Immunomodulation in Vascularized Composite Allotransplantation – Preliminary Results in a Non-Human Primate Model with Tocilizumab

Purpose

Tolerance in vascularized composite allotransplantation (VCA) remains elusive and such patients, especially children, are faced with a lifetime of immunosuppression and the associated risks of metabolic, renovascular, and neoplastic complications. Tocilizumab (anti-IL-6 receptor monoclonal antibody) is currently FDA approved for use in rheumatoid arthritis and juvenile idiopathic arthritis. It mitigates inflammatory responses, reduces the incidence of graft versus host disease (GvHD), and promotes the in vivo proliferation of regulatory T cells, which have a purported pro-tolerogenic effect. We sought to investigate the utility of a short course of tocilizumab as a potential strategy in a non-human primate model (NHP) of facial VCA to achieve prolonged survival and/or tolerance.

Methods & Materials

VCAs were transplanted into MHC mismatched NHPs (n=2) after induction therapy with anti-thymocyte globulin. Post-operative maintenance consisted of triple immunosuppression (FK506, methylprednisolone, MMF) before further conditioning (irradiation and lymphocyte depletion) in preparation for donor bone marrow transplantation (DBMT) on POD 60. Tocilizumab was administered I.V. 10 mg/kg on the day of DBMT, and at weekly intervals thereafter for a total of 5 doses. Post-DBMT, the recipient was maintained on a tapering course of I.M. cyclosporine-A with complete withdrawal after 28 days. VCA viability was assessed by serial clinical assessment and histopathology. Mixed chimerism in peripheral blood was monitored by flow cytometry and in vitro immunologic responses were measured with mixed lymphocyte reaction (MLR) assays.

Results

M6514 (full MHC-mismatched recipient) succumbed 11 days after DBMT due to a lung infection from neutropenic sepsis but the VCA remained rejection-free. M3815 (haplomatched) has been off of all immunosuppression for 5 weeks, and the VCA has remained rejection-free both clinically and histologically. MLR demonstrate decreased anti-donor responses following DBMT and evidence suggestive of mixed chimerism was detected from 6 weeks after DBMT. To date, no systemic sequelae of GvHD or post-transplant lymphoproliferative disorder (PTLD) have been observed.

Conclusions

As with the clinical experience in patients treated with tocilizumab, vigilant monitoring is required following drug administration due to increased susceptibility to infections and neutropenia. Anti-IL-6 blockade appears to promote engraftment after DBMT to allow short-medium term immunosuppression-free VCA survival across haplomatched barriers in an NHP model at the time of this report. Continued follow-up is required to determine if durable mixed chimerism and long-term transplantation tolerance of the VCA has been achieved.