Tissue-specific modifier alleles determine loss-of-function traits.

Knockout (KO) mouse models play critical roles in elucidating biological processes behind disease-associated or disease-resistant traits. As a presumed consequence of gene KO, mice display certain phenotypes. Based on insight into the molecular role of said gene in a biological process, it is inferred that the particular biological process causally underlies the trait.

Diagnostic Value of sIL-2R, TNF-α and PCT for Sepsis Infection in Patients With Closed Abdominal Injury Complicated With Severe Multiple Abdominal Injuries.

Objective: We aimed to evaluate the diagnostic value of soluble interleukin-2 receptor (sIL-2R), tumor necrosis factor-α (TNF-α), procalcitonin (PCT), and combined detection for sepsis infection in patients with closed abdominal injury complicated with severe multiple abdominal injuries.

Patients And Methods: One hundred forty patients with closed abdominal injury complicated with severe multiple abdominal injuries who were diagnosed and treated from 2015 to 2020 were divided into a sepsis group ( = 70) and an infection group ( = 70).

Results: The levels of sIL-2R, TNF-α, and PCT in the sepsis group were higher than those in the infection group ( < 0.

Conditioning treatment with CD27 Ab enhances expansion and antitumor activity of adoptively transferred T cells in mice.

Cyclophosphamide plus fludarabine (C/F) are currently used to improve the expansion and effectiveness of adoptive cell therapy (ACT). However, these chemotherapeutics cause pan-leukopenia and adverse events, suggesting that safer and more effective conditioning treatments are needed to improve ACT outcomes. Previously, we reported that varlilumab, a CD27-targeting antibody, mediates T -preferential T cell depletion, CD8-T cell dominant costimulation, and systemic immune activation in hCD27 transgenic mice and cancer patients.

CD70 expression determines the therapeutic efficacy of expanded human regulatory T cells.

Regulatory T cells (Tregs) are critical mediators of immune homeostasis. The co-stimulatory molecule CD27 is a marker of highly suppressive Tregs, although the role of the CD27-CD70 receptor-ligand interaction in Tregs is not clear. Here we show that after prolonged in vitro stimulation, a significant proportion of human Tregs gain stable CD70 expression while losing CD27.

Development of CDX-527: a bispecific antibody combining PD-1 blockade and CD27 costimulation for cancer immunotherapy.

CD27 is a costimulatory molecule that provides a complementary target to the PD-1/PD-L1 checkpoint axis on T cells. Combining a CD27 agonist antibody with PD-1/PD-L1 blockade has shown synergistic antitumor activity in preclinical models, which led to clinical studies of the combination in cancer patients. We theorized that coupling CD27 costimulation with PD-1/PD-L1 blockade in a bispecific antibody (BsAb) may provide greater immune activating properties than combining the individual mAbs due to enhanced CD27 activation by cross-linking through PD-L1 and Fc receptors.

Development and Characterization of a Preclinical Model for the Evaluation of CD205-Mediated Antigen Delivery Therapeutics in Type 1 Diabetes.

Dendritic cells (DCs) are crucial for the production of adaptive immune responses to disease-causing microbes. However, in the steady state (i.e.

CD27 stimulation unveils the efficacy of linked class I/II peptide vaccines in poorly immunogenic tumors by orchestrating a coordinated CD4/CD8 T cell response.

Despite their promise, tumor-specific peptide vaccines have limited efficacy. CD27 is a costimulatory molecule expressed on CD4 and CD8 T cells that is important in immune activation. Here we determine if a novel CD27 agonist antibody (αhCD27) can enhance the antitumor T cell response and efficacy of peptide vaccines.

Development of CDX-1140, an agonist CD40 antibody for cancer immunotherapy.

Limitations of immunotherapy include poorly functioning events early in the immune response cycle, such as efficient antigen presentation and T cell priming. CD40 signaling in dendritic cells leads to upregulation of cell surface costimulatory and MHC molecules and the generation of cytokines, which promotes effective priming of CD8 effector T cells while minimizing T cell anergy and the generation of regulatory T cells. This naturally occurs through interaction with CD40 ligand (CD40L) expressed on CD4 T-helper cells.

PD-1 Blockade and CD27 Stimulation Activate Distinct Transcriptional Programs That Synergize for CD8 T-Cell-Driven Antitumor Immunity.

PD-1 checkpoint blockade has revolutionized the field of cancer immunotherapy, yet the frequency of responding patients is limited by inadequate T-cell priming secondary to a paucity of activatory dendritic cells (DC). DC signals can be bypassed by CD27 agonists, and we therefore investigated if the effectiveness of anti-PD-1/L1 could be improved by combining with agonist anti-CD27 monoclonal antibodies (mAb). The efficacy of PD-1/L1 blockade or agonist anti-CD27 mAb was compared with a dual-therapy approach in multiple tumor models.

Antibody Tumor Targeting Is Enhanced by CD27 Agonists through Myeloid Recruitment.

Monoclonal antibodies (mAbs) can destroy tumors by recruiting effectors such as myeloid cells, or targeting immunomodulatory receptors to promote cytotoxic T cell responses. Here, we examined the therapeutic potential of combining a direct tumor-targeting mAb, anti-CD20, with an extended panel of immunomodulatory mAbs. Only the anti-CD27/CD20 combination provided cures.

CD27-Mediated Regulatory T Cell Depletion and Effector T Cell Costimulation Both Contribute to Antitumor Efficacy.

CD27, a member of the TNFR superfamily, is constitutively expressed in most T cells and plays crucial roles in T cell effector functions. The costimulation and antitumor activity of CD27 agonistic Abs have been well documented in mouse models. Clinical testing of a human IgG1 anti-CD27 Ab, varlilumab (clone 1F5), is ongoing in cancer patients.

M. tuberculosis-Initiated Human Mannose Receptor Signaling Regulates Macrophage Recognition and Vesicle Trafficking by FcRγ-Chain, Grb2, and SHP-1.

Despite its prominent role as a C-type lectin (CTL) pattern recognition receptor, mannose receptor (MR, CD206)-specific signaling molecules and pathways are unknown. The MR is highly expressed on human macrophages, regulating endocytosis, phagocytosis, and immune responses and mediating Mycobacterium tuberculosis (M.tb) phagocytosis by human macrophages, thereby limiting phagosome-lysosome (P-L) fusion.

Comparison of ambulatory blood pressure and clinic blood pressure in relation to cardiovascular diseases in diabetic patients.

The aim of this study was to evaluate prognostic values of ambulatory blood pressure (ABP) and clinic blood pressure (CBP) in diabetic patients with hypertension. A total of 450 diabetic hypertensive patients without established cardiovascular diseases were enrolled and 416 patients who had finished 12months' follow-up were included in final analysis. Baseline data were collected and Cox proportional hazards regression analysis was used to evaluate prognostic value of ABP and CBP.

Associations of and gene polymorphism with ulinastatin efficacy in patients with severe acute pancreatitis.

We aim to explore the associations between matrix metalloproteinase (MMP) gene polymorphism with ulinastatin (UTI) efficacy in treating severe acute pancreatitis (SAP). A total of 276 SAP patients were assigned into the control (=135) and observation (=141) groups. PCR-restriction fragment length polymorphism (PCR-RFLP) was used for genotype and allele frequency distribution.

Toll-like receptor agonists shape the immune responses to a mannose receptor-targeted cancer vaccine.

Previous studies have documented that selective delivery of protein antigens to cells expressing mannose receptor (MR) can lead to enhanced immune responses. We postulated that agents that influenced the MR expression level, and the activation and migration status of MR-expressing antigen presenting cells, would modulate immune responses to MR-targeted vaccines. To address this question, we investigated the effect of clinically used adjuvants in human MR transgenic (hMR-Tg) mice immunized with an MR-targeting cancer vaccine composed of the human anti-MR monoclonal antibody B11 fused with the oncofetal protein, human chorionic gonadotropin beta chain (hCGβ), and referred to as B11-hCGβ.

Targeting human CD27 with an agonist antibody stimulates T-cell activation and antitumor immunity.

CD27 is an important co-stimulatory receptor of T cells that can potentially be exploited for immunotherapy. We developed a human IgG1 antibody that targets human CD27, and demonstrated its immunostimulatory and antineoplastic activity in various preclinical models. Currently, the antibody (1F5, CDX-1127) is being tested in patients affected by advanced malignancies.

Agonist anti-human CD27 monoclonal antibody induces T cell activation and tumor immunity in human CD27-transgenic mice.

The CD70/CD27 pathway plays a significant role in the control of immunity and tolerance, and previous studies demonstrated that targeting murine CD27 (mCD27) with agonist mAbs can mediate antitumor efficacy. We sought to exploit the potential of this pathway for immunotherapy by developing 1F5, a fully human IgG1 mAb to human CD27 (hCD27) with agonist activity. We developed transgenic mice expressing hCD27 under control of its native promoter for in vivo testing of the Ab.

Development of a human monoclonal antibody for potential therapy of CD27-expressing lymphoma and leukemia.

Purpose: The TNF receptor superfamily member CD27 is best known for its important role in T-cell immunity but is also recognized as a cell-surface marker on a number of B- and T-cell malignancies. In this article, we describe a novel human monoclonal antibody (mAb) specific for CD27 with properties that suggest a potential utility against malignancies that express CD27.

Experimental Design: The fully human mAb 1F5 was generated using human Ig transgenic mice and characterized by analytical and functional assays in vitro.

Targeting of the non-mutated tumor antigen HER2/neu to mature dendritic cells induces an integrated immune response that protects against breast cancer in mice.

Introduction: Given their relative simplicity of manufacture and ability to be injected repeatedly, vaccines in a protein format are attractive for breast and other cancers. However, soluble human epidermal growth factor receptor (HER2)/neu protein as a vaccine has not been immunogenic. When protein is directly targeted to antigen uptake receptors, such as DEC205 (DEC), efficient processing and presentation of antigen take place.

Phase I study utilizing a novel antigen-presenting cell-targeted vaccine with Toll-like receptor stimulation to induce immunity to self-antigens in cancer patients.

Purpose: The use of tumor-derived proteins as cancer vaccines is complicated by tolerance to these self-antigens. Tolerance may be broken by immunization with activated, autologous, ex vivo generated and antigen-loaded, antigen-presenting cells (APC); however, targeting tumor antigen directly to APC in vivo would be a less complicated strategy. We wished to test whether targeted delivery of an otherwise poorly immunogenic, soluble antigen to APC through their mannose receptors (MR) would induce clinically relevant immunity.

Antibody-targeted NY-ESO-1 to mannose receptor or DEC-205 in vitro elicits dual human CD8+ and CD4+ T cell responses with broad antigen specificity.

Immunization of cancer patients with vaccines containing full-length tumor Ags aims to elicit specific Abs and both CD4(+) and CD8(+) T cells. Vaccination with protein Ags, however, often elicits only CD4(+) T cell responses without inducing Ag-specific CD8(+) T cells, as exogenous protein is primarily presented to CD4(+) T cells. Recent data revealed that Ab-mediated targeting of protein Ags to cell surface receptors on dendritic cells could enhance the induction of both CD4(+) and CD8(+) T cells.

Improved cellular and humoral immune responses in vivo following targeting of HIV Gag to dendritic cells within human anti-human DEC205 monoclonal antibody.

Protein vaccines for T-cell immunity are not being prioritized because of poor immunogenicity. To overcome this hurdle, proteins are being targeted to maturing dendritic cells (DCs) within monoclonal antibodies (mAbs) to DC receptors. To extend the concept to humans, we immunized human immunoglobulin-expressing mice with human DEC205 (hDEC205) extracellular domain.

The human cancer antigen mesothelin is more efficiently presented to the mouse immune system when targeted to the DEC-205/CD205 receptor on dendritic cells.

To develop a tumor vaccine directly targeting tumor antigen to dendritic cells in situ, we engineered human mesothelin (MSLN) into an antibody specific for mouse DEC-205, a receptor for antigen presentation. We then characterized both T cell and humoral responses to human MSLN and compared immunizing efficacy of DEC-205-targeted MSLN to nontargeted protein after a single-dose immunization. Targeting human MSLN to DEC-205 receptor induced stronger CD4(+) T-cell responses compared to high doses of mesothelin protein.

[Effects of PTEN gene on human malignant glioma growth in vitro].

Objective: To investigate the biological effects of PTEN gene on the malignant glioma cell line SHG-44. Firstly, A recombinant eukaryotic expression plasmid containing PTEN gene fused with EGFP (enhanced green fluorescence protein) gene was constructed. Secondly, the expression of the recombinant vector in human glioma cells was detected.

Antigenic targeting of the human mannose receptor induces tumor immunity.

Pattern recognition receptors are preferentially expressed on APCs allowing selective uptake of pathogens for the initiation of antimicrobial immunity. In particular, C-type lectin receptors, including the mannose receptor (MR), facilitate APC-mediated adsorptive endocytosis of microbial glyconjugates. We have investigated the potential of antigenic targeting to the MR as a means to induce Ag-specific humoral and cellular immunity.