Impacts of TCR-Nck Interaction Inhibitors on T Cell Activation Driven By Mixed Lymphocyte Reactions

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Hematopoietic stem cell transplantation (HSCT) using allogeneic donors is associated with a high risk of graft- versus-host disease (GvHD). GvHD is a systemic disorder that usually involves the skin, gastrointestinal track, liver, kidneys, eyes and also the hematopoietic system leading to severe morbidity and mortality. The major cause of GvHD is the activation of T cells of the donor by mismatched HLA class I and II haplotypes present in the tissues of the acceptor. The T cell antigen receptor (TCR) of the donor’s T cells binds mismatched HLA and becomes activated leading to T cell activation and differentiation into effector T cells that promote tissue attack. TCR triggering involves the recruitment of the adapter protein Nck among other cytoplasmic effector proteins. The TCR-Nck interaction is an amplifier of TCR-peptide/MHC (TCR-pMHC) interactions.

Here we show that an oral, clinical-stage second generation Nck inhibitor (AX-158) potently modulates the activation of human T cells in Mixed Lymphocyte Reactions (MLR) in vitro, suggesting that disruption of the TCR-Nck interaction is modulatory for T cell responses driven by allogeneic stimuli. Specifically, AX-158 lowered cytokine production upon MLR (Interferon gamma, TNF alpha, IL-2). MLR driven proliferative responses were not significantly impacted, suggesting that Nck inhibition leads to less activated T Cell populations to drive potential benefit. By modulating T Cell activation in response to allogeneic stimuli while sparing responses to strong foreign antigens, Nck inhibitors offer the promise of potentially treating GVHD without strong immunosuppression.