Aim: Current strategies for management of VCA recipients are adapted from solid organ transplant protocols, and almost universally employ induction therapy followed by maintenance triple therapy-based immunosuppression. Unfortunately, this has precluded more than a very small proportion of potential VCA recipients from being engrafted on the basis that maintenance immunosuppression may entail a heavier burden of renal toxicity, infections, tumors and other complications than can be justified in many cases. To begin to clarify what is or what isn't necessary in this context, we have established a murine heterotopic limb VCA model and begun to test various therapies, seeking to achieve long-term VCA survival without maintenance immunosuppression.

Methods: Using a heterotopic murine hindlimb VCA model (BALB/c->C57BL/6) and 6-10 allografts/group for screening, (i) we tested the ability of T cell-depletion strategies to promote VCA survival, and (ii) thereafter analyzed how the most effective of these strategies altered the key pathogenic mechanisms underlying VCA rejection.

Results: Control untreated VCA recipients rejected their grafts by 10 days (with 50% rejected by 7 days). We then tested the efficacy of a depleting anti-TCR mAb that we have previously shown was efficacious in murine cardiac allograft recipients. We found that anti-TCR mAb given for 2 weeks from the time of engraftment, and then stopped, prolonged VCA survival for ∼70 days (50% survival data). Anti-TCR mAb depleted circulating T cells (CD4 and CD8) as shown by flow cytometric analysis of blood samples collected at day 14 post-Tx, whereas the proportions of CD4+Foxp3+ Treg cells were comparable. Comparable depletion was still apparent at 36 days post-Tx, but diminished thereafter. Importantly, the combination of 2 weeks of therapy with anti-TCR mAb plus rapamycin (RPM) led to permanent VCA survival (>100 days).

Conclusion: Maintenance immunosuppression may not be a sine qua non of VCA management. Our studies show that peri-transplant depletional strategies have profound effects that, when coupled with brief RPM therapy, can have lead to permanent VCA survival. Such insights suggest that maintenance immunosuppression may not be absolutely essential for the management of VCA recipients, and have the potential to markedly expand indications for VCA in the clinical context.

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