The Host Cytokine Responses and Protective Immunity in Oropharyngeal Candidiasis

2005 ◽  
Vol 84 (11) ◽  
pp. 966-977 ◽  
Author(s):  
A. Dongari-Bagtzoglou ◽  
P.L. Fidel
Keyword(s):  
T Cells ◽  
Epithelial Cells ◽  
Fungal Infections ◽  
Immunocompromised Host ◽  
Oral Infection ◽  
Immune Protection ◽  
Oropharyngeal Candidiasis ◽  
Immune Effector ◽  
Effector Cells ◽  
Therapeutic Implications

Over the last three decades, the prevalence of oropharyngeal fungal infections has increased enormously, mainly due to an increasing population of immunocompromised patients, including individuals with HIV infection, transplant recipients, and patients receiving cancer therapy. The vast majority of these infections are caused by Candida species. The presence of cytokines in infected tissues ultimately dictates the host defense processes that are specific to each pathogenic organism. During oral infection with Candida, a large number of pro-inflammatory and immunoregulatory cytokines are generated in the oral mucosa. The main sources of these cytokines are oral epithelial cells, which maintain a central role in the protection against fungal organisms. These cytokines may drive the chemotaxis and effector functions of innate and/or adaptive effector cells, such as infiltrating neutrophils and T-cells in immunocompetent hosts, and CD8+ T-cells in HIV+ hosts. Epithelial cells also have direct anti- Candida activity. Several studies have provided a potential link between lower levels of certain pro-inflammatory cytokines and susceptibility to oral C. albicans infection, suggesting that such cytokines may be involved in immune protection. The exact role of these cytokines in immune protection against oropharyngeal candidiasis is still incompletely understood and requires further investigation. Identification of such cytokines with the ability to enhance anti-fungal activities of immune effector cells may have therapeutic implications in the treatment of this oral infection in the severely immunocompromised host.

scholarly journals Next-generation cell therapies: the emerging role of CAR-NK cells

Hematology ◽  
2020 ◽  
Vol 2020 (1) ◽  
pp. 570-578
Author(s):  
Rafet Basar ◽  
May Daher ◽  
Katayoun Rezvani
Keyword(s):  
T Cells ◽  
Cell Therapy ◽  
Natural Killer ◽  
Γδ T Cells ◽  
Antigen Receptors ◽  
T Cell Therapy ◽  
Cell Therapies ◽  
Immune Effector ◽  
Effector Cells ◽  
Immune Effector Cells

Abstract T cells engineered with chimeric antigen receptors (CARs) have revolutionized the field of cell therapy and changed the paradigm of treatment for many patients with relapsed or refractory B-cell malignancies. Despite this progress, there are limitations to CAR-T cell therapy in both the autologous and allogeneic settings, including practical, logistical, and toxicity issues. Given these concerns, there is a rapidly growing interest in natural killer cells as alternative vehicles for CAR engineering, given their unique biological features and their established safety profile in the allogeneic setting. Other immune effector cells, such as invariant natural killer T cells, γδ T cells, and macrophages, are attracting interest as well and eventually may be added to the repertoire of engineered cell therapies against cancer. The pace of these developments will undoubtedly benefit from multiple innovative technologies, such as the CRISPR-Cas gene editing system, which offers great potential to enhance the natural ability of immune effector cells to eliminate refractory cancers.

Soluble CD70: a novel immunotherapeutic agent for experimental glioblastoma

2010 ◽  
Vol 113 (2) ◽  
pp. 280-285 ◽  
Author(s):  
James Miller ◽  
Guenter Eisele ◽  
Ghazaleh Tabatabai ◽  
Steffen Aulwurm ◽  
Gabriele von Kürthy ◽  
...  
Keyword(s):  
T Cells ◽  
Immune Responses ◽  
Malignant Gliomas ◽  
Ectopic Expression ◽  
Glioma Cells ◽  
Interferon Γ ◽  
Soluble Form ◽  
Immune Effector ◽  
Effector Cells ◽  
Immune Effector Cells

Object Given the overall poor outcome with current treatment strategies in malignant gliomas, immunotherapy has been considered a promising experimental approach to glioblastoma for more than 2 decades. A cell surface molecule, CD70, may induce potent antitumor immune responses via activation of the costimulatory receptor CD27 expressed on immune effector cells. There is evidence that a soluble form of CD70 (sCD70) may exhibit biological activity, too. A soluble costimulatory ligand is attractive because it may facilitate immune activation and may achieve a superior tissue distribution. Methods To test the antiglioma effect of sCD70, the authors genetically modified SMA-560 mouse glioma cells to secrete the extracellular domain of CD70. They assessed the immunogenicity of the transfected cells in cocultures with immune effector cells by the determination of immune cell proliferation and the release of interferon-γ. Syngeneic VM/Dk mice were implanted orthotopically with control or sCD70-releasing glioma cells to determine a survival benefit mediated by sCD70. Depletion studies were performed to identify the cellular mediators of prolonged survival of sCD70-releasing glioma-bearing mice. Results The authors found that ectopic expression of sCD70 enhanced the proliferation and interferon-γ release of syngeneic splenocytes in vitro. More importantly, sCD70 prolonged the survival of syngeneic VM/Dk mice bearing intracranial SMA-560 gliomas. The survival rate at 60 days increased from 5 to 45%. Antibody-mediated depletion of CD8-positive T cells abrogates the survival advantage conferred by sCD70. Conclusions These data suggest that sCD70 is a potent stimulator of antiglioma immune responses that depend critically on CD8-positive T cells. Soluble CD70 could be a powerful adjuvant for future immunotherapy trials for glioblastoma.

Strategies to improve the safety profile of CAR-T therapy

2021 ◽  
Vol 8 ◽  
pp. 48-60
Author(s):  
Agnieszka Graczyk-Jarzynka
Keyword(s):  
T Cells ◽  
Adverse Effects ◽  
Safety Profile ◽  
Logic Gates ◽  
Immune Effector ◽  
Effector Cells ◽  
Protein Levels ◽  
Car T Cells ◽  
Car T ◽  
Different Types

The chimeric antigen receptor (CAR) technology has become one of the greatest breakthroughs in immunotherapy in recent years. CARs facilitate the attack of immune effector cells such as T cells or NK cells being directed at virtually any molecule presented on the surface of a cancer cell. The exceptional efficacy of CAR receptors has been demonstrated for the CD19 molecule found on B cell-derived tumors. However, the efficacy of CAR-T therapy targeting other antigens is less satisfactory while being quite frequently associated with a number of adverse effects. The adverse effects are mainly due to the effector cells being activated in a simplified manner; the most serious effect consists in the antigen being detected on healthy cells (“the on-target, off-tumor” effect). A number of ongoing studies aim at enhancing the safety profile of therapies making use of CAR--modified effector cells. In part, this can be achieved by optimizing the structure of the CAR receptor itself or by using transient transfection to modify the effector cells. A more complex solution consists in obtaining remote control over CAR-T lymphocytes within the patient’s body. This approach makes use of different types of systems that limit the functionality of CAR-T cells in the patient, such as suicide genes, regulation at the transcriptional and protein levels, different types of adapters being used to activate the CAR-T cells. The most advanced system consists in the use of logic gates which make it possible for CAR-T cells to recognize and „understand” incoming signals from the environment, allowing for a certain degree of autonomy in the activation of the cells’ cytotoxic potential. This study presents key strategies to improve the safety profiles of CAR-T therapies.

scholarly journals Melanoma cell-derived exosomes in plasma of melanoma patients suppress functions of immune effector cells

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Priyanka Sharma ◽  
Brenda Diergaarde ◽  
Soldano Ferrone ◽  
John M. Kirkwood ◽  
Theresa L. Whiteside
Keyword(s):  
T Cells ◽  
Nk Cells ◽  
Melanoma Cell ◽  
Disease Stage ◽  
Immune Effector ◽  
Effector Cells ◽  
Major Mechanism ◽  
Protein Levels ◽  
Melanoma Patients ◽  
Induced Apoptosis

AbstractMelanoma patients’ plasma contains exosomes produced by malignant and normal cells. Plasma exosomes were isolated and separated by immunocapture into two fractions: melanoma cell-derived exosomes (MTEX) and normal cell-derived exosomes (non-MTEX). Immunosuppressive effects of MTEX on primary human immune cells were evaluated. Exosomes were isolated from plasma of 12 melanoma patients and six healthy donors (HDs). Expression levels of 19 immunoregulatory proteins in MTEX, non-MTEX and HDs exosomes were evaluated by on-bead flow cytometry. Functional/phenotypic changes induced in CD8+ T or natural killer (NK) cells by MTEX or non-MTEX were compared. Plasma protein levels were higher in patients than HDs (P < 0.0009). In patients, MTEX accounted for 23–66% of total exosomes. MTEX were enriched in immunosuppressive proteins (P = 0.03). MTEX, but not HDs exosomes, inhibited CD69 expression (P ≤ 0.0008), induced apoptosis (P ≤ 0.0009) and suppressed proliferation (P ≤ 0.002) in CD8+ T cells and downregulated NKG2D expression in NK cells (P = 0.001). Non-MTEX were enriched in immunostimulatory proteins (P = 0.002) and were only weakly immunosuppressive. Elevated MTEX/total exosome ratios and, surprisingly, non-MTEX ability to induce apoptosis of CD8+ T cells emerged as positive correlates of disease stage. MTEX emerge as the major mechanism of tumor-induced immune suppression and as an underestimated barrier to successful melanoma immunotherapy.

scholarly journals Human macrophage inflammatory protein alpha (MIP-1 alpha) and MIP-1 beta chemokines attract distinct populations of lymphocytes.

1993 ◽  
Vol 177 (6) ◽  
pp. 1821-1826 ◽  
Author(s):  
T J Schall ◽  
K Bacon ◽  
R D Camp ◽  
J W Kaspari ◽  
D V Goeddel
Keyword(s):  
T Cells ◽  
B Cells ◽  
Cytotoxic T Cells ◽  
Human Macrophage ◽  
Immune Effector ◽  
Effector Cells ◽  
Inflammatory Protein ◽  
And Migration ◽  
Macrophage Inflammatory Protein

Lymphocyte trafficking is an essential process in immune and inflammatory functions which can be thought to contain at least two main components: adhesion and migration. Whereas adhesion molecules such as the selections are known to mediate the homing of leukocytes from the blood to the endothelium, the chemoattractant substances responsible for the migration of specific subsets of lymphocytes to sites of infection or inflammation are largely unknown. Here we show that two molecules in the chemokine (for chemoattractant cytokine) superfamily, human macrophage inflammatory protein 1 alpha (MIP-1 alpha) and MIP-1 beta, do not share identical attractant activities for lymphocyte subpopulations. When analyzed in vitro in microchemotaxis experiments, HuMIP-1 beta tends to attract CD4+ T lymphocytes, with some preference for T cells of the naive (CD45RA) phenotype. HuMIP-1 alpha, when tested in parallel with HuMIP-1 beta, is a more potent lymphocyte chemoattractant with a broader range of concentration-dependent chemoattractant specificities. HuMIP-1 alpha at a concentration of 100 pg/ml attracts B cells and cytotoxic T cells, whereas at higher concentrations (10 ng/ml), the migration of these cells appears diminished, and the migration of CD4+ T cells is enhanced. Thus, in this assay system, HuMIP-1 alpha and -1 beta have differential attractant activities for subsets of immune effector cells, with HuMIP-1 alpha having greater effects than HuMIP-1 beta, particularly on B cells.

Autologous Gamma-Delta T (GD-T) Cells in Acute Myeloid Leukemia (AML): Potential Immune Effector Cells for Minimal Disease?.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2538-2538
Author(s):  
Joerg M. Aswald ◽  
Xing-Hua Wang ◽  
Sandra Aswald ◽  
Loralyn A. Benoit ◽  
Mark Minden ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Interferon Gamma ◽  
Residual Disease ◽  
Blast Cell ◽  
Healthy Controls ◽  
Immune Effector ◽  
Effector Cells ◽  
Immune Effector Cells

Abstract Prolonging event-free survival of AML with autologous activated immune cells is a promising concept. GD-T cells are a rare circulating lymphocyte population (1%) and a component of the innate immune system capable of exerting anti-neoplastic activity. Their role as potential anti-cancer immune effector cells deserves further exploration. It is noteworthy that GD-T cells are over-represented in reactive regions surrounding melanoma lesions. While patients with an accumulation of GD-T cells showed a survival benefit over those who did not, such increases were not present in patients with metastatic disease and high tumor cell burden (Bachelez, J. Invest. Dermatol.98:369,1992). Little is known about the role of GD-T cells as immuno-effectors, their absolute numbers in peripheral blood or the feasibility of purifying functional GD-T cells from patients with AML. We are interested in testing the clinical feasibility of using GD-T cells freshly purified from PB against minimal residual disease in AML. As a first step towards achieving this goal, we compared circulating GD-T cell levels sequentially in 33 AML patients with 20 healthy adult volunteers. We used ultra-low volume multi-color flow-cytometry and microbeads to measure absolute numbers of GD-T cells in PB. Functional studies were done by the chromium release assay and single-cell intra-cellular interferon-gamma detection. We observed that AML patients with a high leukemic blast cell burden (e.g. prior to chemotherapy) had marginally decreased GD-T cell levels compared with healthy controls: median 38/μl, Q1-Q3, 27–86/μl, versus median 83/μl, Q1-Q3, 45–122/μl, respectively, p= 0.051. We re-examined the AML patients at several time points after induction therapy and observed significantly increased numbers of GD-T cells in patients with lower but detectable residual disease (either molecular maker positive or borderline bone marrow blast infiltration by morphology) compared to patients with persistently high blast cell burden: median 105/μl, Q1-Q3, 105–133/μl versus median, 7/μl, Q1-Q3, 6–15/μl; p=0.008. Patients with residual disease also showed significantly higher numbers of absolute GD-T cells per microliter blood compared to those retested after they had achieved complete remission (CR); p=0.0025. In CR, GD-T cell counts remained lower than those of healthy individuals: median 33/μl, Q1-Q3, 22–35/μl versus median 83/μl, Q1-Q3, 45–122/μl; p=0.030. Interestingly, we found a sharp increase (on average, 4.9-fold higher than values obtained in CR) in GD-T levels at the time of very early morphologic (n=3) or molecular relapse (n=2). Hence, we were interested in studying the functional properties of the GD-T cells from AML patients. We were able to isolate functional GD-T cells from the PB of patients with AML in CR-1 in sufficient numbers and purity to assay for interferon-gamma and found that similar numbers of GD-T cells expressed the Th1 cytokine compared with healthy controls: 84% versus 93% of all GD-T cells, respectively. We also showed that GD-T cells were able to kill leukemic target cells (AML-OCI2) in vitro more efficiently than CD3+ T cells. Our data suggest that further studies to investigate the potential therapeutic role of autologous GD-T cells in patients with AML in CR are warranted.

Induction of NK and T Cell Immune Responses Against Leukemia Cells By Bispecific NKG2D-CD16 and -CD3 Fusion Proteins

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2558-2558
Author(s):  
Samuel Koerner ◽  
Lothar Kanz ◽  
Ludger Grosse-Hovest ◽  
Gundram Jung ◽  
Helmut R Salih
Keyword(s):  
T Cells ◽  
Nk Cells ◽  
Fusion Proteins ◽  
Conflicts Of Interest ◽  
Ex Vivo ◽  
Specific Binding ◽  
Leukemia Cells ◽  
Dose Titration ◽  
Immune Effector ◽  
Effector Cells

Abstract Monoclonal antibodies (mAbs) have by now become an established tool in therapy of many malignancies. The interaction of a mAb's Fc portion with Fcγ receptors (FcγR) on immune effector cells is important for its efficacy, but often insufficient to potently induce antitumor immunity e.g. due to FcγR polymorphisms. Moreover, Fc parts of mAbs may bind to FcγRs expressed on non-cytotoxic cells (e.g., platelets and B cells) and interact with FcγRs that do not trigger cytotoxicity (e.g. CD16b on granulocytes). These shortcomings can be overcome by novel antibody formats like bispecific antibodies allowing for improved activation of a specific pool of effector cells. Here we report on the development and preclinical characterization of two bispecific fusion proteins that target ligands of the immunoreceptor NKG2D (NKG2DL) which are widely expressed on malignant cells but generally absent on healthy tissue. Our fusion proteins consist of the extracellular domain of NKG2D as targeting moiety for tumor-expressed NKG2DL fused to Fab-fragments of either an agonistic CD3 or CD16 antibody. Specific binding of these NKG2D-CD3 and NKG2D-CD16 constructs was confirmed using NKG2DL-transfectants with regard to their target arm and either NK cells or T cells with regard to their different effector parts. Dose titration assays revealed an increased affinity of NKG2D-CD16 to the FcγR on NK cells as compared to our previously described (e.g., Steinbacher et al, 2014) Fc-optimized NKG2D-IgG1 fusion protein, which was mirrored by a potently increased ability to induce lysis of NKG2DL-tranfectants and NKG2DL-positive primary acute myeloid leukemia (AML) cells by allogeneic NK cells. The novel NKG2D-CD3 construct in turn was found to potently activate allogeneic and autologous CD4+ and CD8+ T cells. Next we comparatively analyzed the efficacy of T cells and NK cells to lyse autologous leukemia cells upon treatment with NKG2D-CD3 and NKG2D-CD16, respectively, by using PBMC of AML patients (blast counts 30-70%) directly ex vivo in long term cytotoxicity assays. NKG2D-CD16 potently induced AML cell lysis, and this was, in line with their proliferative and higher effector potential, by far exceeded upon stimulation of T cells with NKG2D-CD3. Taken together, we here introduce novel "antibody-like" bispecific constructs that take advantage of the highly tumor-restricted expression of NKG2DL and potently activate the reactivity of NK or T cells for immunotherapy of leukemia. Disclosures No relevant conflicts of interest to declare.

scholarly journals Effects of Tenofovir on Cytokines and Nucleotidases in HIV-1 Target Cells and the Mucosal Tissue Environment in the Female Reproductive Tract

2014 ◽  
Vol 58 (11) ◽  
pp. 6444-6453 ◽  
Author(s):  
Nabanita Biswas ◽  
Marta Rodriguez-Garcia ◽  
Zheng Shen ◽  
Sarah G. Crist ◽  
Jack E. Bodwell ◽  
...  
Keyword(s):  
T Cells ◽  
Biological Activity ◽  
Epithelial Cells ◽  
Hiv Infection ◽  
Proinflammatory Cytokines ◽  
Reproductive Tract ◽  
Biological Activities ◽  
Female Reproductive Tract ◽  
Immune Protection ◽  
Tnf Α

ABSTRACTTenofovir (TFV) is a reverse transcriptase inhibitor used in microbicide preexposure prophylaxis trials to prevent HIV infection. Recognizing that changes in cytokine/chemokine secretion and nucleotidase biological activity can influence female reproductive tract (FRT) immune protection against HIV infection, we tested the hypothesis that TFV regulates immune protection in the FRT. Epithelial cells, fibroblasts, CD4+T cells, and CD14+cells were isolated from the endometrium (Em), endocervix (Cx), and ectocervix (Ecx) following hysterectomy. The levels of proinflammatory cytokines (macrophage inflammatory protein 3α [MIP-3α], interleukin 8 [IL-8], and tumor necrosis factor alpha [TNF-α]), the expression levels of specific nucleotidases, and nucleotidase biological activities were analyzed in the presence or absence of TFV. TFV influenced mRNA and/or protein cytokines and nucleotidases in a cell- and site-specific manner. TFV significantly enhanced IL-8 and TNF-α secretion by epithelial cells from the Em and Ecx but not from the Cx. In contrast, in response to TFV, IL-8 secretion was significantly decreased in Em and Cx fibroblasts but increased with fibroblasts from the Ecx. When incubated with CD4+T cells from the FRT, TFV increased IL-8 (Em and Ecx) and TNF-α (Cx and Ecx) secretion levels. Moreover, when incubated with Em CD14+cells, TFV significantly increased MIP-3α, IL-8, and TNF-α secretion levels relative to those of the controls. In contrast, nucleotidase biological activities were significantly decreased by TFV in epithelial (Cx) and CD4+T cells (Em) but increased in fibroblasts (Em). Our findings indicate that TFV modulates proinflammatory cytokines, nucleotidase gene expression, and nucleotidase biological activity in epithelial cells, fibroblasts, CD4+T cells, and CD14+cells at distinct sites within the FRT.

scholarly journals A humanized monoclonal antibody against the endothelial chemokine CCL21 for the diagnosis and treatment of inflammatory bowel disease

PLoS ONE ◽  
2021 ◽  
Vol 16 (7) ◽  
pp. e0252805
Author(s):  
Maegan L. Capitano ◽  
Aruna Jaiswal ◽  
Hal E. Broxmeyer ◽  
Yilianys Pride ◽  
Sarah Glover ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
T Cells ◽  
Antigen Presentation ◽  
Amino Terminus ◽  
Immune Effector ◽  
Effector Cells ◽  
T Cell Migration ◽  
Small Proteins ◽  
Immature Dendritic Cells ◽  
Inflammatory Bowel

Chemokines are small proteins that promote leukocyte migration during development, infection, and inflammation. We and others isolated the unique chemokine CCL21, a potent chemo-attractant for naïve T-cells, naïve B-cells, and immature dendritic cells. CCL21 has a 37 amino acid carboxy terminal extension that is distinct from the rest of the chemokine family, which is thought to anchor it to venule endothelium where the amino terminus can interact with its cognate receptor, CCR7. We and others have reported that venule endothelium expressing CCL21 plays a crucial role in attracting naïve immune cells to sites of antigen presentation. In this study we generated a series of monoclonal antibodies to the amino terminus of CCL21 in an attempt to generate an antibody that blocked the interaction of CCL21 with its receptor CCR7. We found one humanized clone that blocked naïve T-cell migration towards CCL21, while memory effector T-cells were less affected. Using this monoclonal antibody, we also demonstrated that CCL21 is expressed in the mucosal venule endothelium of the large majority of inflammatory bowel diseases (IBD), including Crohn’s disease, ulcerative colitis, and also in celiac disease. This expression correlated with active IBD in 5 of 6 cases, whereas none of 6 normal bowel biopsies had CCL21 expression. This study raises the possibility that this monoclonal antibody could be used to diagnose initial or recurrent of IBD. Significantly, this antibody could also be used for therapeutic intervention in IBD by selectively interfering with recruitment of naïve immune effector cells to sites of antigen presentation, without harming overall memory immunity.

Cellular side of acquired immunity (T cells)

2013 ◽  
Author(s):  
Assia Eljaafari ◽  
Pierre Miossec
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Immune System ◽  
Disease Process ◽  
T Cell Response ◽  
Th2 Cells ◽  
Cell Mediated Immunity ◽  
Immune Effector ◽  
Effector Cells ◽  
Th22 Cells

The adaptive T-cell response represents the most sophisticated component of the immune response. Foreign invaders are recognized first by cells of the innate immune system. This leads to a rapid and non-specific inflammatory response, followed by induction of the adaptive and specific immune response. Different adaptive responses can be promoted, depending on the predominant effector cells that are involved, which themselves depend on the microbial/antigen stimuli. As examples, Th1 cells contribute to cell-mediated immunity against intracellular pathogens, Th2 cells protect against parasites, and Th17 cells act against extracellular bacteria and fungi that are not cleared by Th1 and Th2 cells. Among the new subsets, Th22 cells protect against disruption of epithelial layers secondary to invading pathogens. Finally these effector subsets are regulated by regulatory T cells. These T helper subsets counteract each other to maintain the homeostasis of the immune system, but this balance can be easily disrupted, leading to chronic inflammation or autoimmune diseases. The challenge is to detect early changes in this balance, prior to its clinical expression. New molecular tools such as microarrays could be used to determine the predominant profile of the immune effector cells involved in a disease process. Such understanding should provide better therapeutic tools to counteract deregulated effector cells.

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