Table 10. Model-based recommendations for immunosuppressive and/or immunomodulatory protocols after solid organ transplantation.
| Species | Indication | Strategy | Survival | Immunosuppressive/immunomodulatory protocol | Target serum levels |
|---|---|---|---|---|---|
| NHP | Heterotopic cardiac xenoTx357 | Immunopharmacotherapy | >365 days | 50 mg of anti-CD40 antibody/kg per week, 19 mg of anti-CD20 antibody on POD −14, −7, 0 and 7, 5 mg of ATG/kg on POD −2 and −1, 20 mg of MMF/kg b.i.d., 2 mg of steroids/kg tapered off in 4–6 weeks357 | • n.s.i.357 |
| Liver xenoTx358 | Immunopharmacotherapy | 9 days | Induction therapy: Three doses of thymoglobulin on POD −3, LoCD2bn, CVF, 25 mg/kg anti-CD154 on POD −1, 0 and 5, Az on POD −1 and 0, Maintenance therapy: Started on POD −1 with Tcr and 10 mg of MP/kg on POD 0 then tapered off358 | • 10–25 ng of Tcr/ml358 | |
| Renal xenoTx359 | Immunopharmacotherapy | >125 days | Single dose of 50 mg of anti-CD4/kg i.v. between POD −3 and −1, 50 mg of anti-CD8/kg i.v. on POD 0, 20 mg of anti-CD154/kg i.v. on POD 0, 7 and 14 and then biweekly, MMF (applied dosage in previous studies:360 15 mg/kg s.c. b.i.d. on POD 0–14, then q.d.) and steroids359 (applied dosage in previous studies:360 20 mg of MP on POD 0, 16 mg of MP on POD 1, 12 mg of MP on POD 2, 8 mg of MP on POD 3, 4 mg of MP on POD 4, 3 mg of MP on POD 5–14, then 1 mg per day) | • n.s.i.359 | |
| Renal xenoTx361 | Immunopharmacotherapy | 136 days | 10 mg of ATG/kg on POD −3, 10 mg of RTB/kg on POD −2 and 50 mg of RTB/kg on POD −1, 0, 4, 7 and 14 and weekly, 100 U CVF on POD −1 and 0, 0.01 mg of Rpm/kg b.i.d. from POD −3, 5 mg of MP/kg per day tapering to 0.25/kg per day, 10 mg of tocilizumab/kg on POD −1, 7, 14 and every 2 weeks, 0.5 mg of etanercept/kg on POD 0, 3, 7, 28 and 40361 | • 8–12 ng of Rpm/ml361 | |
| Renal alloTx362 | Immunopharmacotherapy | >3478 days | Splenectomy, TBI (1.5 Gy), TI (7 Gy) on POD −1, 15 mg of CsA/kg per day until POD 28, i.v. 0.3–3.5 × 108/kg donor bone marrow cells on POD 0362 | • >300 ng of CsA/ml362 | |
| Mouse | Cardiac alloTx and pretreated donor spleen cells363 | Cell-based therapy | 35±14.4 days | Pretreatment of donor spleen cells with mitomycin C, on POD −8 transfusion of donor spleen cells, on POD −7 to −1 1.5 mg of Rpm/kg per day p.o.363 | • n.s.i.363 |
| Cardiac alloTx in combination with liver alloTx347 | Strain combination | >100 days (45–100% survival) | No immunosuppression necessary using various strain combinations, for example, B10 with C3H, A.TH with A.TL, B10.BR with C3H; simultaneous heterotopic cardiac alloTx of donor origin in recipients of liver allografts on the same day347 | ||
| Liver alloTx347 | Strain combination | >100 days up to >375 days | No immunosuppression necessary using various strain combinations, for example, B10 with C3H, DBA2 with B10.D2, B10.BR with C3H, B10.D2 with B10JHTG, A.SW with A.TH, B10.BR with B10347 | ||
| Renal alloTx in combination with DCs and CHO cells364 | Cell-based therapy | >80 days (60% survival) | i.p. injection of 10 × 106 CHO cells (transfected with a vector encoding murine OX-2, which leads to an overexpression of OX-2 on the surface), infusion of 5 × 106 DCs (1:1 mixture of DCs cytokine-transduced with either Ad-IL-10 or Ad-TGF-β) into the portal vein, 36 h later renal alloTx were performed364 | ||
| Rat | Cardiac alloTx271 | Pharmacological monotherapy | >200 days | p.o. 40 mg of MMF/kg per day271 | • n.s.i.271 |
| Liver alloTx365 | Strain combination | >100 days | No immunosuppression necessary using various strain combinations, for example, donor: DA, DA-P or DA-L, recipient: PVG365 | ||
| Renal alloTx and pretreated donor spleen cells366 | Cell-based therapy | >200 days | i.v. infusion of 1 × 108 pretreated spleen cells on POD −7 and 1, 2 mg of AAT per rat i.p. on POD −1, pretreatment of spleen cells: incubation with 150 mg of ECDI per 3.2 × 108 spleen cells366 | • n.s.i.366 | |
| Dog | Heterotopic cardiac alloTx367 | Immunopharmacotherapy | >538 days | TLI (total cumulative dose of 1800 rad over 4 weeks), cardiac Tx 72 h after completion of radiotherapy, 0.25–2.0 mg of Az/kg per day i.m. for 90 days, 4 mg of ATG/kg i.m. on POD 0, 2, 4, 6, 8 and 10367 | • n.s.i.367 |
| Orthotopic liver alloTx368, 369 | Pharmacological monotherapy | >241 days | 20 mg of CsA/kg per day on POD 1–30, then reduced to 15 mg of CsA/kg per day until POD 90369 | • >200 ng of CsA/ml369 | |
| Renal alloTx286, 370 | Pharmacological combination therapy | Up to 1440 days | p.o. 10 mg of CsA/kg/12 h, 2–3 mg of Az/kg/48 h, 0.5 mg of P/kg/12 h (then tapered)286, 370 | • 400–500 ng of CsA/ml for the first 6 months after Tx, 350–450 ng of CsA/ml thereafter,286, 370 decrease of CsA dosage ~32.9±13.9% via usage of 5 mg of Fcz/kg per day371 | |
| Renal alloTx in combination with donor bone marrow Tx188 | Pharmacological combination therapy and cell-based therapy | >2078 days | i.v. infusion of ~2 × 108 donor mononuclear BMCs within 8 h of TBI (200 cGy), 15 mg of CsA/kg b.i.d. p.o. on POD 1–63, then tapered (20–30%/month), 10 mg of MMF/kg b.i.d. p.o. on POD 0–63, then tapered (20–30%/month), donor renal Tx was performed following TBI but before BMC Tx188 | • n.s.i.188 | |
| Pig | Cardiac alloTx in combination with renal alloTx372 | Pharmacological monotherapy | >269 days | i.v. 10–13 mg of CsA/kg per day on POD 0–11372 | • 400–800 ng of CsA/ml372 |
| Liver alloTx289 | Pharmacological monotherapy | >126 days | i.m. 20 mg of CsA/kg per day on POD −1 to 19289 | • n.s.i.289 | |
| Renal alloTx in combination with donor bone Tx354 | Pharmacological combination therapy and cell-based therapy | Induced long-term tolerance | TI (700 cGy) and 0.05 mg of pCD3-CRM9/kg i.v. on POD −2, 15–30 mg of CsA/kg per day p.o. on POD −1 to 30, Tx of 100–200 × 108 PBSCs on POD 0, donor-matched renal alloTx on POD 98 or 190354 | • 300–800 ng of CsA/ml354 | |
| Renal alloTx288 | Pharmacological monotherapy | >100 days >730 days373 | i.v. 10 mg of CsA/kg per day for 12 days288 | • Reached serum levels: 701±40 ng of CsA/ml288 | |
| Sheep | Uterus alloTx | Pharmacological combination therapy | >180 days | p.o. 8 mg of CsA/kg per day, i.m. 5 mg of P/kg per day on POD −2 to 14374 | • 150 ng of CsA/ml was reached after 5 days of CsA administration374 |
| Immunopharmacotherapy | >118 days, showed signs of estrus | p.o. 0.02–0.15 mg of Tcr/kg per day and p.o. 1.5 g of MMF per day on POD −2, maintain until the end of the trial, p.o. 40 mg of MP per day on POD 1–15 (tapered off towards to 16 mg of MP per day), perioperatively i.v.: 50 mg of ATG (DDI), 500 mg of MP277 | • 3000–6000 ng of Tcr/ml277 |
Abbreviations: AAT, α1-antitrypsin (key serine protease inhibitor); ATG, antithymocyte globulin; Az, azathioprine; b.i.d., twice a day; cGy, centiGray; CHO, Chinese hamster ovary; CsA, cyclosporin A; CVF, cobra venom factor; DCs, dendritic cells, DDI, duration drip infusion, ECDI, 1-ethyl-3-(3′-dimethylaminopropyl)-carbodiimide (induces apoptosis of the spleen cells); Fcz, fluconazole; GCSF, granulocyte colony-stimulating factor; i.m., intramuscular; i.p., intraperitoneal; i.v., intravenous; LoCD2b, monoclonal mouse anti-human CD2b antibody; MMF, mycophenolate mofetil; MP, methylprednisolone; MSCs, mesenchymal stem cells; NHP, non-human primate; n.s.i., no sufficient information available; P, prednisolone; p.o., oral; POD, postoperative day; q.d., once a day; Rpm, rapamycin; RTB, Rituximab; s.c., subcutaneous; TPC, α-Gal-polyethylene; Tcr, tacrolimus; TI, thymic irradiation; TLI, total lymphoid irradiation; Tx, transplantation; U, unit.