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Previous studies have demonstrated that sirolimus (SRL) is an effective agent for the treatment of refractory/relapsed (R/R) ITP. However, the therapeutic window of sirolimus in the treatment of ITP has not been established. As the toxicity of sirolimus increases with higher blood concentrations, it is crucial to determine the optimal therapeutic concentration of SRL for the treatment of ITP. Thus, in this study, we used a retrospective cohort of ITP patients treated with sirolimus to propose the therapeutic dosage window for sirolimus. A total of 275 laboratory results of SRL blood concentration from 63 ITP patients treated with SRL were analyzed retrospectively. The ITP patients were divided into five groups based on their SRL blood concentration: 0-4 ng/ml, 4-8 ng/ml, 8-12 ng/ml, 12-16 ng/ml and =16 ng/ml. In addition to the SRL blood concentration, platelet counts and adverse events that occurred during the first 6 weeks of SRL treatment were analyzed. These findings were then used to establish the decision matrix tables and ROC curves, which helped identify the therapeutic window of SRL. Based on the values and trends of truepositive rate (TPR) and false-positive rate (FPR) in the ROC curve, patients who achieved a SRL blood concentration of 4-12 ng/ml displayed a higher response rate compared to those with a SRL concentration of 0-4 ng/ml or =16ng/ml. Additionally, the response rate was better for patients with a SRL concentration of 8-12 ng/ml compared to 4-8 ng/ml. Adverse events were related to the concentration of SRL; however, there was no significant difference in the incidence of adverse events between the concentrations of 4-8 ng/ml and 8-12 ng/ml (P > .05). Regression analysis suggested that the concentration of SRL correlated with the patient's age, PLT count at the start of SRL administration, and the dose of SRL. It is suggested that the optimal blood concentration of SRL monotherapy for managing ITP is 8-12 ng/ml. This range may achieve a favorable balance between clinical efficacy and the severity of adverse events. [ABSTRACT FROM AUTHOR]

Programmed death ligand-1 (PD-L1) interacts with programmed death-1 (PD-1) and the immunostimulatory molecule CD80 and functions as a checkpoint to regulate immune responses. The interaction of PD-L1 with CD80 alone has been shown to exacerbate the severity of graft-versus-host disease (CVHD), whereas costimulation of CD80 and PD-1 ameliorates CVHD. Here we have demonstrated that temporary depletion of donor [CD4.sup.+] T cells early after hematopoietic cell transplantation effectively prevents GVHD while preserving strong graft-versus-leukemia (GVL) effects in allogeneic and xenogeneic murine GVHD models. Depletion of donor [CD4.sup.+] T cells increased serum IFN-[gamma] but reduced IL-2 concentrations, leading to upregulation of PD-L1 expression by recipient tissues and donor [CD8.sup.+] T cells. In GVHD target tissues, the interactions of PD-L1 with PD-1 on donor [CD8.sup.+] T cells cause anergy, exhaustion, and apoptosis, thereby preventing GVHD. In lymphoid tissues, the interactions of PD-L1 with CD80 augment [CD8.sup.+] T cell expansion without increasing anergy, exhaustion, or apoptosis, resulting in strong GVL effects. These results indicate that the outcome of PD-L1-mediated signaling in [CD8.sup.+] T cells depends on the presence or absence of [CD4.sup.+] T cells, the nature of the interacting receptor expressed by [CD8.sup.+] T cells, and the tissue environment in which the signaling occurs., Introduction Allogeneic hematopoietic cell transplantation (HCT) is a curative therapy for hematological malignancies (i.e., leukemia and lymphoma), owing to graft-versus-leukemia/lymphoma (GVL) effects mediated by alloreactive T cells. These same T [...]

Regulatory T (Treg) cells are critical in preventing aberrant immune responses. Posttranscriptional control of gene expression by microRNA (miRNA) has recently emerged as an essential genetic element for Treg cell function. Here, we report that mice with Treg cell–specific ablation of miR-142 (hereafter Foxp3CremiR-142fl/fl mice) developed a fatal systemic autoimmune disorder due to a breakdown in peripheral T-cell tolerance. Foxp3CremiR-142fl/fl mice displayed a significant decrease in the abundance and suppressive capacity of Treg cells. Expression profiling of miR-142–deficient Treg cells revealed an up-regulation of multiple genes in the interferon gamma (IFNγ) signaling network. We identified several of these IFNγ-associated genes as direct miR-142-3p targets and observed excessive IFNγ production and signaling in miR-142–deficient Treg cells. Ifng ablation rescued the Treg cell homeostatic defect and alleviated development of autoimmunity in Foxp3CremiR-142fl/fl mice. Thus, our findings implicate miR-142 as an indispensable regulator of Treg cell homeostasis that exerts its function by attenuating IFNγ responses. This study identifies microRNA-142 as a central regulator of the development, homeostasis and function of regulatory T cells. Mechanistically, the miR-142-3p isoform controls regulatory T cell homeostasis and immune tolerance by attenuating IFNγ responses. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is an autoimmune inflammatory disease of the central nervous system with demyelination, axon damage, and paralysis. Induction of mixed chimerism with allogeneic donors has been shown to not cause graft-versus-host disease (GVHD) in animal models and humans. We have reported that induction of MHC-mismatched mixed chimerism can cure autoimmunity in autoimmune NOD mice, but this approach has not yet been tested in animal models of MS, such as experimental autoimmune encephalomyelitis (EAE). Here, we report that MHC-mismatched mixed chimerism with C57BL/6 (H-2b) donor in SJL/J (H-2s) EAE recipients eliminates clinical symptoms and prevents relapse. This cure is demonstrated by not only disappearance of clinical signs but also reversal of autoimmunity; elimination of infiltrating T, B, and macrophage cells in the spinal cord; and regeneration of myelin sheath. The reversal of autoimmunity is associated with a marked reduction of autoreactivity of CD4+ T cells and significant increase in the percentage of Foxp3+ Treg among host-type CD4+ T cells in the spleen and lymph nodes. The latter is associated with a marked reduction of the percentage of host-type CD4+CD8+ thymocytes and an increase of Treg percentage among the CD4+CD8+ and CD4+CD8- thymocytes. Thymectomy leads to loss of prevention of EAE relapse by induction of mixed chimerism, although there is a dramatic expansion of host-type Treg cells in the lymph nodes. These results indicate that induction of MHC-mismatched mixed chimerism can restore thymic negative selection of autoreactive CD4+ T cells, augment production of Foxp3+ Treg, and cure EAE. [ABSTRACT FROM AUTHOR]

Interactions of B7H1 (programmed death ligand 1 [PD-L1]) with its two ligands, PD-1 and CD80, on T cells play a pivotal role in controlling T cell activation, proliferation, anergy, and apoptosis. However, the interactions between the two pathways remain unknown. Using an alloimmune response model of graft-versus-host disease (GVHD), we report in this study that: 1) Comparison of proliferation and apoptosis of wild-type (WT) and PD-1-/-CD4+ conventional T (Tcon) cells in WT and B7H1-/- recipients revealed that B7H1/CD80 interaction per se augments T cell proliferation, and this interaction augments T cell apoptosis mediated by B7H1/PD-1 interaction. This observation was recapitulated in an in vitro MLR assay. 2) Specific blockade of the B7H1/CD80 axis by anti-B7H1 mAb reduces WT-alloreactive Tcon cell proliferation, IL-2 production, expression of PD-1, and apoptosis, resulting in worsening GVHD. In contrast, specific blockade of B7H1/CD80 interaction reduces donor PD-1-/- Tcon cell proliferation without an impact on apoptosis, resulting in ameliorating GVHD. 3) B7H1 fused to an Ig Fc domain (B7H1-Ig), when produced in vivo by hydrodynamic injection of B7H1-Ig plasmid, ameliorates GVHD by augmenting proliferation and apoptosis of WT- alloreactive Tcon cells. Conversely, B7H1-Ig treatment has no impact on apoptosis but augments PD-1-/- T cell proliferation and worsens GVHD. These results indicate that B7H1/CD80 interaction augments Tcon cell proliferation, IL-2 production, and expression of PD-1, which leads to increased apoptosis mediated by the B7H1/PD-1 pathway. Additionally, by engaging both PD-1 and CD80, B7H1-Ig can be a powerful therapeutic reagent for downregulating the T cell immune response. [ABSTRACT FROM AUTHOR]

Background and purpose Is minimal residual disease (MRD) monitoring by multiparameter flow cytometry (MFC) prognostic for acute myeloid leukemia (AML) patients before allogeneic hemopoietic stem cell transplantation (allo-HSCT)? And if so, what level of MRD eradication can be used to help guide the timing of HSCT? Can haplo-HSCT improve the prognosis of AML patients with MRD positive? To figure out these questions, we initiated this retrospective study. Methods 96 AML patients were included retrospectively and divided into 5 groups, according to pre-transplantation MRD levels (from 5 × 10−2 to <1 × 10−4), to analyze the overall survival (OS), disease-free survival (DFS) and cumulative incidence of relapse (CIR). Secondly, we compared the prognosis of MRD-negative (MRDneg) and MRD-positive (MRDpos) AML patients (cutoff value = 1 × 10−3) who underwent allo-HSCT, and further analyzed the prognosis of MRDpos patients after received different transplantation modalities. Results It is found that the 2-year OS and DFS of MRD negative group were better than the MRD positive group, and that the deeper the eradication of MRD before transplantation, the better the prognosis of patients. The CIR in patients received HLA-identical transplantation, was higher in the MRDpos than in the MRDneg. Haploid transplantation reduced the CIR disparity between MRDpos and MRDneg group. Subsequently, in AML patients who remain MRD positive before HSCT, we show that haplo-HSCT offered a better prognosis than HLA-identical transplantation (MSDT and MUDT). Conclusion It is suggested that achieving MFC-MRD <10−3 (10−4 or even better) before allo-HSCT could reduce the relapse of AML and improve OS and DFS significantly, while haplo-HSCT may be preferred for patients not achieving MRD negativity. [ABSTRACT FROM AUTHOR]

STAT3 deficiency (STAT3–/–) in donor T cells prevents graft-versus-host disease (GVHD), but the impact on graft-versusleukemia (GVL) activity and mechanisms of GVHD prevention remains unclear. Here, using murine models of GVHD, we show that STAT3–/– donor T cells induced only mild reversible acute GVHD while preserving GVL effects against nonsusceptible acute lymphoblastic leukemia (ALL) cells in a donor T cell dose–dependent manner. GVHD prevention depended on programmed death ligand 1/programmed cell death protein 1 (PD-L1/PD-1) signaling. In GVHD target tissues, STAT3 deficiency amplified PD-L1/PD-1 inhibition of glutathione (GSH)/Myc pathways that regulate metabolic reprogramming in activated T cells, with decreased glycolytic and mitochondrial ATP production and increased mitochondrial ROS production and dysfunction, leading to tissue-specific deletion of host-reactive T cells and prevention of GVHD. Mitochondrial STAT3 deficiency alone did not reduce GSH expression or prevent GVHD. In lymphoid tissues, the lack of host-tissue PD-L1 interaction with PD-1 reduced the inhibition of the GSH/Myc pathway despite reduced GSH production caused by STAT3 deficiency and allowed donor T cell functions that mediate GVL activity. Therefore, STAT3 deficiency in donor T cells augments PD-1 signaling–mediated inhibition of GSH/Myc pathways and augments dysfunction of T cells in GVHD target tissues while sparing T cells in lymphoid tissues, leading to prevention of GVHD while preserving GVL effects. [ABSTRACT FROM AUTHOR]

Programmed death ligand-1 (PD-L1) interacts with programmed death-1 (PD-1) and the immunostimulatory molecule CD80 and functions as a checkpoint to regulate immune responses. The interaction of PD-L1 with CD80 alone has been shown to exacerbate the severity of graft-versus-host disease (GVHD), whereas costimulation of CD80 and PD-1 ameliorates GVHD. Here we have demonstrated that temporary depletion of donor CD4+ T cells early after hematopoietic cell transplantation effectively prevents GVHD while preserving strong graft-versus-leukemia (GVL) effects in allogeneic and xenogeneic murine GVHD models. Depletion of donor CD4+ T cells increased serum IFN-γ but reduced IL-2 concentrations, leading to upregulation of PD-L1 expression by recipient tissues and donor CD8+ T cells. In GVHD target tissues, the interactions of PD-L1 with PD-1 on donor CD8+ T cells cause anergy, exhaustion, and apoptosis, thereby preventing GVHD. In lymphoid tissues, the interactions of PD-L1 with CD80 augment CD8+ T cell expansion without increasing anergy, exhaustion, or apoptosis, resulting in strong GVL effects. These results indicate that the outcome of PD-L1-mediated signaling in CD8+ T cells depends on the presence or absence of CD4+ T cells, the nature of the interacting receptor expressed by CD8+ T cells, and the tissue environment in which the signaling occurs. [ABSTRACT FROM AUTHOR]

Cutaneous sclerosis is one of the most common clinical manifestations of chronic graft- versus-host disease (cGVHD). Donor CD4+ T and B cells play important roles in cGVHD pathogenesis, but the role of antibodies from donor B cells remains unclear. In the current studies, we generated immunoglobulin (Ig)Hμγ+ DBA/2 mice whose B cells have normal antigen-presentation and regulatory functions but cannot secrete antibodies. With a murine cGVHD model using DBA/2 donors and BALB/c recipients, we have shown that wild-type (WT) grafts induce persistent cGVHD with damage in the thymus, peripheral lymphoid organs, and skin, as well as cutaneous T helper 17 cell (Th17) infiltration. In contrast, IgHμγ1 grafts induced only transient cGVHD with little damage in the thymus or peripheral lymph organs or with little cutaneous Th17 infiltration. Injections of IgG- containing sera from cGVHD recipients given WT grafts but not IgG-deficient sera from recipients given IgHμγ1 grafts led to deposition of IgG in the thymus and skin, with resulting damagein the thymus and peripheral lymph organs, cutaneousTh17 infiltration, and perpetuation of cGVHD in recipients given IgHμγ1 grafts. These results indicate that donor B-cell antibodies augment cutaneous cGVHD in part by damaging the thymus and increasing tissue infiltration of pathogenic Th17 cells. [ABSTRACT FROM AUTHOR]

Purpose: We present a phase I/II first-in-human trial evaluating the safety and efficacy of 50 mg and 200 mg doses of linvoseltamab, a B-cell maturation antigen × CD3 bispecific antibody in relapsed/refractory multiple myeloma (RRMM)., Methods: Phase II eligible patients had RRMM that either progressed on/after ≥three lines of therapy including a proteasome inhibitor (PI), an immunomodulatory drug (IMiD), and an anti-CD38 antibody or was triple-class (PI/IMiD/anti-CD38) refractory. Phase II treatment was once a week through week 14 and then once every 2 weeks. Phase II 200 mg patients who achieved a ≥very good partial response by week 24 received linvoseltamab once every 4 weeks. The primary end point in phase II was overall response rate (ORR)., Results: Among the 117 patients treated with 200 mg, the median age was 70 years, 39% had high-risk cytogenetics, and 28% had penta-refractory disease. At a median follow-up of 14.3 months, the ORR was 71%, with 50% achieving ≥complete response (CR). In 104 patients treated with 50 mg at a median follow-up of 7.4 months, the ORR was 48%, with 21% achieving ≥CR. The median duration of response (DOR) for 200 mg patients (n = 83) was 29.4 months (95% CI, 19.2 to not evaluable). Among 200 mg patients, the most common adverse events included cytokine release syndrome (35.0% Gr1, 10.3% Gr2, 0.9% Gr3), neutropenia (0.9% Gr2, 18.8% Gr3, 23.1% Gr4), and anemia (3.4% Gr1, 4.3% Gr2, 30.8% Gr3). Immune effector cell-associated neurotoxicity syndrome occurred in 7.7% of patients (2.6% each Gr1, Gr2, Gr3). Infections were reported in 74.4% of patients (33.3% Gr3, 2.6% Gr4); infection frequency and severity declined over time., Conclusion: Linvoseltamab 200 mg induced deep and durable responses, with a median DOR of 29.4 months, in patients with RRMM with an acceptable safety profile.