft Mouse	Treatment: ECDI-donor splenocytes 1–3 infusions pre- and posttransplantation ± low-dose rapamycin Methods: Donor splenocytes with apoptosis induced by ECDI Control: No infusion	Median survival approximately <20 days in control vs >20 days in 2x ECDI-splenocyte infusions plus rapamycin (p < 0.01, exact values not reported)
Zhang et al 201951	Islet OR heart allografts Mouse	Treatment: ECDI-donor splenocytes infusions 7 days prior and 1 day after transplantation without other IS Methods: Donor splenocytes with apoptosis induced by ECDI Control: No infusion	Islet allograft: Median survival approximately < 20 days in control vs > 100 days in ECDI-splenocyte infusion group (p < 0.001, exact values not reported) Heart allograft: Median survival approximately <10 days in control vs 15 days in ECDI-splenocyte infusion group (p < 0.01; exact values not reported)
Zhou et al 201953	Skin allograft Mouse	Treatment: ECDI-donor splenocytes infusion 7 days prior and 1 day after transplantation plus rapamycin Methods: Donor splenocytes with apoptosis induced by ECDI Control: ECDI-donor splenocytes infusions alone	Median survival 15 days in control vs 20 days in ECDI-splenocyte infusion plus rapamycin group (no p value reported)
Xingqiang et al 201988	Heart allograft Mouse	Treatment: ECDI-donor splenocyte infusions 7 days prior and 1 day after transplantation plus cordycepin daily from day 0 to day 7 Methods: Donor splenocytes with apoptosis induced by ECDI Control: Multiple groups, primary comparator ECDI-donor splenocytes infusions alone, and no infusion	Median survival approximately 10 days in no infusion group vs > 40 days in ECDI-donor splenocyte infusion alone (p = 0.0006) vs 80 days in ECDI-donor splenocyte infusion with cordycepin infusion (p = 0.0001; exact values not reported)
Dangi et al202085	Islet allograft Sensitized mouse	Treatment: ECDI-donor splenocyte infusion 7 days prior and 1 day after transplantation plus rapamycin daily from 7 days prior to 10 days after transplantation with 4 doses of anti-CD40 Ab. Methods: Donor splenocytes with apoptosis induced by ECDI Control: Multiple groups, primary comparator no anti-CD40 Ab, and no infusion	Median survival approximately 5 days in no infusion group vs 10 days in ECDI-donor splenocyte infusion no anti-CD40 group vs 30 days in anti-CD40 (p < 0.05, exact values not reported)
Lai et al 202072	Heart allograft Mouse	Treatment: ECDI-donor splenocytes + OX40L Ab Methods: Donor splenocytes with apoptosis induced by ECDI Control: Multiple groups, primary comparator no anti-OX40L antibody, and no infusion	Median survival approximately < 10 days in no infusion group vs > 20 days in ECDI-donor splenocyte infusion alone group vs >100 days in ECDI-donor splenocyte infusion plus anti-OX40L Ab group (p < 0.001; exact values not reported)
Schneiderman et al 202274	Heart, renal, or liver allograft Mouse	Treatment: Apoptotic donor leukocyte infusion 7 days prior to transplantation ± rapamycin ± tacrolimus Methods: Donor splenocyte extracorporeal photopheresis by incubating with methoxypsoralen and UV-A irradiation Control: Multiple groups, primary comparator infusion of untreated cells, and no infusion group	Heart allograft: Median survival < 10 days in no infusion group vs > 15 days in apoptotic cell infusion group (p < 0.0001) vs >50 days in apoptotic cell infusion plus rapamycin group (p < 0.05) Liver allograft: Median survival <20 days in no infusion group vs >200 days in apoptotic cell infusion group (p < 0.0001)
Chen et al 201587	Renal allograft Rat	Treatment: ECDI-donor splenocyte infusions 7 days prior and 1 day after transplantation, ± α1-antitrypsin 1 day prior and 1/3 days after transplantation Methods: Donor splenocytes with apoptosis induced by ECDI Control: No infusion	Median survival approximately <10 days in control group vs 50 days in ECDI-splenocyte infusion group vs >200 days in ECDI-splenocyte with α1-antitrypsin infusion (p < 0.05; exact values not reported)
Nonhuman primate models
Lei et al 201581	Islet allograft	Treatment: ECDI-donor lymphocyte infusion day 0 after transplantation plus pretransplant ATG 2 doses, anti-IL-6 Ab 4 doses, and rapamycin for 30 days posttransplant Methods: Lymphoid cells isolated from donor spleen and lymph nodes, incubated with ECDI prior to infusion Control: Identical immunosuppression without ECDI-donor lymphocyte infusion	Mean survival 13.5 days in control vs 85.5 days in ECDI-donor lymphocyte infusion group (p < 0.0177)
Singh et al 201961	Islet allograft (5/6 HLA mismatch model)	Treatment: ECDI-donor lymphocyte infusions 7 days prior and 1 day after transplantation plus anti-CD40 Ab 3 doses, soluble TNF receptor 4 doses, anti-IL-6 Ab 3 doses, and rapamycin for 14 days Methods: Donor blood draw with B cell isolation, B cell culture and expansion; ECDI treatment of donor B cells prior to infusion. Control: Identical immunosuppression without ECDI-donor lymphocyte infusion	Median survival approximately <180 days in control group vs >365 days in ECDI-donor lymphocyte infusion group (p = 0.021)
Clinical trials
Mevorach et al 2014106	Allogeneic hematopoietic stem cell transplant	Treatment: Single infusion of donor mononuclear apoptotic cells plus usual induction therapy with either busulfan or total body irradiation Methods: Donor leukapheresis with cellular apoptosis induced with freezing/thawing cycle followed by cell culture with methylprednisolone Control: No infusion, usual induction therapy	Clinical safety, no immediate adverse outcomes (n = 13) No episodes of GVHD in high dose group (0/6) compared to 43% in low dose group (3/7)