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In this work we studied the effect of different concentrations of interleukin-2 (IL-2) and interferon-γ (IFN-γ) on the proliferation and immunophenotype of lymphocytes obtained from patients with locally advanced breast cancer (stage II-III) after immunomagnetic depletion of regulatory T cells (Tregs) from the general pool of lymphocytes in vitro. The peripheral blood of 11 patients was used as a material. Peripheral blood mononuclear cells (MNCs) were isolated and regulatory T lymphocytes were removed by immunomagnetic separation. After separation, the cells were cultured in a nutrient medium RPMI-1640 with 10% fetal bovine serum (FBS) for 7 days. Lymphocytes were activated on the first day of cultivation with one of the following cytokines: IFN-γ (10 IU/mL), IL-2 (0.1 or 1 μg/mL); IL-2 (0.1 or 1 μg/mL) and IFN-γ together. Lymphocytes without cytokine addition was used as a control. Cells were counted using an automatic counter before addition cytokines and after 2, 4, and 7 days of cultivation with cytokines, and their phenotype was examined. The results showed some phenotypic differences in some elements of cellular immunity between control and experimental samples. Particular attention is paid to the description of changes in the expression of surface markers in the natural killer (NK) subpopulation. It was noted that the proportion of Tregs, despite their preliminary depletion, increased after exposure to cytokines. As a result, the preliminary decrease in the proportion of Treg cells before the stimulation of lymphocytes did not produce the expected effect, therefore the use of depletion in such a methodological mode did not lead to significant results. However, one should not exclude the possibility of inhibiting Tregs by other methods.

This study elucidates the mechanism of CCL25 and CCR9 in rheumatoid arthritis (RA). RA synovial fluid (SF) expresses elevated levels of CCL25 compared to OA SF and plasma from RA and normal. CCL25 was released into RA SF by fibroblasts (FLS) and macrophages (MΦs) stimulated with IL-1β and IL-6. CCR9 is also presented on IL-1β and IL-6 activated RA FLS and differentiated MΦs. Conversely, in RA PBMCs neither CCL25 nor CCR9 are impacted by 3-month longitudinal TNF inhibitor therapy. CCL25 amplifies RA FLS and monocyte infiltration via p38 and ERK phosphorylation. CCL25-stimulated RA FLS secrete potentiated levels of IL-8 which is disrupted by p38 and ERK inhibitors. CCL25 polarizes RA monocytes into nontraditional M1 MΦs that produce IL-8 and CCL2. Activation of p38 and ERK cascades are also responsible for the CCL25-induced M1 MΦ development. Unexpectedly, CCL25 was unable to polarize RA PBMCs into effector Th1/Th17 cells. Consistently, lymphokine like RANKL was uninvolved in CCL25-induced osteoclastogenesis; however, this manifestation was regulated by osteoclastic factors such as RANK, cathepsin K (CTSK), and TNF-α. In short, we reveal that CCL25/CCR9 manipulates RA FLS and MΦ migration and inflammatory phenotype in addition to osteoclast formation via p38 and ERK activation.

1. The objective of this study was to investigate the potential immunomodulatory effects of yeast (Saccharomyces cerevisiae) and yeast-derived products treated with a cell wall lytic enzyme mixture on the gene expression of toll-like receptors and cytokines of chicken B cell line (DT 40) stimulated with lipopolysaccharide. 2. The effect of brewer's yeast (Y), yeast cell wall (YCW), distilled dried grains with solubles (DDGS) and a processed yeast + nucleotide-rich product (PY/N) treated with a yeast cell wall lytic enzyme (E) was assessed using a chicken B cells and LPS challenge model. 3. Relative gene expression of toll-like receptors (TLRs) and cytokines was investigated. Treatment of cells with Y, YCW, YCW + E and PY/N upregulated the expression of TLR2b following LPS challenge. Gene expression of TLR4 was downregulated in E, YCW and YCW + E treatments compared to control, while adding DDGS and PY/N upregulated the expression of TLR4 either before or after enzyme treatment. Following LPS challenge, expression of IL-4 and IL-10 was upregulated in cells treated with YCW and PY/N, both pre and post enzyme incubation. Adding YCW and PY/N to the cells challenged with LPS upregulated the expression of IFN-γ and IL-12 before and after enzyme treatment. Treatment of cells with YCW, DDGS and PY/N increased the expression of IL-6 prior to LPS challenge. 4. In conclusion, the results suggested that yeast-derived products affected immunomodulatory activities by changing the expression of cytokines involved in the innate immune response.

The current study aimed to reduce the toxic effect of different mycotoxins and enhance the immunity against ND virus in broiler chickens by using lymphokines from hyperimmunized birds with Salmonella typhymurium. The study included three stages, the first stage included isolating Salmonella typhymurium. The second stage was immunized chicks with Salmonella typhymurium. The final stage of the study was accomplished by treating 250 broiler chicks (divided into 5 groups, 50 chicks /each) with the following treatments; G1: 0.5 ml lymphokines was injected I/P at day one old with live ND vaccine (la Sota strain) after 30 minutes in drinking water, the process repeated after 10 days; G2: the same as in G1 but inactivated killed vaccine was used s/c,no repetition was carried out at 10 days ; G3: a combination of G1 and G2 with revaccination of live La Sota vaccines only at 10 days; G4 : only vaccinated with live La Sota vaccine repeated at 10 days; G5: no treatments (negative control). All groups were challenge with local isolate of NDV (100ELD50 105) at 25 days, all groups except the fifth group were fed on contaminated diet withmycotoxin. The results of the present study showed a significant increase (P 0.05) in the oxidation status (H2O2, MDA and LPO) and significant increase in the antioxidant defense (GSH-PX) in the liver and spleen samples. We conclude from the current study that the Salmonella immune lymphokines (SIL) helps in enhancement the level of immunity against Newcastle disease and n reduction the side effects of which mycotoxin.

The axial organ is considered as ancestral lymphoïd organ. It contains T and B sea star lymphocytes and Phagocytes. It plays a fundamental rôle in the sea star cell-mediated immune responses and humoral immune ones.Asterids belong to Echinoderma (Invertebrates).An expected rôle of Tiedemann’s bodies is evoked.

© 2015 Springer-Verlag Berlin Heidelberg Profound alterations characterize the adaptive immune response in systemic sclerosis, and several layers of evidence support a prominent role exerted by immune cellular effectors and humoral mediators in the pathogenesis of this disease. These include (i) the presence of oligoclonal T cells in tissues undergoing fibrosis consistent with (auto)antigen-specific recruitment, (ii) the preferential expansion of polarized CD4+ and CD8+ T cells producing pro-fibrotic cytokines such as IL-4 and IL-13, (iii) the presence of increased number of cells producing mediators belonging to the IL-17 family, including IL-22, which may drive and participate in inflammatory pathways involving epithelial cells as well as fibroblasts, (iv) the deficient or redirected function of T regulatory cells favoring fibrosis, and (v) the enhanced expression of CD19 and CD21 on naïve B cells, and the upregulation of co-stimulatory molecules in mature B cells, which together with the increased levels of B cell activating factor (BAFF) underlie the propensity to an exaggerated humoral response possibly favoring fibrogenesis. Despite all the progress made in understanding the features of the aberrant immune response in scleroderma, it remains unclear whether the activation of immune effector pathways ultimately drives the disease pathogenesis or rather represents a defective attempt to limit or even reverse excessive extracellular matrix deposition and progressive vasculopathy, the main hallmarks of this disease.

SUMMARYThe histone modifier Trichostatin A (TSA) ameliorated diabetes and repressed IFN-γ and IL-17A expression in prediabetic female NOD mice. Purified CD4+ cells could be polarized ex vivo into Th1 and Th17 subsets, which comparably transferred diabetes into NOD.scid mice. Polarized Th1 cells were devoid of IL-17A-producing cells and did not transdifferentiate into Th17 cells in an immunodeficient environment. However, Th17 cells had contaminant Th1 cells, which expressed IFN-γ upon adoptive transfer into lymphopenic recipients. Notably, TSA treatment abrogated the transfer of diabetes by CD4+ T-cells cultured under Th1 or Th17 polarizing conditions accompanied by the absence of Ifng and Il17a expression in NOD.scid recipients. Significantly, the histone modifier restored the ability of CD4+ but not CD8+ T-cells to undergo CD3-mediated apoptosis ex vivo in a caspase-dependent manner. Thus, the histone modifier afforded protection against autoimmune diabetes by negative regulation of signature lymphokines and restitution of self-tolerance in CD4+ T cells.

The macrolide antibiotics, FK 506 and rapamycin, have been reported to be potent immunosuppressive drugs. Both FK506 and rapamycin bind to the immunophilin macrophilin-12. Rapamycin, however, acts on T cells by a different mode of action which does not affect the transcription of lymphokines. The anti-inflammatory effects of FK 506 and rapamycin have been tested in mouse models of irritant dermatitis after topical application, and in allergic contact dermatitis after topical or oral application, using mice and domestic pigs. In irritant dermatitis, both FK 506 and rapamycin exerted significant, but moderate topical activity at concentrations of 0.4-3.6%. In allergic contact dermatitis, topical FK 506 proved to be highly active at concentrations of 0.01-0.1% and even superior to corticosteroids. In contrast, rapamycin was inactive. After oral treatment of mice, FK506 was significantly active (2 × 30mg/kg/ day) while rapamycin was inactive up to the highest dose tested (2 × 90 mg/kg/ day). These results indicate that, despite the chemical similarity of FK 506 and rapamycin and their common intracellular receptor, there are different fundamental pharmacological properties of FK 506 and rapamycin, which may reflect their different modes of action.

Background: Monoclonal antibodies plays an important role in surgical disease practice specially cancers, Crohn's Disease and ulcerative colitits. Monoclonal antibodies is a type of biological therapy that utilizes a person’s natural immune defense system to fight diseases. Monoclonal antibodies for cancers is essentially the stimulation of immune system via a variety of reagents such as vaccines infusion of T cells or cytokines. These reagents reacted through one of several mechanisms: 1- By stimulating the antitumor response either by increasing the number of effector cells or be production one or more soluble mediators such as lymphokines. 2- By decreasing suppressors mechanisms. 3- By altering tumor cells to increase their immunogenicity and make them more susceptible to immunological defenses. 4- By improving tolerance to cytotoxic drugs or radiotherapy such as stimulating bone marrow function with granulocyte colony stimulating factor (G- CSF). Monoclonal antibodies is a type of immunotherapy but there is another types of immunotherapy such as nonspecific immunotherapies and cancer vaccines mechanism of monoclonal antibodies in surgical disease. Objective: This work was aimed to study the role of monoclonal antibodies in surgical disease as a new tool to surgical armamentarium. Conclusion: It could be concluded from this study that monoclonal antibodies helps the body to fight disease and infection. Monoclonal antibodies are used to treat many types of carcinoma and cancers.

IL-4 is critical for differentiation of Th2 cells and antibody isotype switching, but our work demonstrated that it is produced in the peripheral LN under both Type 2, and Type 1 conditions, raising the possibility of other functions. We found that IL-4 is vital for proper positioning of hematopoietic and stromal cells in steady state, and the lack of IL-4 or IL-4Rα correlates with disarrangement of both follicular dendritic cells and CD31(+) endothelial cells. We observed a marked disorganization of B cells in these mice, suggesting that the lymphocyte-stromal cell axis is maintained by the IL-4 signaling pathway. This study showed that absence of IL-4 correlates with significant downregulation of Lymphotoxin alpha (LTα) and Lymphotoxin beta (LTβ), critical lymphokines for the development and maintenance of lymphoid organs. Moreover, immunization of IL-4 deficient mice with Type 2 antigens failed to induce lymphotoxin production, LN reorganization, or germinal center formation, while this process is IL-4 independent following Type 1 immunization. Additionally, we found that Type 1 antigen mediated LN reorganization is dependent on IFN-γ in the absence of IL-4. Our findings reveal a role of IL-4 in the maintenance of peripheral lymphoid organ microenvironments during homeostasis and antigenic challenge.

Neoplastic processes occurring in the central nervous system (CNS) have remained a very difficult problem in oncology. Two manifestations of CNS malignancy have been the subjects of recent investigations utilizing lymphokine-activated killer (LAK) cells: primary astrocytic tumors, and leptomeningeal spread of tumor from primary CNS processes or from distant malignancies. Leptomeningeal spread of primary neoplastic processes in the CNS, or spread of non-CNS malignancies, into spinal fluid pathways results in a generally therapeutically refractory burden of leptomeningeal disease. The stimulation of peripheral lymphocytes with interleukin-2, with the resultant transformation to LAK cells with its attendant tumoricidal states was first reported by E. A. Grimm and her associates in 1982. The encumbrances to the application of current LAK cell therapy to this focal disease in the brain continue to be vexing problems in applying LAK or other cytotoxic therapeutic modality to brain tumors.

Coronavirus Disease 2019 (COVID-19) morbidity and mortality was found to be less severe in countries where Bacille Calmette – Guerin (BCG) vaccination of the population is carried out. Conjugating Purified Protein Derivative (PPD) onto tumour cells and injecting into BCG primed mice was found to enhance anti-tumour immune response. We had proposed earlier that in vitro activated autologous anti-tumour T-cells bearing Major Histocompatibility Complex (MHC) II on their surface, if pulsed with PPD and re-infused in a BCG – primed patient, can activate PPD – specific helper T-cells and the focused secretion of lymphokines like the IL-2 can selectively amplify the antitumor T-cell response by their proliferation and activation in a specific manner bypassing the suppression exerted by the anti-idiotypic and suppressor cells. The prime – boost strategy with the BCG–PPD system can also be applied to the immunoprophylaxis and immunotherapy of COVID-19. The autologous anti-Corona virus B and T lymphocytes can be activated in vitro by inactivated virus or mitogens like Concanavalin A to express MHC class II molecules on their surface and pulsed with PPD for carrier targeting in vivo. Such PPD – pulsed activated (MHC-II+ve) anti-viral lymphocytes if transfused back into a patient already vaccinated with BCG during childhood or primed with BCG during adulthood 2 weeks before transfusion, could lead to a high magnitude of selective in vivo amplification of specific anti-viral lymphocytes, which can mount adequate and appropriate immune response to get rid of the virus and cure the patient from COVID-19. Conjugating antigens to PPD and injecting into BCG primed humans may also be helpful for immunoprophylaxis against COVID-19. Thus, PPD may prove to be the red herring in the BCG therapy of COVID-19.

We have previously demonstrated that treatment of female NOD mice with the histone deacetylase inhibitor Trichostatin A (TSA) bestowed irreversible protection against autoimmune diabetes. Herein we show that drug treatment diminished the infiltration of the pancreas with CD4+ and CD8+ T cells and Ly-6C+ monocytes. Significantly, TSA administration selectively repressed the expression of a set of genes exaggerated during diabetes and constitutively expressed primarily in the spleen and rarely in the pancreas. These genes encode lymphokines, macrophage-associated determinants, and transcription factors. Although the copy numbers of many histone deacetylases increased during diabetes in the spleen and pancreas, only those upregulated in the spleen were rendered sensitive to repression by TSA treatment. The T lymphocytes derived from drug-treated donors displayed diminished diabetogenic potential following transfer into immunodeficient NOD.scid mice. In the immunocompromised recipients, diabetes caused by the transfer of activated T lymphocytes from untreated diabetic mice was hampered by the co-transfer of highly purified splenic Ly-6C+ macrophages from drug-treated mice. However, the transfer of Ly-6C+ macrophages from drug-treated mice failed to block ongoing diabetes in wild-type NOD mice. These data demonstrate that the modified gene expression and functional alteration of T lymphocytes and macrophages collectively contribute to diabetes protection afforded by the histone modifier in female NOD mice.

Simple Summary Cytokines are small proteins that impact health and disease. They regulate cell signaling and have been shown to affect the immune response to various diseases, including cancer. Brain metastasis is a deadly disease. When cancer from the lungs, breast, or skin spreads to the brain, the survival of patients decreases. Therefore, understanding how cytokines affect and modulate the metastatic spread of cancer to the brain can help in improving diagnostic capabilities and therapeutic outcomes. Abstract Brain metastases are the most common of all intracranial tumors and a major cause of death in patients with cancer. Cytokines, including chemokines, interferons, interleukins, lymphokines, and tumor necrosis factors are key regulators in the formation of brain metastases. They regulate the infiltration of different cellular subsets into the tumor microenvironment and affect the therapeutic outcomes in patients. Elucidating the cancer cell-cytokine interactions in the setting of brain metastases is crucial for the development of more accurate diagnostics and efficacious therapies. In this review, we focus on cytokines that are found in the tumor microenvironment of brain metastases and elaborate on their trends of expression, regulation, and roles in cellular recruitment and tumorigenesis. We also explore how cytokines can alter the anti-tumor response in the context of brain metastases and discuss ways through which cytokine networks can be manipulated for diagnosis and treatment.

Elevated concentrations of circulating low density lipoprotein (LDL) that is abnormally oxidized and desialylated is both a precursor to and a hallmark of atherosclerosis. Peripheral blood mononuclear cells (PBMCs) treated in vitro with interleukin-2 (IL-2) become lymphokine activated killer (LAK) cells, the primary effectors of which are NK cells and NKT cells. LAK cells display antitumor functions such as increased cytotoxicity and IFN-γ production, and they have been evaluated as a potential cancer therapeutic. Atherosclerotic processes may influence innate immunity against cancer. Because prior studies have shown that low density lipoprotein (LDL) reduces T-cell and NK cell antitumor functions, we asked whether oxidized-desialylated LDL affects the functionality of LAK cells in vitro. We show here that LAK cells take up oxidized-desialylated LDL to a significantly greater extent than native LDL over a period of 72 hours. This resulted in a significant downregulation of LAK cell cytotoxicity against K562 cells. In particular, the expression of IFN-γ, CD56, and NKG2D were reduced upon oxidized-desialylated LDL treatment of LAK cells and, conversely, their expression was enhanced with native LDL. It was also observed that as the number of CD56 and NKG2D positive cells decreased upon treatment with oxidized-desialylated LDL, the number of CD3 positive cells increased in proportion. Additionally, only a slight inhibition of LAK cell cytotoxicity was observed with desialylation alone of LDL, and no significant inhibition was observed with oxidation alone of LDL. Thus, this study describes a new role of oxidized-desialylated LDL as an inhibitor of the antitumor functions of LAK cells. These observations have implications for how atherosclerosis processes, namely oxidation and desialylation of LDL, may influence LAK cell antitumor activity.

SARS -CoV-2; covid-19 and multiple influenza forms such as H5N1 influenza virus can be lethal to humans due to an overreaction...

The mononuclear phagocyte system (MPS) is a family of cells of related function that includes bone marrow progenitors, blood monocytes and resident tissue macrophages. Macrophages are effector cells in both innate and acquired immunity. They are a major resident cell population in every organ and their numbers increase in response to proinflammatory stimuli. Their function is highly regulated by a wide range of agonists, including lymphokines, cytokines and products of microorganisms. Macrophage biology has been studied most extensively in mice, yet direct comparisons of rodent and human macrophages have revealed many functional differences. In this review, we provide an overview of the equine MPS, describing the variation in the function and phenotype of macrophages depending on their location and the similarities and differences between the rodent, human and equine immune response. We discuss the use of the horse as a large animal model in which to study macrophage biology and pathological processes shared with humans. Finally, following the recent update to the horse genome, facilitating further comparative analysis of regulated gene expression between the species, we highlight the importance of future transcriptomic macrophage studies in the horse, the findings of which may also be applicable to human as well as veterinary research.

Flares of joint inflammation and resistance to currently available biologic therapeutics in rheumatoid arthritis (RA) patients could reflect activation of innate immune mechanisms. Herein, we show that a TLR7 GU-rich endogenous ligand, miR-Let7b, potentiates synovitis by amplifying RA monocyte and fibroblast (FLS) trafficking. miR-Let7b ligation to TLR7 in macrophages (MΦs) and FLSs expanded the synovial inflammatory response. Moreover, secretion of M1 monokines triggered by miR-Let7b enhanced Th1/Th17 cell differentiation. We showed that IRAK4 inhibitor (i) therapy attenuated RA disease activity by blocking TLR7-induced M1 MΦ or FLS activation, as well as monokine-modulated Th1/Th17 cell polarization. IRAK4i therapy also disrupted RA osteoclastogenesis, which was amplified by miR-Let7b ligation to joint myeloid TLR7. Hence, the effectiveness of IRAK4i was compared with that of a TNF inhibitor (i) or anti-IL-6R treatment in collagen-induced arthritis (CIA) and miR-Let7b-mediated arthritis. We found that TNF or IL-6R blocking therapies mitigated CIA by reducing the infiltration of joint F480(+)iNOS(+) MΦs, the expression of certain monokines, and Th1 cell differentiation. Unexpectedly, these biologic therapies were unable to alleviate miR-Let7b-induced arthritis. The superior efficacy of IRAK4i over anti-TNF or anti-IL-6R therapy in miR-Let7b-induced arthritis or CIA was due to the ability of IRAK4i therapy to restrain the migration of joint F480(+)iNOS(+) MΦs, vimentin(+) fibroblasts, and CD3(+) T cells, in addition to negating the expression of a wide range of monokines, including IL-12, MIP2, and IRF5 and Th1/Th17 lymphokines. In conclusion, IRAK4i therapy may provide a promising strategy for RA therapy by disconnecting critical links between inflammatory joint cells.

Background Regardless of the agent, the inflammatory response is interconnected with infection. Mostly the initial response to infection is severe sepsis and characterized by a pro-inflammatory state, which then progresses to an anti-inflammatory state that develops and favors secondary infections (Florescu and Kalil, 2011) [1]. T-helper 1 (Th1) cells activated by microorganisms increase transcription of pro-inflammatory cytokines such as tumor necrosis factor (TNF-α), interferon-γ (INF-γ), and interleukin-2 (IL-2) (Hotchkiss and Karl, 2003; Brown and Jones, 2004; Russell, 2006) [[2], [3], [4]]. Different cytokines, TNF-α, interleukins, lymphokines, monokines, IFN-γ, colony-stimulating factor (CSF) and transforming growth factors, released from endothelial cells and subsequently from macrophages can induce lymphocyte activation and infiltration at the sites of infection and will exert direct antiviral effects. Subsequently, with the shift toward an anti-inflammatory state, activated T-helper 2 (Th2) cells secrete interleukin-4 (IL-4) and interleukin-10 (IL-10) (Hotchkiss and Karl, 2003; Russell, 2006) [2,4]. Sometimes, T cells can become anergic and fail to proliferate as wells producing cytokines (Hotchkiss and Karl, 2003) [2]. Type I IFN has a potent anti-influenza virus activity, it induces transcription of several interferon-stimulated genes, which in turn restrict viral replication (Garcia-Sastre, 2011) [5]. However, the influenza virus developed several mechanisms to evade IFN response as NS1 protein, IFN-antagonist produced by the virus, PB1–F2 proteins that inhibit IFN induction, the viral polymerase inhibits IFN function, and M2 protein prevents toll-like receptor (TLR) induction (Garcia-Sastre, 2011) [5]. Influenza virus can also trigger the deregulation of the innate immune system with excessive cytokines release leading to potentially harmful consequences (Teijaro et al., 2011) [6]. Abnormal immune response to influenza can lead to endothelial damage through the remodeling of the cellular cytoskeleton, loss of intercellular junctional integrity, cellular apoptosis, deregulation of coagulation, the consequent alteration of microvascular permeability, tissue edema, and shock (Steinberg et al., 2012) [7]. This increase in permeability of the endothelium is mainly due to the intercellular pathways and to a lesser extent through the transcellular leak (Steinberg et al., 2012) [7]. Such vascular hyperpermeability and multi-organ failure with severe edema, shock, acute lung injury, and even acute encephalopathy have been described in severe influenza infections (Wang et al., 2010; Armstrong et al., 2013) [8,9]. Novel drugs and vaccines such as peramivir, baloxavir marboxil, and 4 egg-based quadrivalent inactivated influenza vaccines have been added recently [10]. These changes require better and more efficient diagnostic and therapeutic approaches to avoid a fatal progression. I would like to report a child patient with H1N1 influenza, who developed rapid fatal viral septicemia.

Abstract The phytotherapeutic compound EPs® 7630, an extract manufactured from Pelargonium sidoides roots, is frequently used for the treatment of airway infections. Nevertheless, the knowledge of the mode of action of EPs® 7630 is still sparse. Our study aimed at further elucidating the underlying pharmacological mechanisms by focusing on antimicrobial defense mechanisms of EPs® 7630. While investigating the influence of EPs® 7630 on lymphokine production by PBMCs, we found that EPs® 7630 is a novel inducer of IL-22 and IL-17. This cytokine-inducing effect was most pronounced for IL-22 and clearly dose-dependent starting from 1 μg/ml of the extract. Furthermore, EPs® 7630 pretreatment selectively enhanced the IL-22 and IL-17 production capacity of CD3/28-activated PBMCs while strongly limiting the IFN-γ production capacity of innate lymphoid cells. The relevance of EPs® 7630–induced IL-22 production was proven in vitro and in vivo, where IL-22 provoked a strong increase of the antimicrobial protein S100A9 in lung epithelial cells and pulmonary tissue, respectively. A detailed analysis of IL-22 induction modi revealed no direct influence of EPs® 7630 on the basal or anti-CD3/CD28 antibody-induced IL-22 production by CD4+ memory T cells. In fact, EPs® 7630–induced IL-22 production by CD4+ memory T cells was found to be essentially dependent on soluble mediators (IL-1/IL-23) as well as on direct cellular contact with monocytes. In summary, our study reveals a new immune-modulating function of EPs® 7630 that might confer IL-22 and IL-17-induced protection from bacterial airway infection. Key messages EPs® 7630 selectively strengthens IL-22 and IL-17 production of memory T cells. EPs® 7630 limits the IFN-y production capacity of innate lymphoid cells. EPs® 7630–caused IL-22 production by T cells is essentially dependent on monocytes. IL-22 increase antimicrobial proteins (AMPs) in airway epithelium. EPs® 7630 might protect against airway infection by induction of AMP-inducers.

Interferon regulatory factor 4 (IRF4) is a multifunctional transcription factor that plays an important regulatory role in the interferon (IFN) signaling. IRF4 participates in the process of anti-virus, Th cell differentiation and B cell maturation by regulating the expression of IFN and some lymphokines. In this study, Cherry Valley duck IRF4 (duIRF4) was cloned and its cDNA was analyzed. Expression of duIRF4 in a wide variety of tissues and changes in duIRF4 expression due to viral infection also was detected by quantitative real-time PCR. The results show that duIRF4 contains 1341 bp of ORF encoding a protein with 446 amino acids and contains three domains: DNA-binding domain (DBD), IRF-association domain (IAD) and nuclear localization signal (NLS). Quantitative real-time PCR analysis showed that duIRF4 was evenly expressed in all tissues examined, with the highest expression in the spleen, followed by the bursa of Fabricius, and lower in the skin and brain. In addition, expression of duIRF4 in the brain and spleen was significantly up-regulated after being infected by duck plague virus, duck Tembusu virus, and novel duck reovirus. These data suggest that duIRF4 may be involved in innate immune response.

Cytokines are proteins secreted by diverse types of immune and non-immune cells and play a role in the communication between the immune and nervous systems. Cytokines include lymphokines, monokines, chemokines, interleukins, interferons, colony stimulating factors, and growth factors. They can be both pro- and anti-inflammatory and have autocrine, paracrine, and endocrine activities. These proteins are involved in initiation and persistence of pain, and the progress of hyperalgesia and allodynia, upon stimulating nociceptive sensory neurons, and inducing central sensitization. The objective of this review is to discuss several types of pro- and anti-inflammatory mediators and their relation with inflammatory pain in masticatory muscles.

Collagen from marine organisms has a broad prospect in biomedical field, yet the knowledge on marine-derived type II collagen is rare. Herein, a novel type II collagen was successfully isolated from squid cartilage for the first time. After being characterized, the immunogenicity of squid type II collagen (SCII) was evaluated and compared with that of bovine type II collagen (BCII). Then investigations were further conducted for the impacts of SCII on pro-inflammatory macrophages and macrophage chemotaxis. The degenerative osteoarthritis (OA) -relieving effects of SCII were explored using OA rat model in vivo. Our results demonstrated that the isolated SCII maintained triple-superhelical structure of native collagen with high purity. Different from BCII, SCII presented no immunogenicity since it neither induced abnormal proliferation of lymphocytes in vitro nor changed the basic levels of IgM, IgG, anti-type II collagen IgG and CD4+/CD8+ lymphocytes ratio in vivo. Additionally, SCII also exerted prominent anti-inflammatory effects. SCII significantly reduced the production of pro-inflammatory cytokines by enhancing the activity of TCPTP and subsequently prompting the dephosphorylation of p-STAT1 in pro-inflammatory macrophages. Besides, it indirectly prevented hypertrophic changes of chondrocytes, and markedly impeded chemotaxis of macrophages. Moreover, inflammation condition in OA rats was significantly alleviated under treatment with SCII. These data suggested that the newly developed SCII could not only avoid the immunogenic risks of collagen derived from terrestrial animals, but more importantly, provide new choice for the control and treatment of OA.

Lysophosphatidylserine (LysoPS) has been shown to have lipid mediator-like actions to induce mast cell degranulation and suppress T lymphocyte proliferation. Recently, three G protein-coupled receptors (GPCRs), LPS1/GPR34, LPS2/P2Y10, and LPS3/GPR174, were found to react specifically with LysoPS, raising the possibility that LysoPS exerts its roles through these receptors. In this study, we show that LPS3 is expressed in various T cell subtypes and is involved in suppression of Interleukin-2 (IL-2) production in CD4 T cells. We found that LysoPS suppressed the IL-2 production from activated T cells at the mRNA and protein levels. In addition, LysoPS did not have such an effect on the splenocytes and CD4 T cells isolated from LPS3-deficient mice. In LPS3-deficient splenocytes and CD4 T cells, anti-CD3/anti-CD28-triggered IL-2 production is somewhat increased. Interestingly, LysoPS with various fatty acids was up-regulated upon T cell activation. The present study raised the possibility that LysoPS exerts its immunosuppressive roles by down-regulating IL-2 production through a LysoPS-LPS3 axis in T cells.

Contains fulltext : 181947pub.pdf (Publisher’s version ) (Open Access) Tumors can be divided into 'hot' (T cell inflamed) or 'cold' (T cell noninflamed) according to the presence of immune cells. In this review, we discuss variables that influence T cell migration into the tumor microenvironment. Chemokines can attract T cells to the tumor site and tumor intrinsic pathways can influence the composition of local chemokines. Tumor-induced vasculature can hamper T cell migration. Other immune cells and tumor-derived molecules can block T cell proliferation and survival. It is important to better understand these mechanisms in order to target them therapeutically. Enhancing T cell infiltration may increase response rates to immunotherapy and increase survival.

Although studies have linked soy phytoestrogen 4,7,4-trihydroxyisoflavone genistein (GEN) to reduced type 1 diabetes (T1D) risk, the mechanism of dietary GEN on T1D remains unknown. In our studies, adult non-obese diabetic (NOD) mouse model was employed to investigate the effects of GEN exposure on blood glucose level (BGL), glucose tolerance, gut microbiome, and immune responses. Adult male and female NOD mice were fed with either soy-based or casein-based diet, and received GEN at 20mg/kg body weight by gavage daily. The BGL and immune responses (represented by serum antibodies, cytokines and chemokines, and histopathology) were monitored, while the fecal gut microbiome was sequenced for 16S ribosomal RNA to reveal any alterations in gut microbial communities. A significantly reduced BGL was found in NOD males fed with soy-based diet on day 98 after initial dosing, and an improved glucose tolerance was observed on both diets. In addition, an anti-inflammatory response (suggested by reduced IgG2b and cytokine/chemokine levels, and alterations in the microbial taxonomy) was accompanied by an altered β-diversity in gut microbial species. Among the NOD females exposed to GEN, a later onset of T1D was observed. However, the profiles of gut microbiome, antibodies and cytokines/chemokines were all indicative of pro-inflammation. This study demonstrated an association among GEN exposure, gut microbiome alteration, and immune homeostasis in NOD males. Although the mechanisms underlying the protective effects of GEN in NOD mice need to be explored further, the current study suggested a GEN-induced sex-specific effect in inflammatory status and gut microbiome.

Korin et al. use CyTOF mass cytometry to characterize immune cell populations in the naive mouse brain (parenchyma, choroid plexus and meninges). This single-cell analysis of cell-surface proteins reveals the presence and phenotype of distinctive immune populations in the mouse brain compartment. The brain and its borders create a highly dynamic microenvironment populated with immune cells. Yet characterization of immune cells within the naive brain compartment remains limited. In this study, we used CyTOF mass cytometry to characterize the immune populations of the naive mouse brain using 44 cell surface markers. By comparing immune cell composition and cell profiles between the brain compartment and blood, we were able to characterize previously undescribed cell subsets of CD8 T cells, B cells, NK cells and dendritic cells in the naive brain. Using flow cytometry, we show differential distributions of immune populations between meninges, choroid plexus and parenchyma. We demonstrate the phenotypic ranges of resident myeloid cells and identify CD44 as a marker for infiltrating immune populations. This study provides an approach for a system-wide view of immune populations in the brain and is expected to serve as a resource for understanding brain immunity.

Infection with the hepatitis C virus (HCV) may progress toward chronic hepatitis, liver cirrhosis, and liver cancer. A therapy for patients with chronic HCV infection is the combination of pegylated interferon-α with ribavirin, which increases the rate of sustained virological response (SVR) to 56%. However, a practical biomarker to predict SVR is lacking. T cells expressing the CD45RA isoform are considered naive, and antigenic stimulation converts them to CD45RO+. CD45RO+ T cells exhibit immediate response and high lymphokine production, leading to the maintenance and upregulation of immune reactions. The aim of this study is to clarify the proportions of CD45RA+ and CD45RO+ T cells associated with rapid virological response and SVR. We collected blood samples from 32 HCV patients receiving the combined treatment. The samples were collected before, during 4th, 12th, and 24th therapy weeks, and 4th week posttherapy, and their T cell populations were analyzed using flow cytometry. Twenty-nine patients (90...

We have reported that excessive nitric oxide (NO), like other reactive oxygen species (ROS), causes a decrease in cytochrome c oxidase (CCO) activity and ATP levels (mitochondrial damage) resulting in lens opacity. In addition, previous reports have shown that oxidative stress caused by ROS enhances amyloid β (Aβ) production in mammalian lenses, and that Aβ1-42 stimulates inducible nitric oxide synthase (iNOS) promoter activity. Based on these reports, we investigated the relationship between NO and Aβ1-42 production in human lens epithelial (HLE) cells. iNOS was induced by the co-incubation of HLE cells with 1000 IU interferon-γ (IFN-γ) and 100ng/ml lipopolysaccharide (LPS) for 48h. This led to enhanced NO release, an increase in the gene expression levels of proteins related to Aβ production, and the cellular accumulation of Aβ1-42. Moreover, both aminoguanidine (AG, a selective inhibitor of iNOS) and diethyldithiocarbamate (DDC, a nuclear factor-kappa B (NFκB) inhibitor) attenuated these changes in IFN-γ and LPS stimulated HLE cells. Based on our finding that Aβ1-42 accumulation is induced by co-incubation of HLE cells with both IFN-γ and LPS, we prepared a HLE cell model with Aβ1-42 accumulation (Aβ-accumulated-HLE cell model) by pre-stimulating cells with IFN-γ and LPS for 48h. Aβ1-42 accumulation caused NO production via iNOS, resulting in an enhancement in the mRNA levels for enzymes necessary for the proteolysis of amyloid precursor protein (APP) to Aβ in HLE cells. In addition, excessive NO produced in response to Aβ1-42 accumulation led to a decrease in CCO activity and ATP levels. Taken together, we hypothesize that excessive NO production in the lens epithelium enhances Aβ1-42 production, and that this enhancement accelerates NO release. The enhancement in NO production in the lens epithelium based on positive feedback (NO-Aβ positive feedback loop, a vicious cycle) may promote the onset of cataracts (lens opacification) via the decrease in CCO activity and ATP levels. These findings provide significant information that can be used to design further studies aimed at developing anti-cataract drugs.

Survival of various immune cell populations has been proposed to preferentially rely on a particular anti-apoptotic BCL-2 family member, for example, naive T cells require BCL-2, while regulatory T cells require MCL-1. Here we examined the survival requirements of multiple immune cell subsets in vitro and in vivo, using both genetic and pharmacological approaches. Our findings support a model in which survival is determined by quantitative participation of multiple anti-apoptotic proteins rather than by a single anti-apoptotic protein. This model provides both an insight into how the sum of relative levels of anti-apoptotic proteins BCL-2, MCL-1 and A1 influence survival of T cells, B cells and dendritic cells, and a framework for ascertaining how these different immune cells can be optimally targeted in treatment of immunopathology, transplantation rejection or hematological cancers.

Inhibition of the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway for immunosuppression in solid organ transplantation is appealing due to its specificity for immune cell function, particularly for JAK3. This is due to its unique association with only the common gamma chain (γc). The γc is an appealing immunosuppression target in transplantation because of the critically important lymphokines that act at it, including IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. Tofacitinib was initially purported to selectively inhibit solely JAK3, but subsequent analyses have also demonstrated its activity at the other members of the JAK family. Clinical outcomes have validated tofacitinib's pan-JAK activity in kidney transplantation after demonstrating an increased risk of infection and malignancy as compared to CNI-based regimens. After these trials, tofacitinib investigation for use in transplantation has effectively ceased. However, a post-hoc analysis has shed new light on the monitoring of tofacitinib exposure in order to predict infection and oncologic events. With new methods to monitor tofacitinib exposure, clinicians may be able to effectively reduce toxicities while providing a high level of immunosuppression. The purpose of this review to identify when, and for whom, JAK inhibitors may provide benefit in solid organ transplantation.

The skin immune system is composed of a vast network of immune cells, including lymphocytes, macrophages, neutrophils, dendritic cells and Langerhans cells, which not only are involved in inflammatory responses but also contribute to homeostatic function and may participate in the various steps of carcinogenesis. Many studies support the notion that innate immunity has a key role in the development, growth and prognosis of cutaneous malignant melanoma (MM), through the release of pro- and/or anti-inflammatory cytokines and tumour growth factors. The tumour environment in a major subset of cutaneous MM shows evidence of a T cell-infiltrated phenotype, but there is less known about the presence and the phenotype of other immune system cells. Response to immunotherapy is largely correlated with the presence of T cells in the tumour microenvironment, while the regulation exerted by stromal components such as macrophages and mast cells has been less investigated. In the current report, we review the recent literature, focusing our attention on the role of macrophages, dendritic cells, mast cells and natural killer cells in orchestrating MM progression, to better understand tumour immunobiology. The identification of new therapeutic targets and the application of approaches aimed at modulating crosstalk between immune and tumour cells, could have a crucial impact on immunotherapy and result in better clinical outcome. We hope this review will be helpful in cutaneous MM research.

Ethnopharmacological relevance Traditional Chinese medicine Yifei Tongluo Granules has been employed clinically with the combination of chemotherapy agents to treat patients with multidrug-resistant tuberculosis. However, the mechanisms underlying the therapeutic potential have not been well elucidated. The present study was employed to verify immunomodulatory effect and to investigate the underlying mechanisms which have not been explored. Materials and methods The study samples of total extracts (FB-E) and polysaccharides (FB-P) were prepared by the extraction of the Yifei Tongluo Granules using appropriate techniques. A simple immunodeficient mice model was established by challenging Balb/c mice with cyclophosphamide in order to avoid the handling of tuberculosis viruses. The in vivo study was thus designed to systematically elucidate the immuno-enhancement effects of Yifei Tongluo Granules extracts in immunosuppressed mice induced by cyclophosphamide. Balb/c mice were orally ingested once daily with the low and high doses of two different extracts for ten consecutive days, respectively, accompanied by intraperitoneal injection of cyclophosphamide (60 mg/kg) on days 1–3 and 10. Results Compared with the model group, the treatment of immunodeficient mice with the low and high doses of the extracts FB-E or FB-P enhanced spleen and thymus indices, T- and B-cell proliferation as well as increased the activities of splenic natural killer, lymphokine activated killer, cytotoxic T lymphocyte cells and peritoneal macrophage phagocytosis. In addition, the FB-E or FB-P treatment balanced the ratio of Th1/Th2 and up-regulated the CD4+/CD8+ ratio in the serum. Conclusions These results demonstrate, for the first time, that the treatment of the cyclophosphamide-challenged mice with the Yifei Tongluo Granules extracts resulted in accelerated recovery of immunosuppression, sugguesting that the immunomodulation might be the mechanism for the observed clinical benefits of Yifei Tongluo Granules. Our findings provide preliminary mechanistic study evidences for clinical application of Yifei Tongluo Granules in patients with immunodeficient diseases such as tuberculosis.

Immunologists face a thought-provoking question in considering natural killer (NK) cells and disease. NK cells activity probably plays no role as a mediator of antigen-associated killing or lymphokine production in such infections as malaria or toxoplasmosis, or in skin disorders like psoriasis or pemphigus vulgaris. In chronic viral infections or autoimmune diseases of viral etiology, NK cells may play a role. Virus-transformed cells can induce Interferon and thereby elevate NK cell activity. Bacterial and parasitic infections cause an early increase in NK cell activity, but chronicity may depress it. In primary syphilis, NK cell activity is normal or elevated; in secondary, latent, and lipoidal Ab-positive syphilis it is reduced. NK cell activity in syphilis thus is activated by disease but is depressed by disease progression. In acute and chronic active hepatitis B virus infection, there have been several reports that acute hepatitis patients have normal NK cell activity and antibody-dependent cellular cytotoxicity.

A basic assumption of the study of central nervous system (CNS)-immune interactions is that the immune system can signal the brain and that the brain can subsequently modify peripheral immune function. The existence of a regulatory pathway from the immune system to the CNS and back to the immune system suggests that the phenomena of conditioning of immune responses may be explained through the action of classical immunoregulatory lymphokines such as IL-1 on humoral and neural regulatory pathways. Bi-directional communication between the central nervous system and the immune system was first proposed by Besedovsky and colleagues. In their model, products of the immune system released from stimulated immune cells signal the brain which consequently induced a response that down-regulated immune function. The impact of CNS signalling on various components of the immune system has been demonstrated through various behavioral conditioning studies.

Lymph is a product of diffusion and filtration of plasma components. Thus, the actual composition of lymph is dictated by capillary filtration rate, permeability of the capillary wall, metabolic state of parenchymal cells, and tissue fluid and lymph transport away via lymphatics. The interstitial fluid to be compared to the lymph is the free interstitial fluid remaining in thermodynamic equilibrium with the interstitial gel. In the protein-producing organs, the lymph protein concentration is lower than in serum. Immune proteins found in the peripheral lymph may originate from three sources: plasma, tissue from which lymph is drained, and free-floating lymph cells. Different lymphokines have been found in lymph draining from tissue that has received local application of antigen. Efferent lymph from the popliteal node of sheep challenged with antigen was found to suppress the in vitro transformation of sheep peripheral blood lymphocytes to a variety of antigens.