Cell-based immunosuppressive therapy is very much in its infancy, but with the inception of The ONE Study, a coordinated effort to bring such treatments to clinical trial is being made; therefore, we must ask, how great are the benefits of regulatory cell therapy in transplantation expected to be? Adoptive transfer of transplant tolerance with isolated populations of regulatory cell types is reliably achieved in homologous animal models, but whether such observations can be extrapolated to patients hinges on proving the equivalence between the animal and human cells in question. Our work centers on human regulatory macrophages (M reg) as a means of attenuating responses against alloantigen. The mouse proves a convenient model to test the combined effect of M reg treatment and conventional immunosuppression, but is only clinically relevant if mouse and human M regs are functional counterparts. M regs from both species arise from equivalent populations of monocytes under directly analogous culture conditions and share many morphological features and express unique markers, distinguishing them from other macrophages. Mouse and human M regs profoundly inhibit allogeneic T cell proliferation in co-culture, through deletion and phagocytosis of activated T cells, and a direct suppressive activity. Yet, differences between mouse and human M regs exist, and weighing these differences against the likenesses is necessarily subjective, so gene expression profiling by microarray was adopted as an unbiased approach to evaluating their true similarity. In co-clustering analyses, M regs from the two species grouped together when the entire set of orthologous genes was considered, so identifying human M regs as the closest counterpart of mouse M regs.[Figure]In a mouse heart transplant model, infusion of donor-strain M regs prior to transplantation significantly prolonged allograft survival in unconditioned, non-immunosuppressed, fully-allogeneic recipients, whereas recipient and third party-derived M regs were not effective. Co-treatment with M regs and rapamycin for 10-days post-transplant enhanced the effect of M regs compared to M reg or rapamycin treatment alone. After injection, M regs from CD45.2+ B6 mice or CD45.2+ BALB/c mice were detectable in the lung, blood, liver and spleen of CD45.1+ B6 recipients for up to two weeks. Donor-derived human M regs were administered to two renal transplant recipients 7-days prior to transplantation. Both patients were minimised to low-dose tacrolimus monotherapy within 24 weeks of transplantation and subsequently maintained excellent graft function. To assess their fate after infusion, M regs were labelled with Indium111-oxine for tracking in serial whole-body SPECT studies, which showed most M regs remained viable and trafficked from the pulmonary vasculature via the blood to liver, spleen and bone marrow.
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