Arthritis & Rheumatism, Volume 60,
October 2009 Abstract Supplement
The 2009 ACR/ARHP Annual Scientific Meeting
Philadelphia October 16-21, 2009.
Depletion of Inducible Co-Stimulator (ICOS) Bearing T Cells Inhibits Expansion of T Follicular Helper Cells (TFH) and Prevents Disease in a Graft Versus Host Mouse Model of Scleroderma
Carlesso1, Gianluca, Lemaire1, Raphael, Taylor1, Devon, Mittereder1, Nanette, Kuta1, Ellen, Burwell1, Timothy, Delaney1, Tracy
Human cluster of differentiation antigen 278, also called inducible T-cell co-stimulator (ICOS) is a T cell-specific surface antigen selectively expressed by recently activated, memory, and T follicular helper (Tfh) T cells. In this study, the function of ICOS in the pathogenesis of a graft-versus-host disease (GvHD) mouse model of scleroderma (SSc) was investigated using a glycoengineered anti-mouse ICOS MAb with enhanced antibody-dependent cellular cytotoxicity (ADCC).
We have generated a glyco-engineered rat anti-ICOS monoclonal antibody (MAb) directed against the ligand binding domain of murine ICOS as mouse IgG2a. The antibody was produced in a fucosyltransferase 8-deficient Chinese Hamster Ovary (CHO) producer cell line (BioWa Potelligent® Technology), a procedure that generates a homogenously afucosylated antibody (anti-ICOS-aFuc) with enhanced ADCC. The activity of the afucosylated anti-mouse ICOS MAb, was evaluated in a murine GvHD model, which recapitulates key aspects of human SSc, including inflammation, fibrosis, and vasculopathy.
Dosing of the anti-ICOS-aFuc MAb reduced severity and incidence of dermal lesions when compared to isotype control MAb and control syngeneic graft. Mean clinical scores were significantly reduced in anti-ICOS-treated groups compared to isotype control MAb-treated mice, as early as 12 days post-graft (3.4-fold, p<0.002), and thereafter up to 4 weeks post graft (8.1-fold, p<0.0001). The anti-ICOS-aFuc MAb also prevented the disease-associated accumulation of TFHcells and the associated expansion of germinal center B cells and immunoglobulin secreting B cells. There were no ICOS MAb-related clinical signs or changes in body weight in animals during the study.
The results from this study indicate that ICOS plays an important role in dermal pathology of murine GvHD-SSc, as depletion of ICOS+ T cells reduced the overall clinical disease score. The identification of dysregulated ICOS+ TFH cells in GvHD-SSc underscore their critical function in driving the generation of pathogenic B cells into germinal center B cells in secondary lymphoid tissues and in the differentiation of immunoglobulin secreting B cells in the skin. Importantly, treatment with the anti-mouse ICOS-aFuc MAb resulted in a significant reduction of the clinical signs of disease and represents an innovative therapeutic strategy for the treatment of T helper associated autoimmune GvHD-SSc.
To cite this abstract, please use the following information:
Carlesso, Gianluca, Lemaire, Raphael, Taylor, Devon, Mittereder, Nanette, Kuta, Ellen, Burwell, Timothy, et al; Depletion of Inducible Co-Stimulator (ICOS) Bearing T Cells Inhibits Expansion of T Follicular Helper Cells (TFH) and Prevents Disease in a Graft Versus Host Mouse Model of Scleroderma [abstract]. Arthritis Rheum 2009;60 Suppl 10 :1065