| Abstract |
T-cell activation and effector function is regulated by a delicate fine-tuning of
antagonistic positive and negative signals carried out by costimulatory and
coinhibitory molecules respectively, in conjunction to the signal provided by the Tcell
receptor. Probably the most important inhibitory molecule on the surface of Tcells
is CTLA-4, a molecule structurally homologous to CD28, which binds to B7
ligands (CD80/CD86) on the surface of professional antigen-presenting cells (APCs) to
terminate T- cell responses. CTLA-4 knockout mice develop an uncontrolled
deleterious immune response and eventually succumb to a serious T-cell
lymphoproliferative disorder. The ability of CTLA-4 to block the activation of T-cells
has been therapeutically exploited for the attenuation of excessive immune system
activation in autoimmune diseases. Abatacept is a recombinant protein consisting of
the extracellular domain of human CTLA-4 fused to the Fc portion of human IgG1
(CTLA4-Ig) and was developed as a soluble CD28 antagonist. Since December 2005,
abatacept is the first FDA approved T-cell costimulation modulator for the treatment
of patients with rheumatoid arthritis.
Dendritic cells constitute a heterogeneous group of cells with multiple
subsets that are able, under different circumstances, to induce either immunity or
tolerance in the periphery. While a unique tolerogenic “signature” for DCs has not
yet been established and is not restricted to one specific DC subset, it is generally
accepted that an immature state, high net expression of co-inhibitory molecules and
production of tolerogenic enzymes, such as indoleamine 2,3 deoxygenase (IDO), are
important, though not the sole, prerequisites for a tolerogenic DC phenotype.
Although competition with CD28 for binding to CD80 and CD86 is considered
to be the major mechanism by which abatacept blocks T-cell activation, its complete
mode of action still remains to be elucidated. The aim of the present study was to
investigate the ability of abatacept to influence the tolerogenic properties of human
DCs both in healthy subjects as well as in RA settings. Specifically, we examined
whether abatacept can induce DCs with a tolerogenic phenotype by assessing the
ability of abatacept-treated DCs to block the proliferation of responder T-cells and
attempted to delineate the mechanism of this inhibition.
5
In our study, treatment of human DCs with abatacept was insufficient to halt
the proliferation of allogeneic T-cells in a mixed leukocyte reaction. Abatacept was
unable to induce either IDO upregulation inside DCs or changes in the expression of
potential tolerogenic surface markers of DCs, such as ICOS-L or PD-L1.
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The effect of abatacept on the tolerogenic potential of human dendritic cells.
