Treatment of Systemic Lupus Erythematosus using BCMA-CD19 Compound CAR.
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ABSTRACT:
SUBMITTER: Zhang W
PROVIDER: S-EPMC8599262 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Dysregulated B-cell activation plays pivotal roles in systemic lupus erythematosus (SLE), which makes B-cell depletion a potential strategy for SLE treatment. The clinical success of anti-CD19 CAR-T cells in treating B-cell malignancies has attracted the attention of researchers. In this study, we aimed to investigate the feasibility of applying anti-CD19 CAR-T cell therapy to SLE treatment in a mouse disease model. We constructed murine anti-CD19 CARs with either CD28 or 4-1BB as the intracellular costimulatory motif and evaluated the therapeutic function of the corresponding CAR-T cells by infusing them into MRL-lpr mice. Furthermore, anti-CD19 CAR-T cells were transferred to MRL-lpr mice before the onset of disease to determine their role in SLE prevention. According to our observations, compared with antibody treatment, the adoptive transfer of our anti-CD19 CAR-T cells showed a more sustained B-cell-depletion effect in MRL-lpr mice. The transfer of syngeneic anti-CD19 CAR-T cells not only prevented disease pathogenesis before the onset of disease symptoms but also displayed therapeutic benefits at a later stage after disease progression. We also tried to optimize the treatment strategy and found that compared with CAR-T cells with the CD28 costimulatory motif, CAR-T cells with the 4-1BB costimulatory motif showed better therapeutic efficiency without cell enrichment. Taken together, these results show that anti-CD19 CAR-T cell therapy was effective in the prevention and treatment of a murine model of SLE, indicating its potential for clinical use in patients.
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Project description:B cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL) play central roles in B cell development and maturation. Soluble forms of their receptors can be generated by proteolytic cleavage; however, their physiological and clinical roles are unknown. This study aimed to assess the relationships between the receptor soluble B cell maturation antigen (sBCMA) and clinical variables in systemic lupus erythematosus (SLE) patients. Serum cytokine concentrations were measured by ELISA for 129 SLE patients and 34 healthy controls (HCs), and the expression of the receptor BCMA was evaluated on B and plasma cells from 40 subjects. SLE patients showed aberrant expression of the receptor BCMA on B and plasma cells. Soluble levels of the receptor sBCMA and its ligands sAPRIL and sBAFF were increased in SLE patients compared with HCs. Additionally, sBCMA (rs?=?0.6177) and sAPRIL (rs?=?0.4952) correlated strongly with disease activity. Active SLE patients who achieved low disease activity showed decreased sBCMA (53.30 vs 35.30?ng/mL; p?<?0.05) and sBAFF (4.48 vs 2.27?ng/mL; p?<?0.05) serum levels after treatment, while sAPRIL expression remained unchanged. At a cutoff value of 22.40?ng/mL, sAPRIL showed high sensitivity (96.12%) and specificity (94.12%) for discrimination between HCs and SLE patients, while sBAFF showed lower sensitivity (82.2%) but higher specificity (94.1%) at a cutoff of 1.195?ng/mL. Relatively high levels of sAPRIL and sBCMA clustered active SLE patients. The receptor sBCMA could be a potential biomarker of disease activity in SLE.
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Project description:Systemic lupus erythematosus is a prototypic autoimmune disease characterized by abnormalities in the activity of B-cells and T-cells. A novel specific treatment for autoimmune diseases is B-cell depletion with monoclonal antibodies. Epratuzumab is a monoclonal antibody that targets CD22 antigen on B-cells. Initial phase II and two terminated early phase III studies suggest that treatment of systemic lupus erythematosus with this immunomodulatory agent is effective, well tolerated and significantly improves the patient's quality of life. In vitro studies and clinical trials with non-Hodgkin lymphoma patients indicate epratuzumab can potentially serve as a complementary drug in combination therapy with another inhibitor of B-cell activity, rituximab, which is a monoclonal anti-CD20 antibody.
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Project description:Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with a broad spectrum of clinical presentations that can affect almost all organ systems. Lupus nephritis (LN) is a severe complication that affects approximately half of the systemic erythematosus lupus (SLE) patients, which significantly increases the morbidity and the mortality risk. LN is characterized by the accumulation of immune complexes, ultimately leading to renal failure. Aberrant activation of T cells plays a critical role in the pathogenesis of both SLE and LN and is involved in the production of inflammatory cytokines, the recruitment of inflammatory cells to the affected tissues and the co-stimulation of B cells. Calcineurin is a serine-threonine phosphatase that, as a consequence of the T cell hyperactivation, induces the production of inflammatory mediators. Moreover, calcineurin is also involved in the alterations of the podocyte phenotype, which contribute to proteinuria and kidney damage observed in LN patients. Therefore, calcineurin inhibitors have been postulated as a potential treatment strategy in LN, since they reduce T cell activation and promote podocyte cytoskeleton stabilization, both being key aspects in the development of LN. Here, we review the role of calcineurin in SLE and the latest findings about calcineurin inhibitors and their mechanisms of action in the treatment of LN.
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Project description:Systemic lupus erythematosus (SLE) is a multifactorial autoimmune disorder. The study of diverse mouse models of lupus has provided clues to the etiology of SLE. Spontaneous mouse models of lupus have led to identification of numerous susceptibility loci from which several candidate genes have emerged. Meanwhile, induced models of lupus have provided insight into the role of environmental factors in lupus pathogenesis as well as provided a better understanding of cellular mechanisms involved in the onset and progression of disease. The SLE-like phenotypes present in these models have also served to screen numerous potential SLE therapies. Due to the complex nature of SLE, it is necessary to understand the effect specific targeted therapies have on immune homeostasis. Furthermore, knowledge gained from mouse models will provide novel therapy targets for the treatment of SLE.
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