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Allosteric Inhibition of SHP2 rescues functional T-cell abnormalities in SAP deficiency



Panchal, Neelam;

Houghton, Benjamin Christopher;

Vassalou, Elina;

Thrasher, Adrian J;

Booth, Claire;

(2022)

Allosteric Inhibition of SHP2 rescues functional T-cell abnormalities in SAP deficiency.

Journal of Allergy and Clinical Immunology


10.1016/j.jaci.2022.06.021.

(In press).


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Abstract

BACKGROUND: X-linked lymphoproliferative disease (XLP) is a primary immunodeficiency arising from SH2D1A mutations leading to loss of SLAM-associated protein (SAP). SAP is an intracellular adaptor protein that binds to SLAM family receptors (SFR) and is expressed in specific lymphoid lineages. In T-cells, SAP relays activatory signals from the T-cell receptor but in its absence SHP1, SHP2 and SHIP proteins induce T-cell inhibitory signals leading to abnormal T-cell responses. This results severe clinical manifestations including immune dysregulation, dysgammaglobulinaemia, lymphoma and haemophagocytic lymphohistiocytosis (HLH). Current treatment relies on supportive therapies including immunoglobulin replacement and symptom directed therapy, with haematopoietic stem cell transplant (HSCT) offering the only curative option. OBJECTIVES: As most XLP symptoms are due to defective T-cell function, we investigated whether inhibition of SHP2 can restore cellular function in the absence of SAP. METHODS: Healthy donor and XLP patient T-cells were activated with anti-CD3/CD28 in T-cell media supplemented with a SHP2 inhibitor (RMC-4550 in vitro for 24h) and functional assays performed to assess T follicular helper cells (TFH) function, CD8 cytotoxicity and sensitivity to restimulation induced cell death (RICD). Additionally, SAP deficient (SAPy/-) mice were treated with RMC-4550 before T-cell mediated challenge with NP-CGG and subsequent assessment of humoral immunity analysing TFH cell population, germinal centre formation and antigen dependent immunoglobulin secretion. RESULTS: We show that the use of RMC-4550 restores T-cell function in XLP patient cells and a SAPy/- model, demonstrating restoration of TFH cell function through immunoglobulin and cytokine secretion analysis alongside rescue of cytotoxicity and RICD. CONCLUSIONS: These data suggest that SHP2 inhibitors could offer a novel and effective targeted treatment approach for XLP patients.

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