Profiling pharmacokinetics of double‐negative T cells and cytokines via a single intravenous administration in NSG mice

Abstract

This study was intended to delineate the profile of double-negative T cells (DNTs) in NOD.Cg-Prkdc scid Il2rg tm1wj /SzJ mice and cytokines released from DNTs in vivo and in vitro. Total 4 � 10 7 cells of RC1012 injection per mice were intravenously infused.IFN-γ, TNF-α, IL-1β, IL-2, IL-4, IL-6, IL-10 were measured in vivo and in vitro. A quantitative polymerase chain reaction (PCR) was employed to determine the gene copies of Notch2-NLA per DNT cell from collected organs. Cytokines were significantly increased in vitro (4 h) and in vivo (3 h). DNT cells were distributed into the lung, liver, heart, and kidney earlier, and redistributed to lymphocyte homing spleen and bone marrow, which seemed to frame a two-compartment pharmacokinetics (PK) model but more data are needed to confirm this, and the clearance of DNT cells fell into first-order kinetics.

Double-negative T cells utilize a TNFα–JAK1–ICAM-1 cytotoxic axis against acute myeloid leukemia

“…Phosphorylated STAT molecules translocate into the nucleus to upregulate inflammatory factors and cytotoxic ligands. 50 Given that DNTs secrete a wide range of inflammatory cytokines, 14 , 51 the significance of JAK-STAT signaling in DNT-AML interactions is currently being explored.…”

Enhancing Therapeutic Efficacy of Double Negative T Cells against Acute Myeloid Leukemia Using Idelalisib

“…While the above study monitored the total DNT levels in the treated patients, the level and persistence of donor-derived DNTs were not examined. Recent studies reported that ex vivo expanded human DNTs can persist for around 14-21 days in naïve mice [17,26]. However, DNT persistence in leukemiabearing hosts, which provides more clinically relevant settings, was never studied.…”

“…A number of studies highlight the importance of infused cell persistence for a favourable clinical outcome of ACT [19][20][21][22][23][24][25]. Previously, we and others have demonstrated that adoptively transferred human DNTs could persist in naïve NSG mice for 2-3 weeks [17,26]. However, DNT engraftment in a leukemia-bearing host may differ from those seen in naïve mice, as AML can hamper immune cell survival and anti-leukemic activity via immunosuppressive function or promote their function and persistence by providing stimulatory signals for T cells to proliferate [27].…”

“…Numerous studies consistently demonstrate the importance of infused cell persistence for favorable outcomes [19][20][21][22][23][24][25]. Recently, we demonstrated that ex vivo expanded human DNTs can persist in naïve immune-deficient mice for at least 14-21 days [17,26]. However, studies with a longer follow up have not been conducted.…”