Arthritis & Rheumatism, Volume 63,
November 2011 Abstract Supplement
Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Chicago, Illinois November 4-9, 2011.
Abatacept (CTLA-4Ig) Treatment Reduces Activation Induced Cell Death (AICD) and Susceptibility of T Cells to Regulatory T Cell Suppression in Patients with Rheumatoid Arthritis (RA).
Bonelli1, Michael, Goeschl1, Lisa, Blueml1, Stefan, Hladik1, Anastasiya, Puujalka1, Emmi, Steiner1, Carl-Walter, Smolen2, Josef
Abatacept (CTLA-4Ig) inhibits the binding of CD28 to the B7 ligands CD80/CD86 on antigen presenting cells (APC) and thereby effector T cell activation. Besides APC, costimulatory molecules can also be expressed on T cells upon activation. Whether this allows CTLA-4Ig to directly affect distinct T cell subsets, exerting a positive or negative effect, remains unclear.
We therefore performed phenotypic and functional analysis of T cells in RA patients before and after the initiation of CTLA-4Ig therapy.
Peripheral blood mononuclear cells (PBMC) were collected from RA patients (n=15) before and 2 and 4 weeks after the initiation of CTLA-4Ig therapy. Proportions of naïve and memory CD4+ T cells and CD4+CD25+Foxp3+ regulatory T cells (Treg) were determined by flow cytometry (FACS). In addition T cells were analyzed for the expression of marker molecules characteristic for activated T cells and Treg. PBMCs from healthy controls (HC) were pre-incubated with different doses of CTLA-4Ig before T cell receptor (TCR) stimulation and analyzed by FACS. Moreover apoptosis was induced in CTLA-4Ig incubated cells by anti-Fas antibody and DNA fragmentation was measured by TUNEL staining. Finally CD4+CD25+ Treg were isolated from RA patients by cell sorting and analyzed for their functional capacity. In addition suppression assays were performed with Treg and responder T cells from HC after pre-incubation of individual cell populations with CTLA-4Ig.
Proportions of CD4+ T cells and Treg substantially increased 2 and 4 weeks after the initiation of CTLA-4Ig treatment. No differences were observed for the percentage of memory and naïve CD4+ T cells. Phenotypic analyses revealed a downregulation of activation associated marker molecules and of CD95 on CD4+ T cells and Treg. Likewise, pre-incubation of PBMCs from HC with CTLA-4Ig before stimulation led to a dose dependent downregulation of activation markers on CD4+ cells and Treg. Moreover in vitro analyses of CD4+ T cells and Treg from HC showed a dose dependent decrease in AICD after incubation with CTLA-4Ig. Functional analysis of isolated Treg from RA patients revealed a diminished suppressive capacity of Treg 4 weeks after treatment with CTLA-4Ig. However, only the pre-incuabtion of responder T cells, but not of Treg, from HC resulted in a decreased T cell suppression.
Within our study we were able to demonstrate for the first time a direct effect of CTLA-4Ig on T cells in RA patients, which results in increased proportions of CD4+ and Treg, the downregulation of CD95 and a decrease in AICD. Blockade of costimulatory molecules on T cells by CTLA-4Ig leads to a diminished susceptibility of T cells for Treg suppression which might be counter balanced by increased Treg numbers.
To cite this abstract, please use the following information:
Bonelli, Michael, Goeschl, Lisa, Blueml, Stefan, Hladik, Anastasiya, Puujalka, Emmi, Steiner, Carl-Walter, et al; Abatacept (CTLA-4Ig) Treatment Reduces Activation Induced Cell Death (AICD) and Susceptibility of T Cells to Regulatory T Cell Suppression in Patients with Rheumatoid Arthritis (RA). [abstract]. Arthritis Rheum 2011;63 Suppl 10 :2359