RESUMEN
OBJECTIVES: This study aims to evaluate the safety and efficacy of BCMA-CD19 compound chimeric antigen receptor T cells (cCAR) to dual reset the humoral and B cell immune system in patients with systemic lupus erythematosus (SLE) with lupus nephritis (LN). METHODS: This is a single-arm open-label multicentre phase 1 study of BCMA and CD19-directed cCAR in patients suffering from SLE/LN with autoantibodies produced by B cells and plasma/long-lived plasma cells. In this clinical trial, we sequentially assigned biopsy-confirmed (classes III-V) LN patients to receive 3×106 cCAR cells/kg postcessation of all SLE medications and conditioning. The primary endpoint of safety and toxicity was assessed. Complete immune reset was indicated by B cell receptor (BCR) deep sequencing and flow cytometry analysis. Patient 11 (P11) had insufficient lymphocyte counts and was underdosed as compassionate use. RESULTS: P1 and P2 achieved symptom and medication-free remission (MFR) from SLE and complete remission from lymphoma. P3-P13 (excluding P11) received an initial dose of 3×106 cCAR cells /kg and were negative for all autoantibodies, including those derived from long-lived plasma cells, 3 months post-cCAR and the complement returned to normal levels. These patients achieved symptom and MFR with post-cCAR follow-up to 46 months. Complete recovery of B cells was seen in 2-6 months post-cCAR. Mean SLE Disease Activity Index 2000 reduced from 10.6 (baseline) to 2.7 (3 months), and renal function significantly improved in 10 LN patients ≤90 days post-cCAR. cCAR T therapy was well tolerant with mild cytokine-release syndrome. CONCLUSIONS: Data suggest that cCAR therapy was safe and effective in inducing MFR and depleting disease-causing autoantibodies in patients with SLE.
RESUMEN
Hypoxia is one of the most common physiological stressors in shrimp farming. Post-transcriptional regulation by microRNAs has been recognized as a ubiquitous strategy to enable transient phenotypic plasticity and adaptation to stressful environment, but involvement of microRNAs in hypoxia stress response of penaeid shrimp remains elusive. In this study, small RNA sequencing and comparative transcriptomic analysis was conducted to construct a comprehensive microRNA dataset for the whiteleg shrimp Litopenaeus vannamei exposed to hypoxia challenge. A total of 3324 known miRNAs and 8 putative novel miRNAs were identified, providing a valuable resource for future investigation on the functional mechanism of miRNAs in shrimp. Upon hypoxia, 1213 miRNAs showed significant differential expression, and many well-known miRNAs involved in hypoxia tolerance such as miR-210, let-7, miR-143 and miR-101 were identified. Remarkably, the vast majority of these miRNAs were up-regulated, suggesting that up-regulation of miRNAs may represent an effective strategy to inhibit protein translation under stressful hypoxic condition. The differentially expressed miRNAs were potentially targeting a wide variety of genes, including those with essential roles in hypoxia tolerance such as HIF1a and p53. GO and KEGG enrichment analysis further revealed that a broad range of biological processes and metabolic pathways were over-represented. Several GO terms associated with gene transcription and translation and KEGG pathways related to cytoskeleton remodeling, immune defense and signaling transduction were enriched, highlighting the crucial roles of these cellular events in the adaptation to hypoxia. Taken together, our study revealed that the differentially expressed miRNAs may regulate host response to hypoxia by modulating the expression of stress response genes such as HIF1a and p53 and affecting key cellular events involved in hypoxia adaptation. The findings would expand our knowledge of the biochemical and molecular underpinnings of hypoxia response strategies used by penaeid shrimp, and contribute to a better understanding of the molecular mechanisms of hypoxia tolerance in decapod crustaceans.
