Belatacept and Rapamycin with Short-Term Use of Tacrolimus Delay Allograft Rejection in a Novel, Large Animal Vascularized Composite Allotransplantation Model

Background:

Vascularized composite allotransplantation(VCA) is a clinical reality with over 80 hand and 20 facial transplants to date globally¹. Although costimulation blockade with CTLA4-Ig (belatacept) and rapamycin together with bone marrow transplantation-based therapy has shown encouraging results in solid organ transplantation², its efficacy has remained unclear in VCA, especially without donor bone marrow components. The aim of this study was to evaluate whether belatacept and rapamycin with or without short-term³ tacrolimus, a calcineurin inhibitor, could prolong allograft survival in a novel major histocompatibility complex (MHC)-mismatched swine VCA model that did not contain donor bone tissue.

Methods:

A total of seven transplants were performed in MGH mini-swine across a full-MHC mismatch and were assigned into control and experimental groups. Vertical rectus abdominis musculocutaneous(VRAM) composite flaps were transplanted on one side of the recipients’ necks. Control animals were treated with rapamycin and belatacept immediately after the surgery. In the experimental groups, tacrolimus was administered from postoperative days 0-13, followed by rapamycin and belatacept, which were started on day 0 or 7. Allograft survival was compared among the groups by clinical assessment and histological analysis.

Results:

Six allografts survived immediately after transplantations and one technical failure was noted due to arterial insufficiency. Vascular characteristics and ischemic time were similar to an established hind-limb transplantation model⁴. In the control group (no tacrolimus), allografts reached acute rejection Grade I by day 9 after transplant and were fully rejected by day 20. In the experimental groups (tacrolimus), allografts reached Grade I rejection on day 33 and were fully rejected by day 59.

Conclusion:

Short-term tacrolimus and delayed belatacept/ rapamycin therapy offers promise to delay early acute rejection and prolong allograft survival in VCA. The VRAM surgical model can be used in various preclinical trials for evaluating strategy to promote donor-specific tolerance without the influence of donor bone marrow components.

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