Results shown are from a total of four mice in the 314.8 only control group, five in the peripheral blood mononuclear cell (PBMC) 314.8 group, and four in the PBMC ISO group. NOD.SCID.gc-null mice (NSG). == Results == With this model, control mice invariably lost excess weight and died by day time 50. In contrast, 65% of the mice receiving a solitary injection of the anti-hICOS mAb survived beyond 100 days. Moreover, a significant improvement in survival was obtained inside a curative xeno-GVHD establishing. Mechanistically, administration of the anti-hICOS mAb was associated with a Benorylate strong reduction in perivascular infiltrates in liver and lungs and reduction in frequencies and numbers of human being T cells in the spleen. In addition, the mAb prevented T-cell expansion in the blood during xeno-GVHD. Importantly, GVHD-protected mice retained the ability to control the P815 mastocytoma cell collection, mimicking GVL in humans. == Conclusion == A mAb-targeting human ICOS alleviated GVHD without impairing GVL in a xenograft murine model. Thus, ICOS represents a encouraging target in the management of BMT, preventing GVHD while preserving GVL. Keywords:graft-vs-host disease, graft vs leukemia effect, antibodies, monoclonal, mice, NSG, ICOS, CD278 Benorylate == Introduction == Graft-vs-host disease (GVHD) is usually a major complication of allogeneic bone marrow transplantation (BMT), used to treat hematological malignancies. However, the allogeneic T-cell response is often necessary to eliminate residual malignant cells, an effect referred to as graft vs leukemia (GVL). Thus, the dilemma for efficient BMT resides around the control of a low-grade GVHD with a sufficient allogeneic response to preserve GVL (1). Targeting costimulatory molecules such as CD28 with monoclonal antibodies (mAbs) has the potential to inhibit T-cell activation and, thus, be favorable for GVHD control (2). Among other costimulatory molecules of the CD28 immunoglobulin superfamily, the Benorylate Inducible T-cell COStimulator (ICOS, CD278) has been shown to be an important mediator of T-cell proliferation and survival (36). ICOS-ligand (ICOS-L, CD275, B7-H1, or B7RP-1) is the only known ICOS partner, constitutively expressed by B cells, and can be induced on macrophages and dendritic cells (4,7). ICOS/ICOS-L conversation has been explained to play an important role in T-cell activation and function such as cytokine production (8) and antibody class Benorylate switching by B cells (9,10). Many studies have reported a crucial role for ICOS in numerous pathologies. For instance, ICOS/ICOS-L conversation is critical for T helper cell-mediated lung mucosal inflammatory responses (5) and for collagen-induced arthritis (11,12). In transplantation, inhibition of the ICOS/ICOS-L conversation also allows better allograft survival (13,14). Other studies have evaluated the efficacy of ICOS blockade in mice models of GVHD. For instance, transplantation of ICOS/T cell or anti-ICOS mAb leads to a reduced acute GVHD (15,16). However, others have found more severe GVHD when ICOS/CD8+T cells were transferred (17,18). Thus, the precise role of ICOS in murine GVHD is still controversial. Furthermore, the impact of ICOS blockade on GVL is currently unknown. To address this question in a human establishing, we used the transfer of human peripheral blood mononuclear cells (PBMC) in irradiated immunocompromised NOD.SCID.c/(NSG) mice that lacks T, B, and NK cells, as described earlier (19). Activation of human cells in this xenogeneic and lymphopenic environment then leads to GVHD symptoms, such as weight loss, infiltration of human cells in various tissues, and ultimately death. Using Rabbit Polyclonal to ARC a model of xeno-GVHD in NSG mice that we previously established (20), we assessed here whether a murine mAb to human ICOS, Benorylate previously reported as an antagonist of ICOS/ICOS-L interactionin vitro(21), would prevent GVHD while preserving GVL. == Materials and Methods == == Antibodies == The 314.8 mouse anti-human ICOS mAb was produced as ascites and purified by protein A binding and elution with the Affi-gel Protein A MAPS II Kit (Bio-rad). Mouse IgG1 isotype control (MOPC-1 clone) was purchased from Bio X Cell (West Lebanon, NH, USA). == Preparation of Human Peripheral Blood Mononuclear Cells (huPBMC) == Human peripheral blood mononuclear cells were collected by Etablissement Franais du Sang from healthy adult volunteers after informed consent in accordance with the Declaration of Helsinki and isolated on a Ficoll gradient (Biocoll). Cells were washed in PBS 3% FCS and diluted at the appropriate cell concentration in 1 PBS before injection into mice. == Mice and Xeno-GVHD Model == All animals used were NSG (NOD.SCID gamma-c/H2-Kd, H2-Db) mice (stock 005557) purchased.