Background
Tocilizumab (anti-IL-6 receptor mAb) is currently FDA approved for use in idiopathic and rheumatoid arthritis. It mitigates inflammation, reduces the incidence of GvHD, and promotes regulatory T-cell proliferation We investigated its utility in a non-human primate model (NHP) of facial VCA to achieve prolonged survival and/or tolerance in reconstructive transplantation.
Methods
Facial allografts were transplanted into MHC-mismatched NHPs (n = 4) after ATGAM induction, maintained post-operatively with FK506, MMF and methylprednisolone, before further conditioning (irradiation, lymphocyte depletion) in preparation for donor bone marrow transplantation (DBMT) on POD 60 Tocilizumab was administered on the day of DBMT, and at weekly intervals thereafter for a total of 5 doses Post-DBMT, recipients received a tapering course of cyclosporine-A with complete withdrawal 28 d later VCA was assessed by serial clinical examination and histopathology; chimerism was monitored by flow cytometry and in vitro immunologic responses were measured with CFSE mixed lymphocyte reaction (MLR) assays.
Results
Prior to DBMT, up to 2 episodes of acute skin rejection (AR) developed and required additional steroid bolus treatment Two recipients had to be euthanized within 2 weeks post-DBMT due to lung infection from neutropenic sepsis and disseminated post-transplant lymphoproliferative disorder (PTLD) respectively but VCAs remained AR-free up to experimental end point Of the remaining 2 recipients, one has just been withdrawn from immunosuppression while the other was off for 36 d before AR developed No evidence of mixed chimerism was detected but in vitro assays demonstrate decreased anti-donor responses after DBMT, which remains up to this time To date, no systemic sequelae of GvHD or PTLD have been observed at up to POD 205.
Conclusions
As with the clinical experience in patients treated with tocilizumab, vigilant monitoring is required following drug administration due to increased susceptibility to infection and neutropenia Anti-IL-6 blockade appears to promote short-medium term immunosuppression-free VCA survival in this NHP model Continued follow-up is required to determine if long-term transplantation tolerance of the VCA has been achieved Of particular clinical concern is the development of PTLD following tolerance induction Further investigations are underway to optimize and develop a safe VCA tolerance protocol for clinical application.