Cutting Edge: Immunological Consequences and Trafficking of Human Regulatory Macrophages Administered to Renal Transplant Recipients

Abstract

Regulatory macrophages (M regs) were administered to two living-donor renal transplant recipients. Both patients were minimized to low-dose tacrolimus monotherapy within 24 wk of transplantation and subsequently maintained excellent graft function. After central venous administration, most M regs remained viable and were seen to traffic from the pulmonary vasculature via the blood to liver, spleen, and bone marrow. By 1 y posttransplantation, both patients displayed patterns of peripheral blood gene expression converging upon the IOT-RISET signature. Furthermore, both patients maintained levels of peripheral blood FOXP3 and TOAG-1 mRNA expression within the range consistent with nonrejection. It is concluded that M regs warrant further study as a potential immune-conditioning therapy for use in solid-organ transplantation. The results of this work are being used to inform the design of The ONE Study, a multinational clinical trial of immunomodulatory cell therapy in renal transplantation.

A Novel Regulatory Macrophage Induced by a Helminth Molecule Instructs IL-10 in CD4+ T Cells and Protects against Mucosal Inflammation

“…Also, human IFN-g induced Mregs are capable of suppressing T cell proliferation and eliminating activated T cells in in vitro cocultures, but do so in an IDO-dependent manner (26). Another study by Brem-Exner et al (18) showed that IFN-g-induced murine macrophages support Foxp3 + Treg enrichment in cocultures with T cells.…”

“…Experimentally, macrophages have been evaluated as good candidates for cell-based therapeutic intervention not only for atopic and autoimmune diseases, but also for the treatment of kidney diseases (18)(19)(20)(21)(22)(23)(24). Furthermore, regulatory macrophages have been successfully applied to human transplantation patients in first clinical trials to interfere with overt immune responses (25,26) and are discussed as a future therapy in solid-organ transplantation and beyond (27).…”

Laser Ablation–Inductively Coupled Plasma Mass Spectrometry: An Emerging Technology for Detecting Rare Cells in Tissue Sections

“…Cell surface staining was performed at 4˚C in DPBS/1% BSA/0.02% NaN 3 / 10% FcR-block (Miltenyi Biotec), as described elsewhere (13). Dead cells were excluded with 7-aminoactinomycin D (BD Biosciences, Heidelberg, Germany).…”

“…Typically, pharmacokinetic studies in humans are performed as part of the early clinical pharmaceutical development process; however, in the case of Mregs, and cell-based medicinal products in general, adequate methods for reliably detecting infused cells in tissues over days or weeks after transfer are not available (17). In a previous study, we used single-photon emission computed tomography to track 111 In oxine-labeled allogeneic human Mregs in one patient: Mregs given by central venous infusion were first concentrated in the pulmonary vasculature but by 3 h postinfusion had migrated to the liver, spleen, and hematopoietically active bone marrow via the blood (13). Although this radiological tracing study provided valuable information, it tells us very little about the precise distribution of Mregs within tissues, and, owing to the short half-life of 111 In, the survival and fate of Mregs after 30 h postinfusion could not be characterized.…”

“…One particularly promising candidate cell type for use as an adjunct immunosuppressive agent in transplantation is the regulatory macrophage (Mreg) (12). The Mreg reflects a unique state of macrophage differentiation, distinguished from macrophages in other activation states by its mode of derivation, robust phenotype, and potent T cell suppressor function (13). Mregs potently suppress mitogen-stimulated T cell proliferation in vitro, which can be attributed to IFN-g-induced IDO activity, as well as contactdependent deletion of activated T cells.…”