TABLE 3.
Assessment of adoptive Treg therapy in NHP transplant recipients.
| Type of graft (species) | IS therapy/conditioning | Type of Tregs (number/infusions) | Result | References |
| Kidney (rhesus) n = 6 | Cyclosporine and post-transplant cyclophosphamide | Autologous splenocyte-derived “suppressive T cells” (approx 107/kg) rendered anergic following co-culture with donor alloAg and anti-CD80/86 mAbs (102 ± 67 × 106 total on day 13 post-transplant) | Donor-specific tolerance in 50% of graft recipients | Bashuda et al., 2005 |
| Kidney (cynomolgus) n = 4 | ATG and low dose rapamycin | Expanded, donor Ag-specific, host splenocyte–derived CD4+CD25+Treg (14 daily infusions; 107per day) | Graft MST prolonged from 22 to 48.5 days | Ma et al., 2011 |
| Kidney (cynomolgus) (n = 5) | Non-myeloablative conditioning and MHC-mismatched BMT. Renal transplantation (from the same BMT donor) conducted 4 months after BMT, with no IS | Expanded polyclonal autologous Treg (15–53 × 106/infusion) during the 1st week post-transplant (days 0, 2, 5, 7) and day + 50 (total dose: 88–96 × 106/kg) | Two of 5 evaluable recipients of Treg + BMT displayed T cell chimerism up to 335 days post-BMT. In one long-term surviving animal, the delayed kidney graft survived > 294 days without IS, however, non-Treg BMT recipients rejected their delayed kidney grafts within 3–4 weeks | Duran-Struuck et al., 2017 |
| Heart (cynomolgus) n = 5 | ATG, tacrolimus, anti-IL-6R mAb and tapered rapamycin maintenance IS therapy | Expanded polyclonal Tregs (single or multiple doses (up to a maximum cumulative cell dose of 1.87 billion cells during the early post-transplant period (up to 1 month post-transplant) | Inferior graft function with multiple infusions; elevated incidences of T effector memory cells, increased IFNγ production by host CD8+ T cells, enhanced levels of proinflammatory cytokines and anti-donor alloAb | Ezzelarab et al., 2016 |
| Heart (cynomolgus) n = 5 | ATG, tacrolimus and anti-IL-6R with tacrolimus conversion to rapamycin at 2 weeks (early cell infusion within 3 weeks post-transplant); ATG and tacrolimus with tacrolimus conversion to rapamycin at 2.5 weeks (delayed cell infusion, 6–8 weeks post-transplant) | Expanded donor Ag alloreactive Tregs; 20.5–120 × 106/kg for each of 2–4 infusions | No prolongation of graft survival; loss of regulatory signature and proliferative/survival capacity by transferred Tregs | Ezzelarab et al., 2020 |
| Pig pancreatic islets (xeno; rhesus) n = 3 | ATG, CVF, anti-CD154 mAb, and rapamycin | Intraportal infusion (x1 or x2) of expanded CD4+CD25hiCD127lo autologous Tregs (1.87–62.0 × 106) following ATG depletion | Treg infusion associated with more stable and durable normoglycemia | Shin et al., 2015 |
| Pig pancreatic islets (xeno; rhesus) n = 2 | ATG, CVF, anti-CD154 mAb and rapamycin | As above (ref 65) | Engrafted pig islets rejected by activated T cells following withdrawal of maintenance IS | Shin et al., 2016 |
| Pig skin graft (xeno; baboon) n = 4 | Splenectomy, TBI, ATG, TI, rapamycin, CVF, GalKO/huCD46/huCD47 transgenic donor pig HSCs, anti-CD40LAb, methylprednisolone | 25 × 106/kg (8 infusions) | Prolonged donor skin graft acceptance | Stern et al., 2017 |
ATG, anti-thymocyte globulin; BMT, bone marrow transplantation; CVF, cobra venom factor; Gal KO, α1,3-galactosyltransferase gene-knockout; HSCs, hematopoietic stem cells; hu, human; IS, immunosuppression; MST, mean/median graft survival time; TBI, total body irradiation; TI, thymic irradiation.