Adoptive Treg Cell Therapy in a Patient With Systemic Lupus Erythematosus

Abstract

Objective Adoptive Treg cell therapy has great potential to treat autoimmune disease. Currently, very little is known about how these cells impact inflamed tissues. This study was undertaken to elucidate how autologous Treg cell therapy influences tissue inflammation in human autoimmune disease. Methods We describe a systemic lupus erythematosus (SLE) patient with active skin disease who received adoptive Treg therapy. We comprehensively quantified Treg cells and immune activation in peripheral blood and skin, with data obtained at multiple time points posttreatment. Results Deuterium tracking of infused Treg cells revealed the transient presence of cells in peripheral blood, accompanied by increased percentages of highly activated Treg cells in diseased skin. Flow cytometric analysis and whole transcriptome RNA sequencing revealed that Treg cell accumulation in skin was associated with a marked attenuation of the interferon‐γ pathway and a reciprocal augmentation of the interleukin‐17 (IL‐17) pathway. This phenomenon was more pronounced in skin relative to peripheral blood. To validate these findings, we investigated Treg cell adoptive transfer of skin inflammation in a murine model and found that it also resulted in a pronounced skewing away from Th1 immunity and toward IL‐17 production. Conclusion We report the first case of a patient with SLE treated with autologous adoptive Treg cell therapy. Taken together, our results suggest that this treatment leads to increased activated Treg cells in inflamed skin, with a dynamic shift from Th1 to Th17 responses.

Methods to manufacture regulatory T cells for cell therapy

“…By comparison, autologous T regs have been detected in circulation for up to 1 year post‐transfer using mass spectrometry. However, similar to findings with allogeneic cells, using a flow cytometry‐based read‐out the percentage of T regs in circulation peaked 7–14 days post‐transfer and fell near the detection limit within 3 months. Thus, more work is required to understand why the majority of infused T regs seem to disappear from the circulation in these different contexts.…”

“…For example, groups using magnetic selection to isolate T regs from peripheral blood deplete CD8 + cells , whereas groups isolating T regs from UCB do not . Groups with access to flow cytometric sorting capability typically include additional markers such as positive selection for CD45RA or negative selection for CD127 . Inclusion of CD45RA or CD127 in the selection strategy increases the purity of the resulting cells compared to those isolated using magnetic selection, as these markers remove most of the CD25 + activated T cells that are primarily CD45RO + CD45RA – and CD127 pos .…”

“…T reg therapy is based on the idea that administering a relatively large proportion of T regs will shift the balance of immunoregulatory versus immune effector cells to favor tolerance induction. Early clinical studies with T regs have shown that this therapy is safe in the context of both transplantation and autoimmunity . Many additional trials are under way with the results of the first randomized studies with control arms (e.g.…”

Reduced Let-7f in Bone Marrow-Derived Mesenchymal Stem Cells Triggers Treg/Th17 Imbalance in Patients With Systemic Lupus Erythematosus

“…However, terminally differentiated cells fulfill opposite functions: Th17 cells cause autoimmunity and inflammation, whereas Treg cells inhibit these phenomena and maintain immune homeostasis (1,2). Emerging studies about patients and experimental models have determined the imbalance between Th17 and Treg cells as well as the related cytokines in the serum, including IL-6, IL-1b, and IL-23, and signal transducer, participated in the onset and progression of autoimmune diseases including SLE (3,27), immune therapy could restore Treg/Th17 imbalance and thus ameliorate SLE and RA (4,8,(28)(29)(30). Considering of the important immune regulatory effect of stem cells on Treg/Th17 (8,15,31), the imbalance between Treg and Th17 cells might be associated with SLE BM-MSC dysfunction.…”

A unique thymus-derived regulatory T cell subset associated with systemic lupus erythematosus

“…A recent study evaluating the efficacy of low-dose IL-2 treatment in patients with SLE found an increase in the number of Treg cells and suppression of follicular helper T cells and Th17 cell numbers in peripheral blood, accompanied by a marked reduction in disease activity [66]. A recent intriguing report described the first case of a patient with SLE treated with autologous adoptive Treg cell therapy, which led to increased activated Treg cells in the inflamed skin, with a marked attenuation of the IFN-γ pathway and a reciprocal augmentation of the IL-17 pathway [67]. This phenomenon was more pronounced in skin than in peripheral blood and was validated in a mouse model undergoing Treg cell adoptive transfer.…”