Journal articles on the topic 'Leukocyte trafficking, Anti-integrins therapies'
To see the other types of publications on this topic, follow the link: Leukocyte trafficking, Anti-integrins therapies.
Create a spot-on reference in APA, MLA, Chicago, Harvard, and other styles
Consult the top 26 journal articles for your research on the topic 'Leukocyte trafficking, Anti-integrins therapies.'
Next to every source in the list of references, there is an 'Add to bibliography' button. Press on it, and we will generate automatically the bibliographic reference to the chosen work in the citation style you need: APA, MLA, Harvard, Chicago, Vancouver, etc.
You can also download the full text of the academic publication as pdf and read online its abstract whenever available in the metadata.
Browse journal articles on a wide variety of disciplines and organise your bibliography correctly.
1
Khanna, Reena, Mahmoud H. Mosli, and Brian G. Feagan. "Anti-Integrins in Ulcerative Colitis and Crohn's Disease: What Is Their Place?" Digestive Diseases 34, no. 1-2 (2016): 153–59. http://dx.doi.org/10.1159/000443132.
Full textAbstract:
Background: Inflammatory bowel diseases (IBD) are a group of heterogeneous conditions, characterized by immune-mediated inflammation of the gastrointestinal tract. Traditionally, medical management of these disorders has been based on use of systemic immunosuppressives. The development of new drugs that selectively inhibit leukocyte trafficking to the gut has the potential to reduce inflammation and minimize systemic toxicities. Key Messages: In this article, we review the immunology of the gut and the mechanism of action these emerging therapies for IBD. Natalizumab, a monoclonal antibody to the α4 integrin, was approved for the treatment of multiple sclerosis and showed promise in Crohn's disease (CD), however it is encumbered by the risk of progressive multifocal leukoencephalopathy. Vedolizumab inhibits the α4β7 integrin to induce clinical remission in patients with both ulcerative colitis and CD. Long-term safety data on this agent is not yet available. We also review agents in the pipeline. Finally, we discuss the positioning of therapies and potential alterations to therapeutic algorithms as new medications emerge. Conclusions: New therapies are emerging for IBD; however, long-term data are pending. The positioning of these agents in algorithms will evolve.
2
Van Assche, Gert, and Paul Rutgeerts. "Physiological Basis for Novel Drug Therapies Used to Treat the Inflammatory Bowel Diseases I. Immunology and therapeutic potential of antiadhesion molecule therapy in inflammatory bowel disease." American Journal of Physiology-Gastrointestinal and Liver Physiology 288, no. 2 (February 2005): G169—G174. http://dx.doi.org/10.1152/ajpgi.00423.2004.
Full textAbstract:
Adhesion molecules regulate the influx of leukocytes in normal and inflamed gut. They are also involved in local lymphocyte stimulation and antigen presentation within the intestinal mucosa. In intestinal inflammation, many adhesion molecules are upregulated, but α4-integrins most likely hold a key position in directing leukocytes into the inflamed bowel wall. Therapeutic compounds directed against trafficking of leukocytes have been designed and are being developed as a novel class of drugs in the treatment of Crohn's disease and ulcerative colitis. This review deals with the immunological aspects of leukocyte trafficking focused on gut homing of T cells. Second, the changes in adhesion molecules and T cell trafficking during intestinal inflammation are discussed. Finally, we review the clinical data that have been gathered with respect to the therapeutic potential and the safety of antiadhesion molecule treatment. Antegren, or natalizumab, a humanized anti-α4 integrin IgG4 antibody, has been most extensively evaluated and may be close to registration. A more specific humanized α4β7-integrin MLN-02 has shown preliminary clinical efficacy in ulcerative colitis, and both antergren and MLN-02 appear to be very safe. Trials with the anti-ICAM-1 antisense oligonucleotide ISIS-2302 in steroid refractory Crohn's disease have provided conflicting efficacy data. In the near future, some of these novel biological agents may prove valuable therapeutic tools in the management of refractory inflammatory bowel disease, although it is too early to define the patient population that will benefit most from these agents.
3
Bergamaschi, Cristina, Vasiliki Stravokefalou, Dimitris Stellas, Sevasti Karaliota, Barbara K. Felber, and George N. Pavlakis. "Heterodimeric IL-15 in Cancer Immunotherapy." Cancers 13, no. 4 (February 17, 2021): 837. http://dx.doi.org/10.3390/cancers13040837.
Full textAbstract:
Immunotherapy has emerged as a valuable strategy for the treatment of many cancer types. Interleukin-15 (IL-15) promotes the growth and function of cytotoxic CD8+ T and natural killer (NK) cells. It also enhances leukocyte trafficking and stimulates tumor-infiltrating lymphocytes expansion and activity. Bioactive IL-15 is produced in the body as a heterodimeric cytokine, comprising the IL-15 and the so-called IL-15 receptor alpha chain that are together termed “heterodimeric IL-15” (hetIL-15). hetIL-15, closely resembling the natural form of the cytokine produced in vivo, and IL-15:IL-15Rα complex variants, such as hetIL-15Fc, N-803 and RLI, are the currently available IL-15 agents. These molecules have showed favorable pharmacokinetics and biological function in vivo in comparison to single-chain recombinant IL-15. Preclinical animal studies have supported their anti-tumor activity, suggesting IL-15 as a general method to convert “cold” tumors into “hot”, by promoting tumor lymphocyte infiltration. In clinical trials, IL-15-based therapies are overall well-tolerated and result in the expansion and activation of NK and memory CD8+ T cells. Combinations with other immunotherapies are being investigated to improve the anti-tumor efficacy of IL-15 agents in the clinic.
4
Miller, Mark J. "Two-Photon Imaging of Immune Cell Dynamics: Moving from 2D Fixed Tissue Sections to 3D Dynamic Histology In Vivo." Blood 122, no. 21 (November 15, 2013): SCI—24—SCI—24. http://dx.doi.org/10.1182/blood.v122.21.sci-24.sci-24.
Full textAbstract:
Abstract Cell-mediated immune responses are highly dependent on environmental context, thus making in vivo studies an important complement to in vitro and molecular approaches. Two-photon microscopy (2PM) is a fluorescence based imaging approach that allows single-cell dynamics to be studied directly in their 3D native tissue context. 2PM is an ideal approach for analyzing leukocyte trafficking dynamics quantitatively and testing cellular immune mechanisms in vivo. Several example applications will be presented where 2PM has uncovered novel immunological phenomena and provided fresh insight into immune responses to infection, autoimmunity and cancer. While 2P imaging has been used extensively to study immune cell trafficking and function in mice, progress is being made to use this imaging technique on clinical biopsy specimens to acquire a multi-dimensional picture of human tissue pathology. We used in vivo 2PM in pre-clinical models of arthritis and bacterial infection to compare and contrast the role of monocytes on neutrophil recruitment. The rapid recruitment of neutrophils and monocytes is critical to early host immune responses to bacterial infection. However, leukocyte recruitment also contributes to chronic inflammatory diseases such as human rheumatoid arthritis. Understanding how cell recruitment is regulated in different inflammatory contexts is crucial for developing safe and effective anti-inflammatory therapies. We found that monocyte depletion with clodronate-liposomes prevented arthritis development in a modified K/BxN serum transfer arthritis model. This protective effect was associated with significantly reduced neutrophil transendothelial migration efficiency. Furthermore, single-cell tracking of a minor population of extravasated neutrophils showed that neutrophil migration and chemotaxis in interstitial tissues was disrupted, contributing to decreased cell localization at phalangeal joints. Similar results were obtained when CCR2+ monocytes were depleted selectively using the monoclonal antibody MC-21, thus implicating CCR2+ monocytes as key regulators of neutrophil extravasation during arthritis initiation. In contrast, neutrophil recruitment to subcutaneous bacterial challenge remained intact and neutrophil extravasation and chemotaxis to sites of infection was not significantly different as compared to non-depleted controls. We also examined whether neutrophil extravasation during acute pulmonary inflammation required monocytes. Neutrophil recruitment in vivo was assessed in a mouse lung transplant-mediated ischemia reperfusion injury model. Similar to the results in the arthritis model, neutrophil recruitment in response to ischemia reperfusion injury was also monocyte dependent. In addition, Ccr2 knockout recipient mice were protected for ischemia reperfusion injury. Results from these complementary mouse models implicate CCR2+ monocytes as key regulators of neutrophil extravasation and chemotaxis in under conditions of aseptic inflammation and further suggest that the cell recruitment signals that that operate during bacterial infection may be quantitatively and/or qualitatively distinct. These studies raise the intriguing possibility that targeting monocytes during chronic inflammatory diseases such as rheumatoid arthritis or acute inflammatory conditions such as ischemia reperfusion injury might provide safer and more selective anti-inflammatory therapies than those that target neutrophils directly. Disclosures: No relevant conflicts of interest to declare.
5
Chalmers, Samantha A., Sayra J. Garcia, Leal Herlitz, Jeanette Ampudia, Cherie Ng, Stephen Connelly, and Chaim Putterman. "CD6 modulation ameliorates immune complex-mediated glomerulonephritis." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 142.18. http://dx.doi.org/10.4049/jimmunol.204.supp.142.18.
Full textAbstract:
Abstract Lupus nephritis (LN) is a serious end organ complication of systemic lupus erythematosus (SLE) in which T cells are thought to play an essential role. CD6 is a co-stimulatory receptor on T cells, that binds to activated leukocyte cell adhesion molecule (ALCAM), a ligand expressed on antigen presentation cells and epithelial and endothelial tissues. The CD6-ALCAM pathway plays an integral role in modulating T cell activation and trafficking, and increased levels of CD6 are associated with pathogenic T cell responses. To assess the role of the CD6-ALCAM pathway in LN pathogenesis, we tested a monoclonal antibody against CD6 in a short-term, validated, inducible murine model of lupus nephritis known as nephrotoxic serum nephritis (NTN). NTN mice were treated 3× per week with an anti-CD6 mAb (10D12, 60ug/dose, n=23) or with vehicle control (n=23). Healthy mice were also included as a control (n=12). Mice treated with the anti-CD6 mAb displayed decreased levels of proteinuria (p<0.001) and significantly improved BUN levels (p<0.01) compared to vehicle control mice. Histology also significantly improved with anti-CD6 treatment (p<0.05). RT-PCR revealed significantly decreased levels of VCAM and RANTES in the kidneys of treated mice, while anti-inflammatory IL-10 was increased, compared to vehicle control mice. Flow cytometry analysis indicated decreased accumulation of both renal-infiltrating activated T cells (CD4+CD25+CD69+, p <0.01) inflammatory macrophages (p<0.05). Overall, these results indicate that the CD6-ALCAM pathway is an important driver of inflammation and pathology in LN and, thus, a promising therapeutic option that is more selective than the immunosuppressive therapies currently offered.
6
Pisani, L. F., G. Crespi, M. Mellai, C. Flavio, M. L. Annunziata, M. Manfredi, P. Luca, and C. Porta. "DOP36 Vedolizumab-treated IBD patients show an increased gut microbial diversity associated with a specific serum metabolic signature." Journal of Crohn's and Colitis 17, Supplement_1 (January 30, 2023): i99—i101. http://dx.doi.org/10.1093/ecco-jcc/jjac190.0076.
Full textAbstract:
Abstract Background A role for gut microbes in IBD has been suspected since the early descriptions of potential infectious agents. IBD is clearly associated with intestinal dysbiosis, that is the imbalance in structures and functions of gut microbiota that disrupts host-microbe and immune homeostasis. Members of the commensal gut microbiota may play a role in etiopathogenesis of IBD. New therapies with diverse mechanisms of action inhibiting leukocyte trafficking or blocking inflammatory cytokines have revolutionized therapeutic approach. A less diverse microbiome, greater abundance of pro-inflammatory and depletion of species with protective mechanisms, such as short-chain fatty acid production, is associated with intestinal inflammation in IBD. Given that intestinal dysbiosis is a hallmark of IBD patients, we investigate the potential role of biologic drugs on both gut microbial and serum metabolomic in the restoration of microbial homeostasis. Methods In 2020-2021, 238 IBD patients (CD=145, UC=93) and 45 healthy controls of the North Italy were enrolled. To define the characteristics of metabolic profile of IBD patients, three different machine learning models based on serum metabolic signatures were developed and applied for the random forest analysis of anti-TNF or anti-integrin users. Stool sample from anti-integrin (N=18) or anti-TNF (N=19)-treated IBD patients was profiled by 16S rRNA gene sequencing, to identify putative associations between medication and microbial composition. Results In IBD patients untargeted metabolomics on serum samples confirmed that both most of the IBD patients (70% of anti-TNF and 100% of vedolizumab users) harbor a metabolic profile enriched of anti-inflammatory and antioxidant molecules. Noteworthy, vedolizumab-treated patients showed a higher microbial diversity than anti-TNF users along with an enrichment of both Bacteroidetes and Proteobacteria. Despite the prevalence of Firmicutes species (60,85-62,97%) in IBD patients, the Firmicutes/Bacteroidetes ratio of vedolizumab (2,9:1) is lower than anti-TNF (5,7:1) users, suggesting that anti-integrin-treated patients have an improved microbial composition. Conclusion The gut microbiome is a key determinant of initiation and propagation of luminal inflammation in IBD. We describe the microbial composition and structure from a large cohort of IBD patients with different biologic therapies, and their metabolomic profile. We found a correlation between an improvement of dysbiosis and a more anti-oxidant and anti-inflammatory metabolic profile in vedolizumab-treated patients. Further experimental studies are important to mechanistically determine how biologic drugs differentially influence gut microbiota and metabolomic and how this may impact IBD course.
7
Liu, Peng, Teresa Tarrant, Rishi Rampersad, Christopher Vallanat, Tatiana Quintero-Matthews, Dhavalkumar Patel, and Alan Fong. "Th17 cells contribute to the exacerbated autoimmune arthritis in CCR2-deficient mice (34.6)." Journal of Immunology 184, no. 1_Supplement (April 1, 2010): 34.6. http://dx.doi.org/10.4049/jimmunol.184.supp.34.6.
Full textAbstract:
Abstract Th17 cells have been implicated in the pathogenesis of autoimmune diseases including rheumatoid arthritis (RA). Chemokine receptor CCR2 mediates leukocyte trafficking to sites of inflammation and is considered to be an important proinflammatory factor in RA. However, as an unexpected paradox, mice lacking CCR2 (CCR2-/-) develop an accelerated and enhanced arthritis in the collagen induced arthritis model (CIA). To investigate the underlying mechanism(s), we examined the role of Th17 cells in CCR2-/- mice with CIA. We found that the number of Th17 cells was increased significantly in draining lymph nodes of CCR2-/- CIA mice (845±144) compared to WT controls (289±136, p=0.017). In contrast, Th1 cells were not significantly different between groups (485±171 vs. 516±86 for WT, p=0.88). Consistently, CCR2-/- CIA mice had elevated levels of sera IL-17 (84.4±15.5 pg/ml) and IL-17 mRNA in arthritic joints (3.43±0.61 fold) compared to WT mice (45±9.7 pg/ml in the serum and 0.21±0.05 fold in the joint, p=0.04 and 0.009 respectively). Furthermore, Th17-favored cytokines IL-6 and IL-1β were up-regulated in the serum of CCR2-/- animals (IL-6: 366.1±54.5 pg/ml vs. 58.7±13.3 pg/ml for WT, p=0.0004; IL-1β: 189.6±21.9 pg/ml vs. 106.4±21.3 pg/ml for WT, p=0.01). These data suggest that Th17 cells contribute to the pathogenesis of the aggravated phenotype of autoimmune arthritis in CCR2-/- mice. Mice deficient in CCR2 may serve as a model for evaluations of anti-Th17 therapies against RA.
8
van der Velden, Saskia, Thijs L. J. van Osch, Amina Seghier, Arthur Bentlage, Juk Yee Mok, Dionne M. Geerdes, Wim J. E. van Esch, et al. "Fc-Mediated Complement Activation Is Associated with Macrophage Trafficking and Induction of Neutrophil Extracellular Traps in Transfusion-Related Acute Lung Injury." Blood 138, Supplement 1 (November 5, 2021): 354. http://dx.doi.org/10.1182/blood-2021-153988.
Full textAbstract:
Abstract Transfusion-related acute lung injury (TRALI) is a leading cause of blood transfusion-related fatalities without available therapies. The pulmonary endothelium is damaged in TRALI, through incompletely understood pathogenic mechanisms, resulting in pulmonary edema. Generally, anti-leukocyte antibodies or biological response modifiers in the transfusion product, in combination with predisposing risk factors in the transfused recipient (e.g. inflammation), are responsible for initiation of TRALI. Remarkably, not all anti-leukocyte antibodies cause TRALI. In a previous in vitro study, we identified increased Fc-mediated complement activation to be a key feature of murine TRALI-inducing antibody 34-1-2S (anti-H-2K d) compared to TRALI-resistant antibody SF1.1.10 (anti-H-2K d) (Zeeuw van der Laan et al, Blood Adv 2020). In the current study, we further explored antibody-mediated TRALI mechanisms in vivo using our previously established TRALI mouse model in which mice are pre-depleted of protective CD4+ T cells and primed with LPS, followed by infusion of antibody 34-1-2S (Kapur et al, Blood 2017, Blood Adv 2018, Blood 2019). A key read-out for TRALI was the lung wet/dry weight ratio (Lung W/D, measure for pulmonary edema). We found that in vitro antibody-mediated complement activation was associated with in vivo antibody-mediated TRALI. 34-1-2S caused severe TRALI (complement activation: +++, Lung W/D: 7.4 ± 0.21), while SF1.1.10 did not cause TRALI (complement activation: +, Lung W/D: 4.68 ± 0.16). Furthermore, Fc-deglycosylated 34-1-2S still caused significant TRALI (complement activation: ++, in vivo Lung W/D: 5.16 ± 0.52). TRALI development was fully Fc-dependent as 34-1-2S-Fab did not cause any TRALI (no complement activation, Lung W/D: 4.35 ± 0.18). Importantly, we found significantly increased levels of complement C1q-C4 complexes in plasma samples of TRALI patients (n=46) compared to healthy controls (n=25): 6.49 ± 5.27 vs 3.84 ± 2.27 AU/ml, respectively, P: 0.0005,***. Similarly, C5a levels were significantly elevated in plasma samples of TRALI patients (n=53) compared to healthy controls (n=30): 2.52 ± 2.17 vs 1.37 ± 1.08 ng/ml, respectively, P: 0.0006,***. To further dissect the effect of the Fc-part of 34-1-2S in TRALI-induction, we aim to investigate the contribution of Fc-mediated complement activation vs Fc-receptor interaction. We therefore successfully generated chimeric variants of 34-1-2S with a humanized IgG1 Fc-domain containing mutations making them functionally complement dead (K322A), Fc-receptor dead (dG236) or both complement and Fc-receptor dead (PG LALA). We are currently investigating the effects of these variants on in vivo TRALI induction. We next investigated how the in vivo murine TRALI reaction was related to numbers of macrophages, monocytes and neutrophils in blood and lungs. We found that 34-1-2S-TRALI was associated with significantly decreased levels of macrophages in the lungs and increased levels in blood, compared to mice infused with PBS, SF1.1.10 or 34-1-2S-Fab, suggesting that Fc-mediated complement activation and TRALI induction is related to macrophage trafficking from lungs to blood. We did not observe any significant differences between blood and lung neutrophil levels of 34-1-2S-TRALI mice compared to SF1.1.10 TRALI-resistant mice. We hypothesized that in TRALI neutrophils undergo formation of neutrophil extracellular traps (NETs) induced by complement. We observed that C5a enabled potent neutrophil-chemotaxis in vitro (P: 0.0048,**). In addition, using direct immunofluorescence staining of extracellular DNA and Citrullinated histone H3, we observed that both LPS and C5a on their own could induce NET formation in vitro, which was synergistically increased with a combination of both LPS and C5a (P: 0.0417,*), as occurring during TRALI. Furthermore, we found increased levels of NETs to be present in plasma samples of TRALI patients (n=53) compared to healthy controls (n=30): 1.64 ± 0.97 vs 0.80 ± 0.34 MPO-DNA OD, respectively, P: 0.0002,***. Finally, we targeted the C5a-receptor (C5aR) using a C5aR-antagonist in our TRALI mouse model. Surprisingly, this did not prevent but even worsened TRALI (P: 0.0398,*), with elevated levels of blood monocytes and macrophages. This suggests that an approach directly targeting complement components may be a more promising therapeutic strategy to explore in combatting TRALI. Disclosures No relevant conflicts of interest to declare.
9
Borjesson, Dori L., Scott I. Simon, Emir Hodzic, Hilde E. V. DeCock, Christie M. Ballantyne, and Stephen W. Barthold. "Roles of neutrophil β2 integrins in kinetics of bacteremia, extravasation, and tick acquisition of Anaplasma phagocytophila in mice." Blood 101, no. 8 (April 15, 2003): 3257–64. http://dx.doi.org/10.1182/blood-2002-04-1019.
Full textAbstract:
AbstractTick saliva contains anti-inflammatory and immunosuppressive substances that facilitate blood feeding and enhance tick-vectored pathogen transmission, including Anaplasma phagocytophila,an etiologic agent of granulocytic ehrlichiosis. As such, inflammation at a tick-feeding site is strikingly different than that typically observed at other sites of inflammation. Up-regulation of CD11b/CD18 occurs in host granulocytes following interaction or infection withA phagocytophila, and the absence of CD11b/CD18 results in early increases in bacteremia. We hypothesized that β2 integrin–dependent infection kinetics and leukocyte extravasation are important determinants of neutrophil trafficking to, and pathogen acquisition at, tick-feeding sites.A phagocytophila infection kinetics were evaluated in CD11a/CD18, CD11b/CD18, and CD18 knock-out mice using quantitative polymerase chain reaction (PCR) of blood, ticks, and skin biopsies in conjunction with histopathology. A marked increase in the rate ofA phagocytophila infection of neutrophils and pathogen burden in blood followed tick feeding. Infection kinetics were modified by β2 integrin expression and systemic neutrophil counts. Significant neutrophil-pathogen trafficking was observed to both suture and tick sites. Despite the prominent role for β2 integrins in neutrophil arrest in flowing blood, successful pathogen acquisition by ticks occurred in the absence of β2 integrins. Establishment of feeding pools that rely less on leukocyte trafficking and more on small hemorrhages may explain the ready amplification of A phagocytophila DNA from ticks infested on CD11/CD18-deficient mouse strains.
10
Carlos, TM, and JM Harlan. "Leukocyte-endothelial adhesion molecules." Blood 84, no. 7 (October 1, 1994): 2068–101. http://dx.doi.org/10.1182/blood.v84.7.2068.2068.
Full textAbstract:
Abstract In the 9 years since the last review on leukocyte and endothelial interactions was published in this journal many of the critical structures involved in leukocyte adherence to and migration across endothelium have been elucidated. With the advent of cell and molecular biology approaches, investigations have progressed from the early descriptions by intravital microscopy and histology, to functional and immunologic characterization of adhesion molecules, and now to the development of genetically deficient animals and the first phase I trial of “anti-adhesion” therapy in humans. The molecular cloning and definition of the adhesive functions of the leukocyte integrins, endothelial members of the Ig gene superfamily, and the selectins has already provided sufficient information to construct an operative paradigm of the molecular basis of leukocyte emigration. The regulation of these adhesion molecules by chemoattractants, cytokines, or chemokines, and the interrelationships of adhesion pathways need to be examined in vitro and, particularly, in vivo. Additional studies are required to dissect the contribution of the individual adhesion molecules to leukocyte emigration in various models of inflammation or immune reaction. Certainly, new adhesion structures will be identified, and the current paradigm of leukocyte emigration will be refined. The promise of new insights into the biology and pathology of the inflammatory and immune response, and the potential for new therapies for a wide variety of diseases assures that this will continue to be an exciting area of investigation.
11
Carlos, TM, and JM Harlan. "Leukocyte-endothelial adhesion molecules." Blood 84, no. 7 (October 1, 1994): 2068–101. http://dx.doi.org/10.1182/blood.v84.7.2068.bloodjournal8472068.
Full textAbstract:
In the 9 years since the last review on leukocyte and endothelial interactions was published in this journal many of the critical structures involved in leukocyte adherence to and migration across endothelium have been elucidated. With the advent of cell and molecular biology approaches, investigations have progressed from the early descriptions by intravital microscopy and histology, to functional and immunologic characterization of adhesion molecules, and now to the development of genetically deficient animals and the first phase I trial of “anti-adhesion” therapy in humans. The molecular cloning and definition of the adhesive functions of the leukocyte integrins, endothelial members of the Ig gene superfamily, and the selectins has already provided sufficient information to construct an operative paradigm of the molecular basis of leukocyte emigration. The regulation of these adhesion molecules by chemoattractants, cytokines, or chemokines, and the interrelationships of adhesion pathways need to be examined in vitro and, particularly, in vivo. Additional studies are required to dissect the contribution of the individual adhesion molecules to leukocyte emigration in various models of inflammation or immune reaction. Certainly, new adhesion structures will be identified, and the current paradigm of leukocyte emigration will be refined. The promise of new insights into the biology and pathology of the inflammatory and immune response, and the potential for new therapies for a wide variety of diseases assures that this will continue to be an exciting area of investigation.
12
Johnston, B., T. B. Issekutz, and P. Kubes. "The alpha 4-integrin supports leukocyte rolling and adhesion in chronically inflamed postcapillary venules in vivo." Journal of Experimental Medicine 183, no. 5 (May 1, 1996): 1995–2006. http://dx.doi.org/10.1084/jem.183.5.1995.
Full textAbstract:
A role for the alpha 4-integrin (alpha 4 beta 1 or alpha 4 beta 7), has been implicated in the recruitment of peripheral blood mononuclear cells (PBMCs) to sites of inflammation. However, the adhesive interactions (i.e., tethering, rolling, and adhesion) mediated by the alpha 4-integrin have not been characterized in vivo. The objective of this study was to establish a model wherein postcapillary venules were chronically inflamed, and then use intravital microscopy to identify the adhesive interactions mediated by the alpha 4-integrin in vivo. Between 4 and 20 d after immunization with Mycobacterium butyricum, animals developed a systemic vasculitis characterized by large increases in the numbers of rolling and adhering leukocytes within mesenteric venules. The selectins could only account for approximately 50% of the leukocyte rolling whereas the remaining cells rolled exclusively via the alpha 4-integrin. Anti-alpha 4 therapy also eliminated the increase in leukocyte adhesion observed in this model, whereas selectin therapies and an anti-CD18 (beta 2-integrin) monoclonal antibody (mAb) did not reduce adhesion. A serum against polymorphonuclear leukocytes (PMNs) was used to confirm that a significant proportion of rolling cells, and most of the adhering cells were PBMCs. Sequential treatment with anti-PMN serum and the anti-alpha 4 mAb demonstrated that alpha 4-dependent rolling was distinct from PMN rolling populations. Initial leukocyte tethering via the alpha 4-integrin could not be demonstrated in this model, whereas L-selectin did support leukocyte tethering. These data suggest that the alpha 4-integrin can mediate both rolling and adhesion in the multistep recruitment of PMBCs in vivo, and these interactions occur independently of the selectins and beta 2-integrins.
13
Koreth, John, Saurabh Chhabra, Joseph Pidala, Thomas C. Shea, Madan Jagasia, Edmund K. Waller, Ryotaro Nakamura, et al. "Equate, a Phase 1b/2 Study Evaluating the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Clinical Activity of a Novel Targeted Anti-CD6 Therapy, Itolizumab, in Subjects with Newly Diagnosed Acute Graft Versus Host Disease." Blood 134, Supplement_1 (November 13, 2019): 4516. http://dx.doi.org/10.1182/blood-2019-127325.
Full textAbstract:
Background: Acute graft versus host disease (aGVHD) occurs in approximately 50% of patients receiving allogeneic hematopoietic stem cell transplant (HSCT) with standard GVHD prophylaxis regimens and is a significant contributor to morbidity and non-relapse mortality (NRM). There are currently no FDA approved therapies for the initial treatment of newly diagnosed aGVHD. T effector cells (Teff), particularly CD4+ T helper cells, play a central role in the pathogenesis of aGVHD. CD6 is a co-stimulatory receptor, predominantly expressed on CD4+ T helper cells, that binds to activated leukocyte cell adhesion molecule (ALCAM), a ligand expressed on antigen presenting cells and various epithelial and endothelial tissues. The CD6-ALCAM pathway plays an integral role in modulating T cell activation and trafficking and is central to immune mediated inflammation. Previous studies by Soiffer et al. in patients receiving allogeneic bone marrow transplants had shown that depleting CD6+ T cells ex-vivo in donor bone marrow using T-12, an anti-CD6 monoclonal antibody (mAb), as a sole method for GVHD prophylaxis lowered the incidence of acute and chronic GVHD. EQ001 (itolizumab) is a humanized IgG1 mAb that binds to CD6 and blocks the interaction with ALCAM and inhibits both the activity and trafficking of T cells without causing T cell depletion. Itolizumab has s previously been developed and is approved for the treatment of Psoriasis in India. The potential effectiveness of an anti-CD6 mAb targeted approach in treating aGVHD is supported by data from pre-clinical models evaluating the prevention and treatment of GVHD with EQ001. The objective of this study is to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and clinical activity of EQ001 in subjects with newly diagnosed aGVHD. Study Design and Methods: This is a multi-center Phase 1b/2 study (NCT03763318) of EQ001 in subjects with aGVHD. Part A (Phase 1b) of the study is an open-label, multiple ascending dose study of EQ001 in adults with newly diagnosed High Risk (MacMillan Criteria) aGVHD following HSCT. Approximately 24 subjects will be enrolled in successive cohorts of 3 to 6 adult subjects using a standard 3 + 3 dose escalation design. For each cohort, subjects will receive EQ001 administered intravenously (IV) every two weeks for five doses with corticosteroids (CS) tapered over the treatment period. A total of four dose levels will be tested ranging from 0.4 mg/kg to 2.4 mg/kg, and subjects will be followed for an additional 10 months after study treatment is completed. The primary objective of Part A is to evaluate safety and tolerability of EQ001. Secondary objectives include an evaluation of PK, PD (including CD6 receptor occupancy, changes in inflammatory cytokines and novel gut biomarkers [ST2, REG3α], and changes in Teff/T regulatory cells populations), and clinical activity (overall aGVHD response rates on Day 29, durability of the response at Day 57 and up to 1 year, cumulative incidence of NRM, rates of chronic GVHD, and CS dose requirements). Data from Part A will inform the dose selection for Part B (Phase 2) of the study. Enrollment to Part A is ongoing. Part B is a double-blind, placebo-controlled study in subjects (age ≥12) with newly diagnosed Grade II-IV aGVHD. Approximately 60 subjects will be randomized in a 2:1 ratio to either treatment with EQ001 (n=40) or placebo (n=20) in addition to and within 72 hours of the first dose of CS. EQ001 or placebo will be administered IV every two weeks for five doses, and subjects will be followed for an additional 10 months after the last dose of study treatment. The primary objective of Part B is to evaluate the overall response rate of aGVHD in patients treated with EQ001 versus placebo. Secondary objectives include an evaluation of safety and other clinical endpoints. The primary endpoint is the overall response rate at Day 29 as defined by a complete response, very good partial response or partial response. Additional clinical endpoints include assessment of NRM, chronic GVHD rates, and CS dose requirements. Conclusion: Inhibiting the CD6-ALCAM pathway with EQ001 represents a unique and promising approach for the treatment of aGVHD following HSCT by inhibiting both the activity and trafficking of T cells. This is the first clinical study to examine the effects of an anti-CD6 therapy for the treatment of patients with newly diagnosed aGVHD. Disclosures Koreth: Equillium: Consultancy; Cugene: Consultancy; Amgen: Consultancy. Shea:Jazz: Consultancy; Amgen: Consultancy; Merck: Consultancy. Jagasia:Kadmon: Consultancy; Incyte: Consultancy; Janssen: Research Funding. Waller:Pharmacyclics: Other: Travel expenses, Research Funding; Cerus Corporation: Other: Stock, Patents & Royalties; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Chimerix: Other: Stock; Cambium Oncology: Patents & Royalties: Patents, royalties or other intellectual property ; Amgen: Consultancy; Kalytera: Consultancy. Nakamura:Celgene: Other: support for an academic seminar in a university in Japan; Merck: Membership on an entity's Board of Directors or advisory committees; Alexion: Other: support to a lecture at a Japan Society of Transfusion/Cellular Therapy meeting ; Kirin Kyowa: Other: support for an academic seminar in a university in Japan. Ng:Equillium: Employment, Equity Ownership. Sonnemann:Equillium Inc.: Employment. Light:Equillium Inc.: Consultancy. Nanayakkara:Equillium Inc.: Consultancy. Essayan:Equillium Inc.: Consultancy. Rothman:Equillium Inc.: Employment, Equity Ownership. Connelly:Equillium: Employment, Equity Ownership. Polu:Equillium Inc.: Employment, Equity Ownership. Kean:HiFiBio: Consultancy; BlueBirdBio: Research Funding; Gilead: Research Funding; Regeneron: Research Funding; EMDSerono: Consultancy; FortySeven: Consultancy; Magenta: Research Funding; Kymab: Consultancy; Jazz: Research Funding; Bristol Meyers Squibb: Patents & Royalties, Research Funding. Ritz:Draper Labs: Consultancy; Talaris Therapeutics: Consultancy; TScan Therapeutics: Consultancy; Equillium: Research Funding; Merck: Research Funding; Kite Pharma: Research Funding; Aleta Biotherapeutics: Consultancy; Celgene: Consultancy; Avrobio: Consultancy; LifeVault Bio: Consultancy. Soiffer:Gilead, Mana therapeutic, Cugene, Jazz: Consultancy; Juno, kiadis: Membership on an entity's Board of Directors or advisory committees, Other: DSMB; Kiadis: Other: supervisory board; Mana therapeutic: Consultancy; Cugene: Consultancy; Jazz: Consultancy. Cutler:Kadmon: Consultancy; Omeros: Consultancy; ElsaLys: Consultancy; BiolineRx: Other: DSMB; Cellect: Other: DSMB; Kalytera: Other: DSMB; Incyte: Consultancy; Genentech: Consultancy; Jazz: Consultancy; BMS: Consultancy; Fate Therapeutics: Consultancy; Pharmacyclics: Consultancy. OffLabel Disclosure: EQ001 (itolizumab) is an investigational agent being developed for the treatment of acute GVHD. Itolizumab has not received regulatory approval for the treatment of GVHD. The abstract being submitted describes the study design for the phase 1b/2 study. No data is being presented.
14
Chin, J. E., C. A. Hatfield, G. E. Winterrowd, J. R. Brashler, S. L. Vonderfecht, S. F. Fidler, R. L. Griffin, et al. "Airway recruitment of leukocytes in mice is dependent on alpha4-integrins and vascular cell adhesion molecule-1." American Journal of Physiology-Lung Cellular and Molecular Physiology 272, no. 2 (February 1, 1997): L219—L229. http://dx.doi.org/10.1152/ajplung.1997.272.2.l219.
Full textAbstract:
The involvement of the alpha4-integrin very late activation antigen 4 and vascular cell adhesion molecule-1 (VCAM-1) in leukocyte trafficking into the airways of ovalbumin (OA)-sensitized and OA-challenged mice was investigated using in vivo administration of anti-alpha4 monoclonal antibodies (mAb) PS/2, R1-2, and M/K-2.7 (MK2), specific for VCAM-1. VCAM-1 was upregulated on endothelial cells in lung tissue after OA inhalation. PS/2, R1-2, or MK2 significantly inhibited the recruitment of eosinophils and lymphocytes into the bronchoalveolar lavage (BAL) fluid and decreased inflammation in the lung tissues. Escalating in vivo doses of PS/2 or MK2 increased circulating levels of rat immunoglobulin G in the plasma. The binding of phycoerytherin-labeled anti-alpha4 mAb to blood T cells from PS/2-treated mice was reduced, implying that alpha4 sites were already occupied. T cells and eosinophils in BAL fluid from mice treated with PS/2 or MK2 were phenotypically different from controls. Selective decreases of alpha4+ T cells in the BAL fluid after PS/2 or MK2 treatment were coupled with changes in CD8+, CD11a, and CD62L expression. The alpha4-integrin and VCAM-1 may have important roles in the antigen-induced recruitment of T cells and eosinophils during OA-induced airway inflammation. The data suggest that these adhesion molecules may be suitable targets for therapeutic intervention in certain conditions of pulmonary inflammation.
15
Eddy, Allison. "Serine proteases, inhibitors and receptors in renal fibrosis." Thrombosis and Haemostasis 101, no. 04 (2009): 656–64. http://dx.doi.org/10.1160/th08-12-0779.
Full textAbstract:
SummaryChronic kidney disease (CKD) is estimated to affect one in eight adults. Their kidney function progressively deteriorates as inflammatory and fibrotic processes damage nephrons. New therapies to prevent renal functional decline must build on basic research studies that identify critical cellular and molecular mediators. Plasminogen activator inhibitor-1 (PAI-1), a potent fibrosis-promoting glycoprotein, is one promising candidate. Absent from normal kidneys, PAI-1 is frequently expressed in injured kidneys. Studies in genetically engineered mice have demonstrated its potency as a pro-fibrotic molecule. Somewhat surprising, its ability to inhibit serine protease activity does not appear to be its primary pro-fibrotic effect in CKD. Both tissue-type plasminogen activator and plasminogen deficiency significantly reduced renal fibrosis severity after ureteral obstruction, while genetic urokinase (uPA) deficiency had no effect. PAI-1 expression is associated with enhanced recruitment of key cellular effectors of renal fibrosis – interstitial macrophages and myofibroblasts. The ability of PAI-1 to promote cell migration involves interactions with the low-density lipoprotein receptor-associate protein-1 and also complex interactions with uPA bound to its receptor (uPAR) and several leukocyte and matrix integrins that associate with uPAR as co-receptors. uPAR is expressed by several cell types in damaged kidneys, and studies in uPAR-deficient mice have shown that its serves a protective role. uPAR mediates additional anti-fibrotic effects – it interacts with specific co-receptors to degrade PAI-1 and extracellular collagens, and soluble uPAR has leukocyte chemoattractant properties. Molecular pathways activated by serine proteases and their inhibitor, PAI-1, are promising targets for future anti-fibrotic therapeutic agents.
16
Christofides, Anthos, Carol Cao, Rinku Pal, and Vassiliki A. Boussiotis. "RIAM regulates myeloid cell fate commitment and macrophage polarization and controls tumor progression." Journal of Immunology 206, no. 1_Supplement (May 1, 2021): 101.04. http://dx.doi.org/10.4049/jimmunol.206.supp.101.04.
Full textAbstract:
Abstract Initiation of immune responses requires integrin-mediated adhesion between T cells and APC, linking innate and adaptive immunity. Integrins also regulate leukocyte trafficking and extravagation at sites of inflammation. Among the few molecules implicated in integrin activation is the Rap1-interacting molecule (RIAM). Tumor-driven emergency myelopoiesis induces expansion of myeloid progenitors and output of immature, immunosuppressive myeloid derived suppressor cells (MDSC), and tumor-associated macrophages (TAM). TAMs are classified into two groups: M1, which have a pro-inflammatory and anti-tumor function and M2, which have an anti-inflammatory role and facilitate tumor progression. To determine whether RIAM affects the properties of myeloid cells and tumor progression, we generated mice with conditional targeting of RIAM and crossed them with LysMCre mice (RIAMfl/flLysMCre) to delete RIAM specifically in the myeloid compartment. Using the B16-F10 melanoma and MC17-51 fibrosarcoma tumor models, we determined that RIAMfl/flLysMCre mice displayed an accelerated growth and significantly larger tumors compared to RIAMfl/fcontrol mice. There were no numerical differences in CD11b+F4/80+ macrophages, CD11b+Ly6ChiLy6G− monocytic (M-MDSC), CD11b+Ly6CloLy6G+ polymorphonuclear (PMN-MDSC) or CD11c+MHCII+ dendritic cells between the two groups. However, TAMs and splenic macrophages of RIAMfl/flLysMCre mice exhibited an M2-like phenotype. Bone marrow derived macrophages from RIAMfl/flLysMCre had an imprinted M2 polarization program. Thus, RIAM has a previously unidentified role in myeloid cell fate commitment that regulates macrophage polarization and controls tumor progression.
17
Rieu, P., T. Ueda, I. Haruta, C. P. Sharma, and M. A. Arnaout. "The A-domain of beta 2 integrin CR3 (CD11b/CD18) is a receptor for the hookworm-derived neutrophil adhesion inhibitor NIF." Journal of Cell Biology 127, no. 6 (December 15, 1994): 2081–91. http://dx.doi.org/10.1083/jcb.127.6.2081.
Full textAbstract:
The A-domain is a approximately 200-amino acid peptide present within structurally diverse proadhesive proteins including seven integrins. A recombinant form of the A-domain of beta 2 integrins CR3 and LFA-1 has been recently shown to bind divalent cations and to contain binding sites for protein ligands that play essential roles in leukocyte trafficking to inflammatory sites, phagocytosis and target cell killing. In this report we demonstrate that the neutrophil adhesion inhibitor, NIF produced by the hookworm Ancyclostoma caninium is a selective CD11b A-domain binding protein. NIF bound directly, specifically and with high affinity (Kd of approximately 1 nM) to recombinant CD11b A-domain (r11bA). The binding reaction was characterized by rapid association and very slow dissociation, and was blocked by an anti-r11bA monoclonal antibody. No binding was observed to rCD11aA. The NIF-r11bA interaction required divalent cations, and was absent when the mutant r11bA D140GS/AGA (that lacks divalent cation binding capacity) was used. The NIF binding site in r11bA was mapped to four short peptides, one of which being an iC3b binding site. The interaction of NIF with CR3 in intact cells followed similar binding kinetics to those with r11bA, and occurred with similar affinity in resting and activated human neutrophils, suggesting that the NIF epitope is activation independent. Binding of NIF to CR3 blocked its ability to bind to its ligands iC3b, fibrinogen, and CD54, and inhibited the ability of human neutrophils to ingest serum opsonized particles. NIF thus represents the first example of a disintegrin that targets the integrin A-domain, and is likely to be used by the hookworm to evade the host's inflammatory response. The unique structure of NIF, which lacks a disintegrin motif, emphasizes basic structural differences in antagonists targeting A+ and A- integrins, that should be valuable in drug design efforts aimed at generating novel therapeutics. Identification of the region in NIF mediating A-domain binding should also be useful in this regard, and may, as in the case of disintegrins, unravel a new structural motif with cellular counterparts mediating important physiologic functions.
18
Vetter, Marcel, and Markus F. Neurath. "Emerging oral targeted therapies in inflammatory bowel diseases: opportunities and challenges." Therapeutic Advances in Gastroenterology 10, no. 10 (September 5, 2017): 773–90. http://dx.doi.org/10.1177/1756283x17727388.
Full textAbstract:
To improve quality of life and prevent long-term risks in patients with inflammatory bowel diseases (IBDs: Crohn’s disease, ulcerative colitis), it is essential to suppress inflammatory activity adequately. However, corticosteroids are only suitable for therapy of acute flares and the evidence for positive effects of immunosuppressive substances like azathioprine or 6-mercapropurine is mainly limited to maintenance of remission. In addition, only subgroups of patients benefit from biologicals targeting tumour necrosis factor α or α4β7 integrins. In summary, until now the disease activity is not sufficiently controlled in a relevant fraction of the patients with IBD. Thus, there is an urge for the development of new substances in the therapy of ulcerative colitis and Crohn’s disease. Fortunately, new oral and parenteral substances are in the pipeline. This review will focus on oral substances, which have already passed phase II studies successfully at this stage. In this article, we summarize data regarding AJM300, phosphatidylcholine (LT-02), mongersen, ozanimod, filgotinib and tofacitinib. AJM300 and ozanimod were tested in patients with ulcerative colitis and target lymphocyte trafficking through inhibition of the α subunit of integrin, respectively binding to the sphingosine-1-phosphate receptor (subtypes 1 and 5) on lymphocytes. Mongersen was utilized in patients with Crohn’s disease and accelerates the degradation of SMAD7 mRNA, which consequently strengthens the mainly anti-inflammatory signalling pathway of transforming growth factor β1. Various Janus kinase (JAK) inhibitors were developed, which inhibit the intracellular signalling pathway of cytokines. For example, the JAK1 blocker filgotinib was tested in Crohn’s disease, whereas the JAK1/3 inhibitor tofacitinib was tested in clinical trials for both Crohn’s disease and ulcerative colitis. A different therapeutic approach is the substitution of phosphatidylcholine (LT-02), which might recover the colonic mucus. Taken together, clinical trials with these new agents have opened avenues for further clinical studies and it can be expected that at least some of these agents will be finally approved for clinical therapy.
19
Li, Yi, Jianping Chen, Andrew A. Bolinger, Haiying Chen, Zhiqing Liu, Yingzi Cong, Allan R. Brasier, Irina V. Pinchuk, Bing Tian, and Jia Zhou. "Target-Based Small Molecule Drug Discovery Towards Novel Therapeutics for Inflammatory Bowel Diseases." Inflammatory Bowel Diseases 27, Supplement_2 (November 15, 2021): S38—S62. http://dx.doi.org/10.1093/ibd/izab190.
Full textAbstract:
Abstract Inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn’s disease (CD), is a class of severe and chronic diseases of the gastrointestinal (GI) tract with recurrent symptoms and significant morbidity. Long-term persistence of chronic inflammation in IBD is a major contributing factor to neoplastic transformation and the development of colitis-associated colorectal cancer. Conversely, persistence of transmural inflammation in CD is associated with formation of fibrosing strictures, resulting in substantial morbidity. The recent introduction of biological response modifiers as IBD therapies, such as antibodies neutralizing tumor necrosis factor (TNF)-α, have replaced nonselective anti-inflammatory corticosteroids in disease management. However, a large proportion (~40%) of patients with the treatment of anti-TNF-α antibodies are discontinued or withdrawn from therapy because of (1) primary nonresponse, (2) secondary loss of response, (3) opportunistic infection, or (4) onset of cancer. Therefore, the development of novel and effective therapeutics targeting specific signaling pathways in the pathogenesis of IBD is urgently needed. In this comprehensive review, we summarize the recent advances in drug discovery of new small molecules in preclinical or clinical development for treating IBD that target biologically relevant pathways in mucosal inflammation. These include intracellular enzymes (Janus kinases, receptor interacting protein, phosphodiesterase 4, IκB kinase), integrins, G protein-coupled receptors (S1P, CCR9, CXCR4, CB2) and inflammasome mediators (NLRP3), etc. We will also discuss emerging evidence of a distinct mechanism of action, bromodomain-containing protein 4, an epigenetic regulator of pathways involved in the activation, communication, and trafficking of immune cells. We highlight their chemotypes, mode of actions, structure-activity relationships, characterizations, and their in vitro/in vivo activities and therapeutic potential. The perspectives on the relevant challenges, new opportunities, and future directions in this field are also discussed.
20
Halsey, Christina, Mark TS Williams, Yasar Yousafzai, Klaus Rehe, Olaf Heidenreich, Josef Vormoor, Brenda Gibson, and Gerard Graham. "Central Nervous System Involvement in a Xenograft Model of Pre-B Acute Lymphoblastic Leukaemia Is Associated with Dysfunctional CXCR4 Expression and Upregulation of the Neurotropic Chemokine Receptors CCR6 and CX3CR1,." Blood 118, no. 21 (November 18, 2011): 3449. http://dx.doi.org/10.1182/blood.v118.21.3449.3449.
Full textAbstract:
Abstract Abstract 3449 Despite huge advances in the treatment of paediatric acute lymphoblastic leukaemia (ALL) challenges remain. Disease in the central nervous system (CNS) continues to pose difficulties in diagnosis, prevention and treatment. Understanding the biological mechanisms of leukaemic cell entry into the CNS should allow better detection and monitoring of leukemia and may identify novel therapeutic targets for resistant and relapsed disease. We hypothesize that leukaemic cell dissemination to the CNS is associated with the abnormal expression of molecules governing physiological leukocyte trafficking i.e. chemokine receptors, selectins and integrins. To address this hypothesis we have developed a xenograft model of CNS disease using IV tail vein injection of human leukaemic cell lines and primary cells into immunodeficient (NOD/SCID/IL2R gamma null) mice. Pre-B leukaemic cell lines were seen to differ in their capacity to home to the CNS. Using Taqman low density array plates quantitative expression of a panel of chemokine receptors, selectins and integrins was compared between these cell lines. Rapid onset of CNS disease was associated with significantly higher expression of P-selectin glycoprotein ligand 1 and the chemokine receptor CCR6 both known to be essential for blood:CSF barrier transit of leukocytes (Kivisakk et al PNAS 2003, 100, 8389–8394, Reboldi et al Nat Immunology 2009, 10, 514–523). Other genes upregulated in CNS homing cells included (1) the integrins alphaM beta2 and beta 7 (2) ICAM-1 and −3 and (3) the chemokine receptors CCR1, CCR7 and CXCR3. Interestingly the chemokine receptor CXCR4 showed down-regulation when measured by qPCR and flow cytometry in CNS homing cells, with levels of receptor expression inversely proportional to the rapidity of onset of CNS disease. Furthermore in vitro studies showed that the migratory response of CXCR4 to its ligand CXCL12 was blunted or absent in cell lines which produced a more rapid onset of CNS disease. Two of the cell lines were Philadelphia positive, raising the possibility that p190 bcr-abl could be interfering with CXCR4 signalling or receptor levels as previously demonstrated for the p210 bcr-abl fusion protein (Geay et al Cancer Res 2005, 65, 2676–2683). Although non-migratory cells had higher levels of bcr-abl expression than migratory cells the blunted responses could not be reversed by treatment with the bcr-abl inhibitor imatinib. CXCR4 mutations were excluded by direct sequencing. Since functional CXCR4-CXCL12 interactions are known to be important for retention of cells in the bone marrow microenvironment (Ma et al, Immunity 1999, 10, 463–71), disruption of this interaction may be a necessary pre-requisite for cell migration to other sites. To examine potential micro-environmental influences on gene expression patterns in vivo, cells were retrieved from the CNS, bone marrow, liver, spleen and kidneys of engrafted mice using anti-human CD19 magnetic bead sorting and species specific primers for qPCR. Cells derived from the CNS had higher levels of CCR6 and the neurochemokine CX3CR1 (fractalkine receptor) compared to the original cell line in vitro and cells retrieved from other sites. Increased CCR6 may represent sub-clonal selection of CCR6 high expressors during transit across the BCSFB. Fractalkine and its receptor are highly expressed in the central nervous system and are important for maintenance of microglial-neuronal communication with fractalkine activating pro-survival signaling pathways in cells bearing its receptor (Meucci et al PNAS 2000, 97, 8075–8080). This provides a possible mechanism by which fractalkine expression would provide a competitive advantage to cells and allow survival of pre-B cells in this normally hostile microenvironment. In conclusion, we present a xenograft model of CNS leukemia and its utilization to identify increased CCR6 and P-selectin glycoprotein ligand 1 expression and reduced CXCR4 expression (and/or function) as candidate mechanisms by which leukaemic pre-B cells cross the blood:CSF barrier. In addition we propose that the Fractalkine receptor CX3CR1 may act as a potential pro-survival mechanism for pre-B cells residing in the CNS. As well as shedding light on the biology of CNS disease in pre-B cell ALL these molecules may be valid novel therapeutic targets for resistant or relapsed CNS disease. Disclosures: No relevant conflicts of interest to declare.
21
Weidow, Brandy L., Jacqueline Vidosh, and John P. Biggerstaff. "The Role of Soluble Fibrin and Fibrin Inhibitory Peptides in Cancer Metastasis." Blood 108, no. 11 (November 16, 2006): 5200. http://dx.doi.org/10.1182/blood.v108.11.5200.5200.
Full textAbstract:
Abstract Circulating soluble fibrin (sFn) is a marker for ongoing disseminated intravascular coagulation and may have prognostic significance, especially in metastatic cancers. Anti-coagulant therapies have been effective in reducing metastasis in several cancers, but with increased risk of bleeding. The authors have previously demonstrated that soluble fibrin (sFn), which is elevated in many cancer patients, enhances metastasis in an experimental model, and increases platelet/tumor cell adherence by cross-linking platelet aIIbb3 to tumor cell CD54 (a receptor for two of the leukocyte b2 integrins aLb2 and aMb2). sFn also binds to monocyte aMb2 (Mac1), and the peptide sequences of the fibrin(ogen) binding sites for aMb2 and CD54 have recently been identified. It was, therefore, hypothesized that sFn binding to these receptors would result in inhibition of monocyte/tumor cell adherence, and consequently cytotoxicity, which may be reversed by inclusion of blocking peptides. To test this, monocyte adherence to A375 melanoma cells was quantified at physiologically relevant shear rates (35–560 s−1) using a laminar flow perfusion chamber mounted on a Leica DMIRB inverted microscope equipped with a computer controlled digital imaging camera. Effector and target cells were untreated, or incubated with sFn (fibrinogen (Fg), 0.5 mg/ml; fibrin polymerization inhibitor Gly-Pro-Arg-Pro amide (GPRPa), 4 mM; and human thrombin (0.125 U/ml)) in the presence or absence of specific single or combined blocking peptides directed against the sFn binding sites on CD54 (P1) and aMb2 (P2), or the sFn g-chain binding sites for CD54 (P3) and aMb2 (P4). The effect of peptides on thrombin (0.125 U/ml) induced clotting of purified Fg (0.5 mg/ml) was assessed visually. The effect of sFn on monocyte cytotoxicity (effector: target 20:1) against green fluorescent protein (GFP) transfected A375 melanoma cells was measured by GFP release from lysed cells using a Perkin-Elmer Victor-3 96-well fluorescence plate reader. Pre-treatment of tumor cells with sFn significantly (P<0.01) increased monocyte adherence to 68.5 + 0.7% compared to the untreated control (32.9 +1.3%), whereas monocyte pre-treatment had no significant effect (P>0.05) on adherence. However, pre-incubation of both cells with sFn resulted in a significant (P<0.01) inhibition of adherence to 15.95 ± 1.0% (62% inhibition). sFn mediated inhibition of adherence was significantly reduced by pre-treatment of cells with a combination of P1 + P2 (to 22.3 ± 13.8% inhibition; P<0.01), and by pre-incubation of sFn with P3 + P4 (to 9.9 ± 3.6% inhibition; P<0.01). Single peptides blocked to an intermediate level, and controls performed appropriately. Furthermore, blocking peptides did not inhibit thrombin induced clotting of Fg. Pretreatment of both monocytes and A375 cells significantly inhibited specific cytotoxicity by 40% (P < 0.01 compared to untreated cytotoxicity − 28.6 ± 0.7%), and intermediate killing was observed when only one cell type was sFn treated. These results show that sFn incubation with both effector and target cells inhibits both cellular adherence and cytotoxicity by a mechanism involving monocyte aMb2 and tumor cell CD54. Adherence was restored by inclusion of sFn blocking peptides, which did not affect clotting. Clinically, these peptides may be effective therapeutically in reducing sFn mediated immunosuppression and may enhance the immune response to metastasizing cancer cells, without the risk of bleeding problems associated with other therapies.
22
Greenfield, Katharine, Saloomeh Mokhtari, Melissa Haug, Christopher D. Porada, and Graca Almeida-Porada. "Identification and Phenotypic Characterization of a Subpopulation of Acute Myelogenous Leukemia (AML) Cells with Increased Plastic Adherence." Blood 120, no. 21 (November 16, 2012): 2556. http://dx.doi.org/10.1182/blood.v120.21.2556.2556.
Full textAbstract:
Abstract Abstract 2556 The high incidence of relapse in acute myelogenous leukemia (AML) patients has been attributed to the existence of a small population of leukemic stem cells (LSC) that current therapies are unable to eradicate. LSC, in similarity to normal hematopoietic stem cells (HSC), are able to engraft, self-renew, and interact with cells within the bone marrow (BM) niche. During leukemogenesis, changes within the BM microenvironment promote LSC survival and expansion, and shelter leukemic cells from chemotherapy. Therefore, displacing these cells from the BM niches prior to chemotherapy may decrease drug resistance and prevent relapse of the disease. The binding of α4β1 integrins (VLA-4 or CD49d/CD29) to the stromal extracellular matrix and cell surface ligands is a key component in homing and trafficking, specifically in the migration of HSC beneath marrow stromal cells, and VLA-4 has been shown to be crucial for the persistence of minimal residual disease in AML. KG1a is a differentiation-resistant AML cell line containing a very primitive population of CD34+CD38- cells. Upon culture, the majority of KG1a cells remain in suspension, while a small percentage adheres to the tissue culture plastic (Adh-KG1a). Here, we hypothesized that characterization of adhesion molecules that were either unique or significantly altered in this subset could lead to identification of putative therapeutic targets for dislodging AML cells from microenvironmental niches. KG1a and Adh-KG1a populations were evaluated by flow-cytometry for the presence of CD49d and CD29.The FACSort results were then analyzed using FlowJo7.6 software. No statistically significant (p>0.05) differences were found in the percentage of Adh-KG1a and KG1a that expressed CD49d (91.6±3% vs. 86.2±5%) or CD29 (95.0±2% vs. 91.8±1.8%). However, we found that there is a small and unique population of adherent CD29+ cells, with lower fluorescent intensity (MFI=326), that is not present in the non-adherent population (MFI=435), suggesting that this low level of surface expression is unique to the adherent fraction. Analysis of CD11a, CD44, CD18, CD106, CD105, CD34, CD107 and CD38 showed that none of these molecules were expressed at significantly different levels between KG1a and the Adh-KG1a fraction. Addition of anti-CD44 or anti-CD29 antibodies to the cells in culture did not result in decreased numbers of Adh-KG1a cells/flask, but resulted in induction of heterotypic aggregation of Adh-KG1a. Cell cycle analysis did not show significant differences between the 2 populations. However, analysis of CD54 expression demonstrated that 12.2% more of the Adh-KG1a were positive for CD54 than the non-adherent cells. Furthermore, characterization of gangliosides on KG1a and Adh-KG1a showed that the non-adherent fraction contained significantly more GM3 than the Adh-KG1a. Given prior reports showing that: 1) high levels of VLA-4 (CD49d/CD29) are associated with better prognosis in AML; 2) high levels of CD54 correlate with low relapse-free survival probability in AML; and 3) ganglioside composition has been shown to exert a pronounced effect on drug-resistance/sensitivity in AML, our findings of an adherent population of primitive hematopoietic stem/progenitor cells within KG1a that are CD29dim, express high levels of CD54, and contain lower levels of GM3, suggest that this unique subpopulation may play an important role in relapse in AML, and could represent a target for novel therapeutics that could better eradicate the elusive LSC and promise an improved disease-free survival rate in AML. Disclosures: No relevant conflicts of interest to declare.
23
Al-Bawardy, Badr, Raina Shivashankar, and Deborah D. Proctor. "Novel and Emerging Therapies for Inflammatory Bowel Disease." Frontiers in Pharmacology 12 (April 14, 2021). http://dx.doi.org/10.3389/fphar.2021.651415.
Full textAbstract:
Inflammatory bowel diseases (IBD) such as ulcerative colitis and Crohn’s disease are chronic, relapsing and remitting disorders of intestinal inflammation with potential systemic manifestations. Despite the availability of current biologics, such as anti-tumor necrosis factor (anti-TNF), anti-integrins, anti-interleukins and small molecules such as tofacitinib, the rates of primary and secondary treatment failure remain high in IBD. This highlights the importance of continued development of new therapeutic targets and modifications of existing ones to improve the treatment response rates and to also improve the safety profile and tolerability of these medications. In this review we will discuss novel treatment target agents including selective janus kinase (JAK) inhibitors, anti-interleukin (IL) (IL-12/IL-23), leukocyte trafficking/migrating inhibitors (such as sphingosine-1-phosphate receptor modulator) and other small molecules currently in development.
24
Higashiyama, Masaaki, and Ryota Hokaria. "New and Emerging Treatments for Inflammatory Bowel Disease." Digestion, November 10, 2022, 1–8. http://dx.doi.org/10.1159/000527422.
Full textAbstract:
<b><i>Background:</i></b> The specific etiopathogenesis of inflammatory bowel disease (IBD) is still unknown. Although the conventional anti-inflammatory or immunomodulatory drugs relatively nonspecific to pathogenesis have been quite useful in many cases, elucidating the pathogenesis has gradually facilitated developments of disease-specific therapies for refractory cases in the last 2 decades. <b><i>Summary:</i></b> With a greater understanding of the multiple overactive signaling pathways of the gut mucosal immune response and enhanced leukocyte trafficking, several biological agents or small molecule drugs following the first novel biologic, anti-tumor necrosis factor α (anti-TNFα), have been developed against several modes of action including adhesion molecules, sphingosine-1-phospate receptors, cytokines (IL-12/23, TL1A, and IL-36), Janus kinase (JAK), and phosphodiesterase. Although preceding biological agents have dramatically changed the IBD treatment strategy, many patients still require alternative therapies due to failure or side effects. Newer treatments are now expected to be provided for better efficacy with an improved adverse event profile. In addition, translational studies have highlighted the new therapeutic concepts’ potential, including modulation of host-microbiome interactions, stem therapy for perianal fistula, regulation of fibrosis, regulation of the gut-brain axis, and control of previously less targeted immune cells (B cells and innate lymphoid cells). This paper comprehensively reviewed not only the latest already or shortly available therapies but also emerging promising treatments that will be hopefully established in the future for IBD. <b><i>Key Messages:</i></b> Many kinds of new treatments are available, and promising treatments with new perspectives are expected to emerge for refractory IBD in the future.
25
Luzentales-Simpson, Matthew, Yvonne C. F. Pang, Ada Zhang, James A. Sousa, and Laura M. Sly. "Vedolizumab: Potential Mechanisms of Action for Reducing Pathological Inflammation in Inflammatory Bowel Diseases." Frontiers in Cell and Developmental Biology 9 (February 3, 2021). http://dx.doi.org/10.3389/fcell.2021.612830.
Full textAbstract:
Inflammatory bowel diseases (IBD), encompassing ulcerative colitis (UC), and Crohn’s disease (CD), are a group of disorders characterized by chronic, relapsing, and remitting, or progressive inflammation along the gastrointestinal tract. IBD is accompanied by massive infiltration of circulating leukocytes into the intestinal mucosa. Leukocytes such as neutrophils, monocytes, and T-cells are recruited to the affected site, exacerbating inflammation and causing tissue damage. Current treatments used to block inflammation in IBD include aminosalicylates, corticosteroids, immunosuppressants, and biologics. The first successful biologic, which revolutionized IBD treatment, targeted the pro-inflammatory cytokine, tumor necrosis factor alpha (TNFα). Infliximab, adalimumab, and other anti-TNF antibodies neutralize TNFα, preventing interactions with its receptors and reducing the inflammatory response. However, up to 40% of people with IBD become unresponsive to anti-TNFα therapy. Thus, more recent biologics have been designed to block leukocyte trafficking to the inflamed intestine by targeting integrins and adhesins. For example, natalizumab targets the α4 chain of integrin heterodimers, α4β1 and α4β7, on leukocytes. However, binding of α4β1 is associated with increased risk for developing progressive multifocal leukoencephalopathy, an often-fatal disease, and thus, it is not used to treat IBD. To target leukocyte infiltration without this life-threatening complication, vedolizumab was developed. Vedolizumab specifically targets the α4β7 integrin and was approved to treat IBD based on the presumption that it would block T-cell recruitment to the intestine. Though vedolizumab is an effective treatment for IBD, some studies suggest that it may not block T-cell recruitment to the intestine and its mechanism(s) of action remain unclear. Vedolizumab may reduce inflammation by blocking recruitment of T-cells, or pro-inflammatory monocytes and dendritic cells to the intestine, and/or vedolizumab may lead to changes in the programming of innate and acquired immune cells dampening down inflammation.
26
Sloas, Christopher, Saar Gill, and Michael Klichinsky. "Engineered CAR-Macrophages as Adoptive Immunotherapies for Solid Tumors." Frontiers in Immunology 12 (November 24, 2021). http://dx.doi.org/10.3389/fimmu.2021.783305.
Full textAbstract:
Cellular immunotherapies represent a promising approach for the treatment of cancer. Engineered adoptive cell therapies redirect and augment a leukocyte’s inherent ability to mount an immune response by introducing novel anti-tumor capabilities and targeting moieties. A prominent example of this approach is the use of T cells engineered to express chimeric antigen receptors (CARs), which have demonstrated significant efficacy against some hematologic malignancies. Despite increasingly sophisticated strategies to harness immune cell function, efficacy against solid tumors has remained elusive for adoptive cell therapies. Amongst cell types used in immunotherapies, however, macrophages have recently emerged as prominent candidates for the treatment of solid tumors. In this review, we discuss the use of monocytes and macrophages as adoptive cell therapies. Macrophages are innate immune cells that are intrinsically equipped with broad therapeutic effector functions, including active trafficking to tumor sites, direct tumor phagocytosis, activation of the tumor microenvironment and professional antigen presentation. We focus on engineering strategies for manipulating macrophages, with a specific focus on CAR macrophages (CAR-M). We highlight CAR design for macrophages, the production of CAR-M for adoptive cell transfer, and clinical considerations for their use in treating solid malignancies. We then outline recent progress and results in applying CAR-M as immunotherapies. The recent development of engineered macrophage-based therapies holds promise as a key weapon in the immune cell therapy armamentarium.