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Review
. 2018 May;79(5):258-265.
doi: 10.1016/j.humimm.2017.11.008. Epub 2017 Nov 22.

Preclinical and Clinical Studies for Transplant Tolerance via the Mixed Chimerism Approach

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Free PMC article
Review

Preclinical and Clinical Studies for Transplant Tolerance via the Mixed Chimerism Approach

Hajime Sasaki et al. Hum Immunol. .
Free PMC article

Abstract

Based upon observations in murine models, we have developed protocols to induce renal allograft tolerance by combined kidney and bone marrow transplantation (CKBMT) in non-human primates (NHP) and in humans. Induction of persistent mixed chimerism has proved to be extremely difficult in major histocompatibility complex (MHC)-mismatched primates, with detectable chimerism typically disappearing within 30-60 days. Nevertheless, in MHC mismatched NHP, long-term immunosuppression-free renal allograft survival has been achieved reproducibly, using a non-myeloablative conditioning approach that has also been successfully extended to human kidney transplant recipients. CKBMT has also been applied to the patients with end stage renal disease with hematologic malignancies. Renal allograft tolerance and long-term remission of myeloma have been achieved by transient mixed or persistent full chimerism. This review summarizes the current status of preclinical and clinical studies for renal and non-renal allograft tolerance induction by CKBMT. Improving the consistency of tolerance induction with less morbidity, extending this approach to deceased donor transplantation and inducing tolerance of non-renal transplants, are critical next steps for bringing this strategy to a wider range of clinical applications.

Keywords: Allograft tolerance; Chimerism; Donor bone marrow transplantation; Hematopoietic stem cell transplantation; Kidney transplantation.

Figures

Fig. 1
Fig. 1
Nonmyeloablative regimens for NHPs: A. Standard regimen for living donor transplant. The regimen consisted of TBI (1.5 Gy × 2) on Day −6, −5, TI (7 Gy) on Day −1, intravenous horse ATG (50 mg/kg/day) on Day −2, −1 and 0 and kidney and bone marrow transplantation, followed by a 1-month course of cyclosporine. The initial regimen (upper panel) included Splenectomy on Day 0. The modified regimen (lower panel) included treatment with anti-CD154 mAb (20 mg/kg/day on Day 0, 2, 4, 6, 8 and 10) or belatacept (20 mg/kg/day on Day 0 and 2, and 10 mg/kg/day on Day 5 and 15) in place of splenectomy. B. Delayed tolerance regimen for deceased donor transplant: All recipients initially underwent kidney transplantation alone with a conventional triple drug immunosuppressive regimen consisting of tacrolimus, mycophenolate mofetil and prednisone. The recipients then undergo conditioning and donor bone marrow transplantation 4 months later. The initial conditioning regimen consisted of TBI (1.5 Gy × 2) on Day −6, −5, TI (7 Gy) on Day −1, intravenous horse ATG (50 mg/kg/day) on Day −2, −1 and 0, followed by anti-CD8 mAb (5 mg/kg/day on Day 0 and 2). Frozen BBM is administered on Day 0, followed by anti-CD154 mAb (20 mg/kg/day on Day 0, 2, 5, 7, 9 and 12) and a one-month course of cyclosporine. In most recent regimen, that uses only clinically available reagents (lower panel), thymoglobulin (20 mg/kg/day on Day −2 and −1) and belatacept (20 mg/kg/day on Day 0 and 2, and 10 mg/kg/day on Day 5 and 12) are substituted for horse ATG and anti CD154 mAb, respectively.
Fig. 2
Fig. 2
Full-thickness skins from a kidney donor and an allogeneic third-party were grafted on 337 days after kidney transplantation. Photograph (right panel) shows that acceptance of kidney donor skin surviving in perfect condition over 100 days was observed while third-party frozen and fresh skin grafts were rejected by day 10. Renal allograft biopsy was performed at 13 years after kidney transplantation. Histology (left panel) of the donor kidney graft showed no evidence of rejection, interstitial fibrosis and tubular atrophy.
Fig. 3
Fig. 3
Two recipients (M2411 and M4012) developed persistent mixed and achieved lung-allograft tolerance. The third recipient (M912) developed only transient chimerism up to day 75 but achieved long-term lung-allograft survival without immunosuppression. One recipient that failed to develop chimerism rejected lung allograft on day 176.
Fig. 4
Fig. 4
A hypothesis of renal allograft tolerance via transient mixed chimerism: Chimeric donor cells provide significant donor-antigen presentation under co-stimulatory blockade. This may result in generation of donor-specific memory T-cells that can produce cytokines (such as Th3 that produce TGF-β) upon stimulation by donor antigens. Upon encountering donor antigens in the graft, these T cells locally produce cytokines that favor conversion of no Tregs cells to Tregs in the renal allograft.
Fig. 5
Fig. 5
The initial conditioning regimen (NKD03) consisted of cyclophosphamide (60 mg/kg) on Days −5 and −4; humanized anti-CD2 mAb (MEDI 507) (0.6 mg/kg/dose) on Days −2, −1, 0 and 0.1; cyclosporine A (CyA) (5 mg/kg) i.v. on Day −1 and thymic irradiation (7 Gy) on Day −1. On Day 0, kidney transplantation was followed by i.v. infusion of unprocessed donor bone marrow (DBM; 2–3 × 108 mononuclear cells/kg). Oral CyA (Neoral) was administered postoperatively at 8–12 mg/kg/day with target trough blood levels of 250–350 ng/mL, then tapered and discontinued over several months. The protocol was modified after treatment of the third subject, with the addition of rituximab, 375 mg/m2/dose on Days −7 and −2 (red arrows); and prednisone, 2 mg/kg/dose starting on the day of transplantation and tapering to withdrawal over the next 10 post-transplant days (mod NKD03). Since subjects treated with this mod NKD03 still developed donor-specific antibodies (DSAs) after discontinuation of immunosuppression, the regimen was further modified to add two more doses of rituximab (375 mg/m2/dose) on Days 5 and 12 (red arrows), plus a more prolonged course of prednisone until Day 20, and tacrolimus in place of CyA (ITN036). Tacrolimus was slowly tapered over several months and completely discontinued at 8 months after confirming no rejection by a 6-month protocol biopsy. To overcome acute kidney injury (AKI) observed in 9/10 recipients of cyclophosphamide-based regimen, a pilot study with a modified regimen, in which TBI substituted cyclophosphamide, was tested in two patients (TBI Pilot)(For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.).

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