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 and is expressed in specific lymphoid lineages. In T cells, SAP relays activatory signals from the T-cell receptor but in its absence SH2 containing protein tyrosine phosphase-1 (SHP1), SH2 containing protein tyrosine phosphase-2 (SHP2), and SH2 containing inositol 5'-phosphatase proteins (SHIP) induce T-cell inhibitory signals leading to abnormal T-cell responses. This results in severe clinical manifestations including immune dysregulation, dysgammaglobulinemia, lymphoma, and hemophagocytic lymphohistiocytosis. Current treatment relies on supportive therapies including immunoglobulin replacement and symptom-directed therapy, with hematopoietic stem cell transplant offering the only curative option.
Objectives: As most XLP symptoms are due to defective T-cell function, this study 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 24 hours) and functional assays were performed to assess follicular T (T) cell function, CD8 cytotoxicity, and sensitivity to restimulation-induced cell death. Additionally, SAP-deficient (SAP) mice were treated with RMC-4550 before T-cell mediated challenge with 4-hydroxy-3-nitrophenylacetly conjugated chicken gammaglobulin and subsequent assessment of humoral immunity analyzing T cell population, germinal center formation, and antigen-dependent immunoglobulin secretion.
Results: This study shows that the use of RMC-4550 restores T-cell function in XLP patient cells and a SAP model, demonstrating restoration of T cell function through immunoglobulin and cytokine secretion analysis alongside rescue of cytotoxicity and restimulation-induced cell death.
Conclusions: These data suggest that SHP2 inhibitors could offer a novel and effective targeted treatment approach for patients with XLP.
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| http://dx.doi.org/10.1016/j.jaci.2022.06.021 | DOI Listing |
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