In this study, we test the therapeutic effects of rapamycin in a murine model of SLE-like experimental lupus nephritis induced by chronic graft-versus-host disease (cGVHD). Our results suggest that rapamycin treatment reduced autoantibody production, inhibited T lymphocyte and subsequent B cell activation, and reduced inflammatory cytokine and chemokine production, thereby protecting renal function and alleviating histological lupus nephritis by reducing the occurrence of albuminuria. To explore the potential mechanism of rapamycin’s reduction of kidney damage in mice with lupus nephritis, a series of functional assays were conducted. As expected, rapamycin remarkably inhibited the lymphocytes’ proliferation within the morbid mice. Interestingly, significantly increased proportions of peripheral CD4+FOXP3+ and CD4+CD25high T cells were observed in rapamycin-treated group animals, suggesting an up-regulation of regulatory T cells (Tregs) in the periphery by rapamycin treatment. Furthermore, consistent with the results regarding changes in mRNA abundance in kidney by real-time PCR analysis, intracellular cytokine staining demonstrated that rapamycin treatment remarkably diminished the secretion of Th1 and Th2 cytokines, including IFN-γ, IL-4 and IL-10, in splenocytes of the morbid mice. However, the production of IL-2 from splenocytes in rapamycin-treated mice was significantly higher than in the cells from control group animals. These findings suggest that rapamycin treatment might alleviate systemic lupus erythematosus (SLE)-like experimental lupus nephritis through the recovery of IL-2 production, which promotes the expansion of regulatory T cells while inhibiting effector T cell activation. Our studies demonstrated that, unlike other commonly used immunosuppressants, rapamycin does not appear to interfere with tolerance induction but permits the expansion and suppressive function of Tregs in vivo.

All-trans retinoic acid–based differentiation therapies have succeeded in the treatment of acute promyelocytic leukemia, which is a rare subtype of acute myeloid leukemia (AML). Their clinical efficacy is negligible, however, for other subtypes of AML. Here, we showed that strobilurin derivatives, a well-established class of inhibitors of mitochondrial electron transport chain (ETC) complex III, possessed differentiation-inducing activity in AML cells. Impairment of mitochondrial ETC activity was involved in the differentiation effects of strobilurin derivatives, where reactive oxygen species generation appeared unnecessary. Conversely, strobilurin derivative-mediated differentiation was triggered by pyrimidine deficiency, which resulted from the inhibition of the mitochondrial-coupled dihydroorotate dehydrogenase enzyme. Moreover, strobilurin derivative-mediated pyrimidine depletion led to the activation of the Akt/mTOR cascade, which was required for the differentiation. Our study provided evidence that strobilurin derivatives may represent a novel class of differentiation-inducing agents for the treatment of AML.

Therapeutic interventions for hematopoietic acute radiation syndrome (H-ARS) remain limited in both variety and efficacy, falling short of achieving durable recovery of the hematopoietic system. Here, we develop 2B9F, a novel thrombopoietin-mimetic peptide engineered for enhanced stability and designed with the intention of achieving low immunogenicity. A single subcutaneous dose of 2B9F administered postexposure achieved complete survival in a lethal murine irradiation model, surpassing the efficacy of the clinically approved agent romiplostim. Treatment with 2B9F accelerated the recovery of peripheral blood counts and bone marrow nucleated cells, expanded functional hematopoietic stem cells (HSCs), and enhanced both in vitro clonogenic potential and in vivo competitive repopulation capacity. Mechanistic studies revealed that 2B9F promoted HSC quiescence and survival through transcriptional modulation of apoptosis and cell-cycle regulators. Importantly, a single low dose of 2B9F also conferred durable protection, mitigating delayed bone marrow suppression for up to six months postirradiation. These findings position 2B9F as a promising single-dose, low-immunogenicity therapeutic candidate for H-ARS, indicating strong potential for clinical translation in nuclear emergencies.

As the predominant antibody isotype at human mucosal surfaces, immunoglobulin A (IgA) exerts critical functions in mucosal defense and systemic immune homeostasis. The two IgA subclasses, IgA1 and IgA2, possess distinct structural and functional features and assemble into dimeric IgA (dIgA) and secretory IgA (sIgA) under physiological conditions. With advances in cryo-electron microscopy, the molecular architecture and assembly of sIgA have been clearly characterized. While IgA protects hosts from pathogenic infection and sustains immune balance, aberrantly altered IgA contributes to the pathogenesis of IgA nephropathy and autoimmune encephalitis. To date, IgA-based therapeutics have displayed promising therapeutic efficacy against respiratory disorders, inflammatory bowel diseases and oral fungal infections. Through standardized retrieval and categorical sorting of the published literature covering IgA structure, physiological functions, disease pathogenic mechanisms and therapeutic research, this review systematically organizes relevant research advances, analyzes the bottlenecks and translational prospects of IgA-targeted therapeutics, and provides objective references to accelerate the clinical translation of IgA antibody agents.

Immune thrombocytopenia (ITP) is an autoimmune bleeding disorder in which enhanced platelet destruction and impaired platelet production coexist, and a substantial proportion of patients remain refractory to available therapies. Here, we evaluated 2B9-Fc, a thrombopoietin (TPO) mimetic peptide engineered from a cyclic peptide with high affinity for both human and mouse c-MPL, in passive (anti-CD41 monoclonal antibody R300) and active (guinea pig anti-mouse platelet serum, GP-APS) immunization male C57BL/6J and humanized c-MPL receptor transgenic mouse models of ITP. 2B9-Fc (500 μg/kg, subcutaneously) significantly elevated peripheral platelet counts in both models (p < 0.01), without affecting WBC, RBC, or hemoglobin, and alleviated skin purpura and bleeding scores in the active model. In addition, 2B9-Fc treatment was associated with a reduced splenic M1/M2 macrophage ratio, increased regulatory T cells (Tregs), downregulated IL-6 and iNOS while upregulating TGF-β1 and Foxp3, and suppressed STAT1 phosphorylation. In humanized c-MPL receptor transgenic (MT) mice, 2B9-Fc promoted CD41⁺ megakaryocyte generation in vitro and sustained platelet recovery in vivo through day 14. These results indicate that 2B9-Fc ameliorates ITP and is associated with promotion of megakaryocyte maturation and restoration of immune tolerance, likely involving inhibition of STAT1-mediated M1 polarization and Treg expansion, supporting its potential for clinical translation.