*Purpose: We have previously reported that a regimen including anti-CD3 immunotoxin, 45 days of cyclosporine, and pre-transplant total body irradiation (TBI) promoted tolerance of kidney allografts with transient chimerism in non-human primates. Donor islets were also tolerated when transplanted in composite islet-kidney (IK) grafts. However, data from a rodent model demonstrated that durable chimerism may be required to reverse the autoimmunity responsible for type-1 diabetes (T1D). As the first step toward our goal of curing T1D and diabetic nephropathy by transplantation of IKs, we aimed to develop a clinically applicable protocol to induce tolerance of allogeneic kidneys with >6 months durable chimerism in NHPs.

*Methods: Cynomolgus macaques received mobilized peripheral blood hematopoietic stem cell transplantation (PBHSCTx) on Day 0 followed by donor kidney Tx (DKTx) on Day 42 from one haplotype-mismatched donors. Recipients in Group 1 (n=5) received PBHSCTx that contained 3.7-20×10^7 cells/kg recipient body weight (bwt) CD34+ cells. Recipients in Group 2 (n=4) received PBHSCTx containing a lower dose of CD34+ cells (2×10^7 cells/bwt). All recipients received Rituximab, rATG, and 100cGy of TBI before PBHSCTx. Tacrolimus was administered daily starting on Day -1 and was stopped at Day 41. Anti-CD40mAb was administered twice weekly until 30 days after DKTx.

*Results: All animals developed and maintained multilineage chimerism with evidence of bone marrow (BM) engraftment throughout the experimental period. However, animals in Group 1 developed severe GVHD or cytokine storm requiring euthanasia at early time points (Days 33, 43, 45, 55, 92). In contrast, recipients in Group 2 had no evidence of GVHD or cytokine storm, and demonstrated prolonged rejection-free survival (p<0.02). Although one animal was euthanized at Day 78 due to ureteral stent complication and another animal was euthanized at Day 118 due to CMV disease, the other two survived >7 months (218 days [euthanized due to CMV disease] and >246 days which is ongoing [Cre 1.1mg/dL]). In these long-term survivors, we observed (1) donor-specific unresponsiveness in vitro, (2) donor cells in the host thymus, and (3) donor-derived recent thymic emigrants along with multilineage peripheral blood chimerism and BM chimerism >200 days after PBHSCTx, with stable renal allograft function.

*Conclusions: This is the first demonstration of reproducible, long-term (>7 months), multilineage durable chimerism with BM engraftment and kidney graft tolerance in our cynomolgus HSCTx with kidney Tx model. Achieving long-term durable chimerism, which may be necessary to overcome autoimmunity of T1DM, allows us to confidently extend this protocol to composite IK Tx, moving us one step closer to a clinical trial.

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