scholarly journals Mycobacterium tuberculosis in Chemokine Receptor 2-Deficient Mice: Influence of Dose on Disease Progression

2002 ◽  
Vol 70 (11) ◽  
pp. 5946-5954 ◽  
Author(s):  
Holly M. Scott ◽  
JoAnne L. Flynn
Keyword(s):  
Immune Response ◽  
Mycobacterium Tuberculosis ◽  
Cell Migration ◽  
Chemokine Receptor ◽  
Chemokine Receptors ◽  
Low Dose ◽  
High Dose ◽  
Long Term Effects ◽  
Spread Of Infection ◽  
Oxide Synthase

ABSTRACT Within a Mycobacterium tuberculosis-induced granuloma, lymphocytes and macrophages work together to control bacterial growth and limit the spread of infection. Chemokines and chemokine receptors are involved in cell migration and are logical candidates for a role in granuloma formation. In the present study we addressed the role of CC chemokine receptor 2 (CCR2) in M. tuberculosis infection. In previous studies (W. Peters et al., Proc. Natl. Acad. Sci. USA 98:7958-7963, 2001), CCR2−/− mice were found to be highly susceptible to a moderate or high dose of H37Rv administered intravenously (i.v.). We have expanded those studies to demonstrate that the susceptibility of CCR2−/− mice is dose dependent. After low-dose aerosol or i.v. infection of CCR2−/− mice with M. tuberculosis, there was a substantial delay in cell migration to the lungs and delayed expression of gamma interferon and inducible nitric oxide synthase. The CCR2−/− mice had a severe and prolonged deficiency in the number of macrophages in the lungs and an early increase in the number of neutrophils. Despite these deficiencies in cell migration, the CCR2−/− mice did not have increased bacterial loads in the lungs compared to wild-type (C57BL/6) mice and successfully formed granulomas. This finding is in contrast to CCR2−/− mice infected with a high dose of M. tuberculosis administered i.v. These results indicate that with low-dose infection, a delay in immune response in the lungs does not necessarily have detrimental long-term effects on the progression of the disease. The fact that CCR2−/− mice survive with substantially fewer macrophages in the low-dose models implies that the immune response to low-dose M. tuberculosis infection in mice is more robust than necessary to control the infection. Finally, these data demonstrate that, in cases of infectious disease in knockout models, clear phenotypes may not be evident when one is solely evaluating bacterial numbers and survival. Functional assays may be necessary to reveal roles for components of the multifactorial immune system.

scholarly journals Expression of the Nitric Oxide Synthase 2 Gene Is Not Essential for Early Control of Mycobacterium tuberculosis in the Murine Lung

2000 ◽  
Vol 68 (12) ◽  
pp. 6879-6882 ◽  
Author(s):  
Andrea M. Cooper ◽  
John E. Pearl ◽  
Jason V. Brooks ◽  
Stefan Ehlers ◽  
Ian M. Orme
Keyword(s):  
Nitric Oxide ◽  
Mycobacterium Tuberculosis ◽  
Nitric Oxide Synthase ◽  
Low Dose ◽  
Interleukin 12 ◽  
Infection Model ◽  
Rapid Progression ◽  
Ifn Γ ◽  
Nitric Oxide Synthase 2 ◽  
Oxide Synthase

ABSTRACT The interleukin-12 and gamma interferon (IFN-γ) pathway of macrophage activation plays a pivotal role in controlling tuberculosis. In the murine model, the generation of supplementary nitric oxide by the induction of the nitric oxide synthase 2 (NOS2) gene product is considered the principal antimicrobial mechanism of IFN-γ-activated macrophages. Using a low-dose aerosol-mediated infection model in the mouse, we have investigated the role of nitric oxide in controllingMycobacterium tuberculosis in the lung. In contrast to the consequences of a systemic infection, a low dose of bacteria introduced directly into the lungs of mice lacking the NOS2 gene is controlled almost as well as in intact animals. This is in contrast to the rapid progression of disease in mice lacking IFN-γ or a key member of the IFN signaling pathway, interferon regulatory factor 1. Thus while IFN-γ is pivotal in early control of bacterial growth in the lung, this control does not completely depend upon the expression of the NOS2 gene. The absence of inducible nitric oxide in the lung does, however, result in increased polymorphonuclear cell involvement and eventual necrosis in the pulmonary granulomas of the infected mice lacking the NOS2 gene.

scholarly journals EPCT-16. LENALIDOMIDE ACTIVITY IN PILOCYTIC ASTROCYTOMA AND OPTIC PATHWAY GLIOMAS: REPORT ON CHILDREN’S ONCOLOGY GROUP ACNS1022

2021 ◽  
Vol 23 (Supplement_1) ◽  
pp. i50-i50
Author(s):  
Katherine Warren ◽  
Gilbert Vezina ◽  
Linda Springer ◽  
Allen Buxton ◽  
Cody Peer ◽  
...  
Keyword(s):  
Pilocytic Astrocytoma ◽  
Low Dose ◽  
Objective Response ◽  
Low Grade Glioma ◽  
Activity Level ◽  
High Dose ◽  
Low Grade ◽  
Optic Pathway ◽  
Long Term Effects ◽  
Optic Pathway Gliomas

Abstract Children with low-grade glioma have excellent survival rates but often suffer from the morbidity of treatment, particularly from cytotoxic chemotherapies. Targeted agents appear to have some activity but the long-term effects of inhibiting normal developmental pathways are unknown. Lenalidomide is an oral immunomodulatory agent with additional properties including anti-angiogenesis. Phase I studies indicated greater tolerability of this agent compared to adults, and a potential dose-response effect. We performed a Phase 2 trial of lenalidomide in children with pilocytic astrocytoma and optic pathway gliomas who failed initial therapy. The primary objective was to determine the objective response rate of children randomized to Regimen A low-dose (20 mg/m2 /dose) or Regimen B high-dose (115 mg/m2 /dose) lenalidomide, each administering lenalidomide daily x 21 days of each 28-day course. Secondary objectives included estimation of event-free survival (EFS) in this population and correlation of plasma lenalidomide concentration with toxicity and outcome. Results 74 eligible patients were enrolled (n=37 to each arm). The pre-defined activity level of interest was achieved for both arms. Objective responses were observed in both arms, with 4 partial responses in each. A total of n=18 patients completed 26 courses of therapy (Arm A, n=12, Arm B, n=6) The median number of courses on each arm was 14 (range 2–26) for Arm A and 11 for Arm B (range 1- 26). Of the 74 eligible patients who received study drug, 30 required a dose reduction for toxicity (Arm A, n=6, Arm B, n=24) and 16 discontinued treatment on protocol due to toxicity (Arm A, n=2, Arm B, n=14). Conclusion Lenalidomide demonstrates a sufficient level of activity in children with low-grade glioma to warrant further exploration in Phase 3 studies. Low-dose (20 mg/m2) lenalidomide appears to have better tolerability.

scholarly journals CXCR4 inhibition in human pancreatic and colorectal cancers induces an integrated immune response

2020 ◽  
Author(s):  
Daniele Biasci ◽  
Martin Smoragiewicz ◽  
Claire M. Connell ◽  
Zhikai Wang ◽  
Ya Gao ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Immune Response ◽  
T Cell ◽  
Continuous Infusion ◽  
Chemokine Receptor ◽  
Chemokine Receptors ◽  
Immune Cell ◽  
Colorectal Cancers ◽  
Chemokine Receptor Cxcr4 ◽  
Anti Cancer

AbstractInhibition of the chemokine receptor CXCR4 in combination with blockade of the PD-1/PD-L1 T cell checkpoint induces T cell infiltration and anti-cancer responses in murine and human pancreatic cancer. Here we elucidate the mechanism by which CXCR4 inhibition effects the tumor immune microenvironment. In human immune cell-based chemotaxis assays, we find that CXCL12-stimulated CXCR4 inhibits the directed migration mediated by CXCR1, CXCR3, CXCR5, CXCR6, and CCR2, respectively, chemokine receptors expressed by all the immune cell types that participate in an integrated immune responses. Inhibiting CXCR4 in an experimental cancer medicine study by one-week continuous infusion of the small molecule inhibitor, AMD3100 (plerixafor), induces an integrated immune response that is detected by transcriptional analysis of paired biopsies of metastases from patients with microsatellite stable colorectal and pancreatic cancer. This integrated immune response occurs in three other examples of immune-mediated damage to non-infected tissues: rejecting renal allografts, melanomas clinically responding to anti-PD1 antibody therapy, and microsatellite instable colorectal cancers. Thus, signaling by CXCR4 causes immune suppression in human PDA and CRC by impairing the function of the chemokine receptors that mediate the intratumoral accumulation of immune cells.Statement of significanceContinuous infusion of AMD3100, an antagonist of the chemokine receptor, CXCR4, induces an integrated anti-cancer immune response in metastases of patients with microsatellite stable pancreatic and colorectal cancer that is predictive of response to T cell checkpoint inhibition.

scholarly journals Relationship between chorionic gonadotropin immunomodulating effects and the initial functional activity of the splenocytes mediating the adoptive immune response

1993 ◽  
Vol 39 (1) ◽  
pp. 54-57 ◽  
Author(s):  
S. V. Shirshev ◽  
N. N. Kevorkov
Keyword(s):  
Immune Response ◽  
Chorionic Gonadotropin ◽  
Functional Activity ◽  
Low Dose ◽  
Interleukin 2 ◽  
Prostaglandin Synthesis ◽  
High Dose ◽  
Transfer System ◽  
Male Mice ◽  
Stimulation Of

CBA and (СВАхC57BL/6) F1 male mice were used in experiments. One hour incubation of splenocytes with chorionic gonadotropin in doses 10 or 50 MU/ml statistically significantly reduced the count of antibody-producing cells detectable in the syngeneic transfer system. Addition of conA or recombinant human interleukin 2 to the splenocyte culture did not alter the processes of the formation of antibodyproducing cells. Addition of chorionic gonadotropin simultaneously with conA resulted in discontinuation of the immunosuppression induced by a low hormone dose, whereas 50 MU/ml of chorionic gonadotropin in the presence of conA had a marked immunodepressant effect. Combination of interleukin 2 with chorionic gonadotropin lead either to immunosuppression cessation (10 MU/ml) or to more than twofold stimulation of the adoptive immune response (50 MU/ml). Voltaren a cycloxygenase inhibitor, was used in some experiments to elucidate the degree of endogenic prostaglandin relationships with the mechanisms of chorionic gonadotropin immunomodulating effects. Cycloxygenase activity was found to be related to the immunosuppressive effect of chorionic gonadotropin low dose, whereas the costimulating effect of a high dose of the hormone in the presence of interleukin 2 was unrelated to endogenic prostaglandin synthesis.

The long term effects of intrascrotal low dose and high dose N-acetylcysteine on testis damage in rat model of testicular torsion

2020 ◽  
Vol 55 (4) ◽  
pp. 672-680 ◽  
Author(s):  
Tuğba Acer-Demir ◽  
Mirhüseyn Mammadov ◽  
Pınar Öcbe ◽  
Asyanur Çoruhlu ◽  
Dicle Coşkun ◽  
...  
Keyword(s):  
Rat Model ◽  
Testicular Torsion ◽  
Low Dose ◽  
High Dose ◽  
Long Term Effects

scholarly journals Kinetics of CXCL12 binding to atypical chemokine receptor 3 reveal a role for the receptor N terminus in chemokine binding

2019 ◽  
Vol 12 (598) ◽  
pp. eaaw3657 ◽  
Author(s):  
Martin Gustavsson ◽  
Douglas P. Dyer ◽  
Chunxia Zhao ◽  
Tracy M. Handel
Keyword(s):  
Cell Migration ◽  
G Proteins ◽  
Chemokine Receptor ◽  
Chemokine Receptors ◽  
Scavenger Receptor ◽  
Amino Terminus ◽  
Alternative Mechanism ◽  
Globular Domain ◽  
Kinetic Measurements ◽  
Membrane Spanning

Chemokines bind to membrane-spanning chemokine receptors, which signal through G proteins and promote cell migration. However, atypical chemokine receptor 3 (ACKR3) does not appear to couple to G proteins, and instead of directly promoting cell migration, it regulates the extracellular concentration of chemokines that it shares with the G protein–coupled receptors (GPCRs) CXCR3 and CXCR4, thereby influencing the responses of these receptors. Understanding how these receptors bind their ligands is important for understanding these different processes. Here, we applied association and dissociation kinetic measurements coupled to β-arrestin recruitment assays to investigate ACKR3:chemokine interactions. Our results showed that CXCL12 binding is unusually slow and driven by the interplay between multiple binding epitopes. We also found that the amino terminus of the receptor played a key role in chemokine binding and activation by preventing chemokine dissociation. It was thought that chemokines initially bind receptors through interactions between the globular domain of the chemokine and the receptor amino terminus, which then guides the chemokine amino terminus into the transmembrane pocket of the receptor to initiate signaling. On the basis of our kinetic data, we propose an alternative mechanism in which the amino terminus of the chemokine initially forms interactions with the extracellular loops and transmembrane pocket of the receptor, which is followed by the receptor amino terminus wrapping around the core of the chemokine to prolong its residence time. These data provide insight into how ACKR3 competes and cooperates with canonical GPCRs in its function as a scavenger receptor.

Non-Myeloablative Transplantation

Hematology ◽  
2002 ◽  
Vol 2002 (1) ◽  
pp. 392-421 ◽  
Author(s):  
David G. Maloney ◽  
Brenda M. Sandmaier ◽  
Stephen Mackinnon ◽  
Judith A. Shizuru
Keyword(s):  
Immune Response ◽  
T Cell ◽  
Residual Disease ◽  
Autologous Transplantation ◽  
Allogeneic Transplantation ◽  
High Dose ◽  
Low Grade ◽  
Long Term Effects ◽  
Minor Histocompatibility Antigens ◽  
Unrelated Donors

Abstract The concept of utilizing enhanced immunosuppression rather than myeloablative cytotoxic conditioning has allowed the engraftment of allogeneic stem cells from related and unrelated donors with lower early transplant-related mortality (TRM) and morbidity. This approach shifts tumor eradication to the graft-vs-host immune response directed against minor histocompatibility antigens expressed on tumor cells. This is not without risk, as the long-term effects of graft-versus-host disease (GVHD), it’s treatment, or resulting complications and immunodeficiency may be life threatening. However, this approach does allow the application of a potentially curative procedure to elderly or medically infirm patients who would not tolerate high-dose conditioning regimens. Section I, by Dr. Sandmaier, describes the current use of nonmyeloablative regimens and matched related or unrelated donors for the treatment of patients with CLL, CML, acute leukemia, MDS, lymphoma, and myeloma. In Section II, Dr. Maloney discusses the use of cytoreductive autologous followed by planned non-myeloablative allografts as treatment for patients with myeloma or NHL. This tandem transplant approach has a lower TRM than conventional high dose allografting. The nonmyeloablative allograft may allow the graft-versus-tumor (GVT) immune response to eradicate the minimal residual disease that causes nearly all patients with low-grade NHL or myeloma to relapse following autologous transplantation. In Section III, Dr. Mackinnon discusses the risks and benefits of T cell depletion strategies to prevent acute GVHD, while retaining GVT activity by planned donor lymphocyte infusions. Finally, in Section IV, Dr. Shizuru discusses the relationship between GVHD and GVT activity. Future studies, employing a greater understanding of these issues and the separation of GVHD from GVT activity by immunization or T cell cloning, may allow nonmyeloablative allogeneic transplantation to be safer and more effective.

scholarly journals STUDIES ON THE REGULATION OF AVIDITY AT THE LEVEL OF THE SINGLE ANTIBODY-FORMING CELL

1970 ◽  
Vol 132 (1) ◽  
pp. 77-88 ◽  
Author(s):  
Birger Andersson
Keyword(s):  
Immune Response ◽  
Present Method ◽  
Low Dose ◽  
Cellular Level ◽  
Plaque Formation ◽  
High Dose ◽  
High Avidity ◽  
Specific Inhibition ◽  
Cellular Events ◽  
Free Antigen

The hemolytic plaque formation of cells producing antibody against heterologous albumins was tested for sensitivity to specific inhibition by free antigen. The inhibition characteristics of plaques in this system were found to be a measure for the avidity of the antibody produced by the plaque-forming cells (PFC:s). High avidity-producing PFC:s were more sensitive to inhibition than low avidity PFC:s. Immunization with a high dose of antigen induced PFC:s that produced antibody with a lower avidity as compared to PFC:s from animals immunized with a low dose. The avidity was increased with time. Determinations of avidity at the serum level were also made, and the results were in agreement with the findings at the cellular level. The present method made it possible to demonstrate differences in avidity of antibody at the level of the single antibody-forming cell. It may also constitute a useful tool for the analysis of the cellular events leading to the production of antibodies with varying affinities during the immune response.

scholarly journals Low-dose aerosol infection model for testing drugs for efficacy against Mycobacterium tuberculosis.

1996 ◽  
Vol 40 (12) ◽  
pp. 2809-2812 ◽  
Author(s):  
B P Kelly ◽  
S K Furney ◽  
M T Jessen ◽  
I M Orme
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Low Dose ◽  
Bacterial Load ◽  
Lung Model ◽  
Exposure Model ◽  
Infection Model ◽  
High Dose ◽  
Level Of Activity ◽  
Days Of Therapy ◽  
Aerosol Infection

As a paradigm for chronic infectious diseases, tuberculosis exhibits a variety of clinical presentations, ranging from primary pulmonary tuberculosis to reactivation tuberculosis and cavitary disease. To date, the animal models used in evaluating chemotherapy of tuberculosis have been high-dose intravenous models that mimic the disseminated forms of the disease. In the present study, we have used a low-dose aerosol exposure model which we feel better reflects newly diagnosed tuberculosis in patients converting to tuberculin positivity. As appropriate examples of chemotherapy, four rifamycins (rifampin, rifabutin, rifapentine, and KRM-1648) were tested, first in an in vitro murine macrophage model and then in the low-dose aerosol infection model, for their activity against Mycobacterium tuberculosis. In both models, KRM-1648 had the highest level of activity of the four compounds. In the infected-lung model, rifabutin, rifapentine, and KRM-1648 all had sterilizing activity when given orally at 5 mg/kg of body weight per day. When given at 2.5 mg/kg/day, KRM-1648 had the highest level of activity of the four drugs, reducing the bacterial load by 2.7 logs over 35 days of therapy.

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