Invariant Natural Killer T (iNKT) cells are a T cell subset

Invariant Natural Killer T (iNKT) cells are a T cell subset expressing an invariant T Cell Receptor (TCR) that recognizes glycolipid antigens rather than peptides. the mouse invariant TCR that by changing the Fc construct can specifically deplete or trigger iNKT cells in otherwise fully immuno-competent animals. We have used both the depleting and activating version of the antibody in the NOD model of T1Deb. As exhibited previously using genetically iNKT cell deficient NOD mice, and in studies of glycolipid antigen activated iNKT cells in standard NOD mice, we found that antibody mediated depletion or activation of iNKT cells respectively BRL-49653 accelerated and retarded T1Deb onset. In BALB/c mice, ovalbumin (OVA) mediated BRL-49653 air passage hyper-reactivity (AHR) was abrogated with iNKT cell depletion prior to OVA sensitization, confirming studies in knockout mice. Depletion of iNKT cells after sensitization had no effect on AHR in the conducting airways but did reduce AHR in the lung periphery. This result raises caution in the meaning of studies that use animals that are genetically iNKT cell deficient from birth. These activating and depleting antibodies provide a novel tool to assess the therapeutic potential of iNKT cell manipulation. Introduction Invariant Natural Killer T (iNKT) cells have an invariant T Cell receptor (TCR), that in contrast to conventional T cells recognize glycolipid antigens that are presented on the MHC I like molecule CD1deb. iNKT cells share surface markers and functional characteristics with both conventional T cells and natural killer (NK) cells [1,2]. iNKT cells represent a very small subset of the total T cell populace in human and non-human peripheral blood. In humans, their abundancy ranges from less than 0.01% of all T cells to higher than 1.0%, with the majority of individuals clustering at the lower end of the range. In inbred mice iNKT cells are still a rare populace but in the higher range of 0.5%-2% with very little within-strain animal to animal variation [3]. Despite their low frequency iNKT cells have potent immune-regulatory functions as they are constitutively conveying high levels of a wide variety pro-inflammatory as well as immune-regulatory cytokines and chemokines that are rapidly released upon iTCR engagement [2]. While iNKT cell activity has been implicated in the pathogenesis of asthma and inflammatory diseases such as sickle cell BRL-49653 disease (SCD) [4,5,6,7,8,9,10], the pharmacologic activation of iNKT cells using glycolipid superagonist alpha-Galactosyl-ceramide (GalCer) has shown them to be protective in the NOD mouse model of autoimmune Type 1 diabetes (T1Deb) [11,12]. The absence or functional defects in iNKT cell Rabbit Polyclonal to PLCB3 (phospho-Ser1105) function has been exhibited to lead to accelerated T1Deb onset in NOD mice [13,14], while iNKT cell activation has also been shown to boost anti-tumor immunity [15,16]. Therapeutic means to reduce or deplete iNKT cells could treat inflammatory diseases, while approaches to promote their activation may have therapeutic potential in certain infectious diseases, cancer or autoimmunity. NKT Therapeutics, Inc has developed an anti-human invariant TCR antibody that can deplete iNKT cells [17] that is usually currently in a Phase 1 trial in patients with SCD. To better understand the role of iNKT cells in preclinical models of disease we recently developed anti-mouse invariant TCR specific monoclonal antibodies. We report here that by changing their Fc-portion these represent the first identified antibodies with a capacity to either deplete (NKT14) or activate (NKT14m) iNKT cells in otherwise fully immuno-competent mice. To validate the function of the antibodies tested their efficacy in the NOD model of T1Deb and in a mouse model of allergic air passage inflammation and air passage hyperresponsiveness (AHR) [5] a model of allergic asthma [7]. Results Leveraging EUREKA Therapeutics proprietary human phage display library we identified a mouse invariant TCR specific antibody clone. Full length antibodies were made by cloning them in frame with either murine wild type IgG2a Fc to obtain a depleting antibody (NKT14) or an IgG2a with 4 point.

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