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Abatacept (CTLA4-Ig) modulates human T-cell proliferation and cytokine production but does not affect lipopolysaccharide-induced tumor necrosis factor alpha production by monocytes

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Background and objectives

Activated T cells play a central role in the inflammatory cascade leading to the joint inflammation and destruction characteristic of rheumatoid arthritis (RA). The cytokines secreted by activated T cells are thought to both initiate and propagate the immunologically driven inflammation associated with RA.

Abatacept, the first of a new class of agents for the treatment of RA that selectively modulates the co-stimulatory signal required for full T-cell activation, was evaluated for its ability to regulate human T-cell proliferation and cytokine production in vitro. The effect of abatacept on lipopolysaccharide (LPS)-induced tumor necrosis factor alpha (TNF-α) from monocytes was evaluated to distinguish the impact of this agent on innate versus adaptive, antigen-specific immune responses.


T cells were isolated from normal healthy human volunteers. The effect of abatacept on antigen-dependent T-cell activation was evaluated using either an irradiated human B-cell line (PM-LCL) as the antigen-presenting cells (APCs) for a primary mixed lymphocyte reaction (MLR), or autologous E-PBMCs as APCs for a recall response to tetanus toxin (TT). Cytokines were measured at various times post activation, with proliferation determined on day 5. Monocytes were isolated by elutriation, challenged with LPS and TNF-α levels measured at 6 hours. Chi L6 was included as a non-specific fusion protein control.


Abatacept significantly downmodulated T-cell proliferation, in both primary and recall responses, at concentrations between 0.3 and 100 μg/ml, with maximal inhibition (~60–80%) observed at ~3–10 μg/ml. These concentrations are below the abatacept trough plasma levels observed in patients receiving a clinically effective dose [1]. Under conditions of maximal inhibition of proliferation, and similar to trough plasma levels in patients (30 μg/ml), abatacept also inhibited IL-2, TNF-α and interferon gamma secretion in both primary and TT-dependent recall responses. However, the extent, kinetics and rank order of cytokine inhibition by abatacept was somewhat different between primary and recall responses. In contrast, abatacept did not inhibit LPS-induced TNF-α production in primary human monocytes, demonstrating that its action is restricted to antigen-dependent T-cell responses.


Abatacept, a selective co-stimulation modulator, significantly inhibited the activation (as measured by cytokine production) and proliferation of human T cells in the context of a primary MLR or TT-dependent memory response. This inhibition occurred at concentrations below the serum Cmin levels observed in patients receiving a clinically effective dose of abatacept [1] (10 mg/kg monthly), consistent with suppression of T-cell activation in vivo. There was no effect of abatacept on LPS-stimulated TNF-α production in monocytes indicating that this agent may largely preserve innate immune responses.


  1. 1.

    Kremer JM, Westhovens R, Leon M, Di Giorgio E, Alten R, Steinfeld S, Russell A, Dougados M, Emery P, Nuamah IF, et al: Treatment of rheumatoid arthritis by selective inhibition of T-cell activation with fusion protein CTLA4Ig. N Engl J Med. 2003, 349: 1907-1915. 10.1056/NEJMoa035075.

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  • Abatacept
  • Mixed Lymphocyte Reaction
  • Recall Response
  • Primary Human Monocyte
  • Trough Plasma Level