Zoledronate decreases CTLA-4 in vivo and in vitro independently of its action on bone resorption

Giusti, A.; Camellino, D.; Saverino, D.; Iervasi, E.; Girasole, G.; Bianchi, G.; Papapoulos, S.E. (2020)

Article / Letter to editor

Acute phase response (APR) following intravenous zoledronate (ZOL) administration is related to activation and increased proliferation of gamma delta T cells, attributed to the molecular mechanism of action of nitrogen-containing bisphosphonates (N-BPs). ZOL, however, has also been reported to inhibit the proliferation of regulatory T cells in vitro and to reduce the expression of Cytotoxic T-Lymphocyte Antigen-4 (CTLA-4), a negative regulator of T cell activation that is increased in patients with autoimmune diseases. There are, however, no data on the relationship between ZOL treatment and soluble(s)CTLA-4 either in vivo in relevant patient populations or in vitro with the use of assays relevant to the mechanism of action of N-BPs. The objectives of the present study were firstly, to characterize the ZOL-induced APR in patients with inflammatory rheumatic diseases (IRDs) and its relationship with changes in circulating sCTLA-4 and secondly, to investigate the effects of ZOL on CTLA-4 production and expression by peripheral blood mononuclear cells (PBMCs). We studied 10 postmenopausal women with IRDs treated with intravenous ZOL 5 mg. Five women experienced APR (APR + ) associated with significant decreases in blood lymphocytes and increases in granulocytes and serum CRP. Serum sCTLA-4 values were increased in all patients before ZOL administration and decreased significantly 72 h after the ZOL infusion (from 30.0 +/- 2.9 to 6.3 +/- 1.8 ng/ml; p < 0.001) with no differences between APR + and APR- patients. Consistent with the results of the in vivo study, ZOL (1 mu M) decreased the production of sCTLA-4 by 87% and 57% after 3 and 5 days in cultures of peripheral blood mononuclear cells (PBMCs) in vitro, respectively, and inhibited the expression of both cytoplasmic and membrane-bound CTLA-4. Our results reveal a novel immunoregulatory action of ZOL that is not related to its action on bone resorption but might be associated with reported clinically significant extraskeletal outcomes of ZOL treatment.

• Acute phase response
• Bisphosphonates
• CTLA-4
• Inflammatory rheumatic diseases
• Zoledronate

• All authors: Giusti, A.; Camellino, D.; Saverino, D.; Iervasi, E.; Girasole, G.; Bianchi, G.; Papapoulos, S.E.
• Date: 2020-09-01
• Journal: BONE
• Volume: 138
• DOI: doi:10.1016/j.bone.2020.115512