Engineered murine IL-21-secreting leukemia cells induce granzyme B T cells and CD4CD44CD62L effector memory cells while suppressing regulatory T cells, leading to long-term survival.

We have explored the use of an IL-21 cell-based anti-leukemia treatment in a mouse model of acute lymphoblastic leukemia. 70Z/3 leukemia cells, engineered to secrete IL-21 and injected into the peritoneum of syngeneic mice, induced a strong anti-leukemia response resulting in 100% survival. Mice that mounted an IL-21-induced anti-leukemia immune response were immune to the parent cell line (no IL-21) when rechallenged.

Case Report: Persistent Moderate-to-Severe Creatine Kinase Enzyme Activity Elevation in a Subclinical Dog.

A 4-year-old, male-castrated, mixed breed dog was presented for a routine wellness examination at which time a moderate increase in serum creatine kinase (CK) enzyme activity (hyperCKemia) (15,137 IU/L; reference interval 10-200 IU/L), and moderate increases in alanine transaminase and aspartate aminotransferase enzyme activities were first identified. There was no history of clinical abnormalities (e.g.

Cytotoxic CD4 T Cells in Bladder Cancer-A New License to Kill.

CD4 T cells with cytotoxic capability are increasingly recognized as potentially key actors in anti-tumor immunity. A new report in Cell elucidates the presence and potential role of a population of cytotoxic CD4 T cells in bladder cancer using single cell sequencing technology.

Neurokinin-1 Receptor Signaling Is Required for Efficient Ca Flux in T-Cell-Receptor-Activated T Cells.

Efficient Ca flux induced during cognate T cell activation requires signaling the T cell receptor (TCR) and unidentified G-protein-coupled receptors (GPCRs). T cells express the neurokinin-1 receptor (NK1R), a GPCR that mediates Ca flux in excitable and non-excitable cells. However, the role of the NK1R in TCR signaling remains unknown.

Interleukin-15 in cancer immunotherapy: IL-15 receptor complex versus soluble IL-15 in a cancer cell-delivered murine leukemia model.

Cytokines of the common γ-chain receptor family such as IL-15 are vital with respect to activating immune cells, sustaining healthy immune functions, and augmenting the anti-tumor activity of effector cells, making them ideal candidates for cancer immunotherapy. IL-15, either in its soluble form (IL-15sol) or complexed with IL-15Rα (IL-15Rc), has been shown to exhibit potent anti-tumor activities in various experimental cancer studies. Here we describe the impact of intraperitoneal IL-15 in a cancer cell-delivered IL-15 immunotherapy approach using the 70Z/3-L leukemia mouse model.

c-Myb Exacerbates Atherosclerosis through Regulation of Protective IgM-Producing Antibody-Secreting Cells.

Mechanisms that govern transcriptional regulation of inflammation in atherosclerosis remain largely unknown. Here, we identify the nuclear transcription factor c-Myb as an important mediator of atherosclerotic disease in mice. Atherosclerosis-prone animals fed a diet high in cholesterol exhibit increased levels of c-Myb in the bone marrow.

Differential regulation of IgA B cells in vitro by stromal cells from distinctive anatomical compartments.

B cell development is regulated by stromal cells (SCs) that form a supportive microenvironment. These SCs along with other cell types produce cytokines, chemokines, and adhesion molecules that guide B cell commitment and differentiation. BM, spleen (Sp), and the gut lamina propria (LP) constitute distinctive anatomical compartments that support B cell differentiation.

Functional Consequences of the Postnatal Switch From Neonatal to Mutant Adult Glycine Receptor α1 Subunits in the Mouse Model of Startle Disease.

Mutations in GlyR α1 or β subunit genes in humans and rodents lead to severe startle disease characterized by rigidity, massive stiffness and excessive startle responses upon unexpected tactile or acoustic stimuli. The recently characterized startle disease mouse mutant carries a missense mutation (Q177K) in the β8-β9 loop within the large extracellular N-terminal domain of the GlyR α1 subunit. This results in a disrupted hydrogen bond network around K177 and faster GlyR decay times.

Cytokines and depression in cancer patients and caregivers.

Objective: A better understanding of the biobehavioral mechanisms underlying depression in cancer is required to translate biomarker findings into clinical interventions. We tested for associations between cytokines and the somatic and psychological symptoms of depression in cancer patients and their healthy caregivers.

Patients And Methods: The GRID Hamilton Rating Scale for Depression (Ham-D) was administered to 61 cancer patients of mixed type and stage, 26 primary caregivers and 38 healthy controls.

Bone marrow basophils provide survival signals to immature B cells in vitro but are dispensable in vivo.

Immature B cells are the first B cell progenitors to express a fully formed B cell receptor and are therefore subject to extensive selection processes that act to mitigate the emergence of autoreactive clones. While it is well appreciated that most B cell generation in the bone marrow is highly dependent on access to molecules present in the local milieu, the existence of extrinsically provided factors that modulate immature B cell biology is ambiguous. Nonetheless, a population of CD49b+CD90lo cells has demonstrated in vitro potential to promote immature B cell survival.

Disruption of a Structurally Important Extracellular Element in the Glycine Receptor Leads to Decreased Synaptic Integration and Signaling Resulting in Severe Startle Disease.

Functional impairments or trafficking defects of inhibitory glycine receptors (GlyRs) have been linked to human hyperekplexia/startle disease and autism spectrum disorders. We found that a lack of synaptic integration of GlyRs, together with disrupted receptor function, is responsible for a lethal startle phenotype in a novel spontaneous mouse mutant , caused by a missense mutation, Q177K, located in the extracellular β8-β9 loop of the GlyR α1 subunit. Recently, structural data provided evidence that the flexibility of the β8-β9 loop is crucial for conformational transitions during opening and closing of the ion channel and represents a novel allosteric binding site in Cys-loop receptors.

Preclinical validation: LV/IL-12 transduction of patient leukemia cells for immunotherapy of AML.

Interleukin-12 (IL-12) is a potent cytokine that may be harnessed to treat cancer. To date, nearly 100 IL-12-based clinical trials have been initiated worldwide. Yet systemic administration of IL-12 is toxic.

Pro- and anti-inflammatory cytokine associations with major depression in cancer patients.

Objective: Cytokines may be linked to depression, although it has been challenging to demonstrate this association in cancer because of the overlap between depressive symptoms and other sickness behaviors. This study investigates the relationship between cytokines and depression in cancer patients, accounting for confounding clinical and methodological factors.

Methods: The GRID Hamilton Rating Scale for Depression and Neurotoxicity Rating Scale (NRS) for cytokine-induced sickness behaviors were administered to 61 cancer patients and 38 healthy controls.

Hemokinin-1 mediates anxiolytic and anti-depressant-like actions in mice.

The tachykinin NK1 receptor was suggested to be involved in psychiatric disorders, but its antagonists have failed to be effective as antidepressants in clinical trials. Hemokinin-1 (HK-1), the newest tachykinin, is present in several brain regions and activates the NK1 receptor similarly to substance P (SP), but acts also through other mechanisms. Therefore, we investigated the roles of the Tac4 gene-derived HK-1 in comparison with SP and neurokinin A (NKA) encoded by the Tac1 gene, as well as the NK1 receptor in anxiety and depression-like behaviors in mice.

Tumor-secreted products repress B-cell lymphopoiesis in a murine model of breast cancer.

Growing cancers are known to modify immune responses through suppressive mechanisms manifested within the local tumor microenvironment. Accumulating evidence indicates that secreted tumor products can also influence on distant immunological compartments, including myelopoiesis in the bone marrow. However, it is unknown if a similar effect can occur to regulate B-cell lymphopoiesis in breast cancer.

Inflammation rapidly reorganizes mouse bone marrow B cells and their environment in conjunction with early IgM responses.

Systemic inflammation perturbs the bone marrow environment by evicting resident B cells and favoring granulopoiesis over lymphopoiesis. Despite these conditions, a subset of marrow B cell remains to become activated and produce potent acute immunoglobulin M (IgM) responses. This discrepancy is currently unresolved and a complete characterization of early perturbations in the B-cell niche has not been undertaken.

CD4 T cell plasticity engenders robust immunity in response to cytokine therapy.

CD4 T cells represent an entire arm of the immune system that has hitherto been incompletely understood, but their potential to act as both helper and effector may make them optimal protagonists in immunotherapeutic approaches to treat cancer. Cytokine therapy can activate this population in a manner that ensures maximal diversification of effector function for a robust immune response.

Hemokinin-1 is an important mediator of endotoxin-induced acute airway inflammation in the mouse.

Objective: Hemokinin-1, the newest tachykinin encoded by the preprotachykinin C (Tac4) gene, is predominatly produced by immune cells. Similarly to substance P, it has the greatest affinity to the tachykinin NK1 receptor, but has different binding site and signaling mechanisms. Furthermore, several recent data indicate the existence of a not yet identified own receptor and divergent non-NK1-mediated actions.

Murine splenic CD4⁺ T cells, induced by innate immune cell interactions and secreted factors, develop antileukemia cytotoxicity.

Inciting the cellular arm of adaptive immunity has been the fundamental goal of cancer immunotherapy strategies, specifically focusing on inducing tumor antigen-specific responses by CD8(+) cytotoxic T lymphocytes (CTL). However, there is an emerging appreciation that the cytotoxic function of CD4(+) T cells can be effective in a clinical setting. Harnessing this potential will require an understanding of how such cells arise.

Pten deletion in RIP-Cre neurons protects against type 2 diabetes by activating the anti-inflammatory reflex.

Inflammation has a critical role in the development of insulin resistance. Recent evidence points to a contribution by the central nervous system in the modulation of peripheral inflammation through the anti-inflammatory reflex. However, the importance of this phenomenon remains elusive in type 2 diabetes pathogenesis.

Role of neurokinin 1 receptors in dextran sulfate-induced colitis: studies with gene-deleted mice and the selective receptor antagonist netupitant.

Objective And Design: The function of the neurokinin 1 (NK1) receptor was investigated in the DSS-induced mouse colitis model using NK1 receptor-deficient mice and the selective antagonist netupitant.

Subjects: Colitis was induced by oral administration of 20 mg/ml DSS solution for 7 days in C57BL/6 and Tacr1 KO animals (n = 5-7).

Treatment: During the induction, one-half of the C57BL/6 and Tacr1 KO group received one daily dose of 6 mg/kg netupitant, administered intraperitoneally, the other half of the group received saline, respectively.

Localized interleukin-12 delivery for immunotherapy of solid tumours.

Interleukin (IL)-12 is the key cytokine in the initiation of a Th1 response and has shown promise as an anti-cancer agent; however, clinical trials involving IL-12 have been unsuccessful due to toxic side-effects. To address this issue, lentiviral vectors were used to transduce tumour cell lines that were injected as an autologous tumour cell vaccine. The focus of the current study was to test the efficacy of this approach in a solid tumour model.

GATA-3 regulates the self-renewal of long-term hematopoietic stem cells.

The transcription factor GATA-3 is expressed and required for differentiation and function throughout the T lymphocyte lineage. Despite evidence it may also be expressed in multipotent hematopoietic stem cells (HSCs), any role for GATA-3 in these cells has remained unclear. Here we found GATA-3 was in the cytoplasm in quiescent long-term stem cells from steady-state bone marrow but relocated to the nucleus when HSCs cycled.

Role of tachykinin 1 and 4 gene-derived neuropeptides and the neurokinin 1 receptor in adjuvant-induced chronic arthritis of the mouse.

Objective: Substance P, encoded by the Tac1 gene, is involved in neurogenic inflammation and hyperalgesia via neurokinin 1 (NK1) receptor activation. Its non-neuronal counterpart, hemokinin-1, which is derived from the Tac4 gene, is also a potent NK1 agonist. Although hemokinin-1 has been described as a tachykinin of distinct origin and function compared to SP, its role in inflammatory and pain processes has not yet been elucidated in such detail.