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Crohn's & Colitis 360 Jul 2022Vedolizumab is a gut-selective anti-lymphocyte trafficking agent approved for the treatment of moderate to severely active inflammatory bowel disease (IBD: ulcerative...
BACKGROUND
Vedolizumab is a gut-selective anti-lymphocyte trafficking agent approved for the treatment of moderate to severely active inflammatory bowel disease (IBD: ulcerative colitis [UC] and Crohn's disease [CD]).
METHODS
A systematic literature review (SLR) of real-world studies was conducted to assess the effectiveness of dose escalation of vedolizumab every 8 weeks (Q8W) during maintenance treatment to achieve a response in patients who were either vedolizumab responders experiencing secondary loss of response (SLOR) or non-responders. MEDLINE and EMBASE databases were searched from January 2014 to August 2021.
RESULTS
Screening of SLR outputs identified 72 relevant real-world study publications featuring dose escalation of vedolizumab maintenance therapy. After qualitative review, ten eligible studies (9 articles, 1 abstract) were identified as reporting clinical response and/or clinical remission rates following escalation of intravenous vedolizumab 300 mg Q8W maintenance dosing to every 4 weeks (Q4W) maintenance dosing in adult patients with UC/CD (≥10 patients per study). Overall, 196/395 (49.6%) patients with IBD had a response within 54 weeks of vedolizumab maintenance dose escalation. Although definitions for clinical response/remission varied across the 10 studies, clinical response rates after escalated vedolizumab Q8W maintenance dosing ranged from 40.0% to 73.3% (9 studies) and from 30.0% to 55.8% for remission (4 studies) over a range of 8 to <58 weeks' follow-up.
CONCLUSIONS
This synthesis of real-world effectiveness data in vedolizumab-treated patients with IBD indicates that approximately half were able to achieve or recapture clinical response after escalating vedolizumab maintenance dosing.
PubMed: 36777427
DOI: 10.1093/crocol/otac020 -
International Journal of Molecular... Jan 2023Chemokines are known to be immunoregulatory proteins involved not only in lymphocyte chemotaxis to the site of inflammation, but also in neuromodulation, neurogenesis,... (Review)
Review
Chemokines are known to be immunoregulatory proteins involved not only in lymphocyte chemotaxis to the site of inflammation, but also in neuromodulation, neurogenesis, and neurotransmission. Multiple lines of evidence suggest a peripheral proinflammatory state and neuroinflammation in at least a third of patients with schizophrenia. Therefore, chemokines can be active players in these processes. In this systematic review, we analyzed the available data on chemokine dysregulation in schizophrenia and the association of chemokines with neuroinflammation. It has been shown that there is a genetic association of chemokine and chemokine receptor gene polymorphisms in schizophrenia. Besides, the most reliable data confirmed by the results of meta-analyses showed an increase in CXCL8/IL-8, CCL2/MCP-1, CCL4/MIP-1β, CCL11/eotaxin-1 in the blood of patients with schizophrenia. An increase in CXCL8 has been found in cerebrospinal fluid, but other chemokines have been less well studied. Increased/decreased expression of genes of chemokine and their receptors have been found in different areas of the brain and peripheral immune cells. The peripheral proinflammatory state may influence the expression of chemokines since their expression is regulated by pro- and anti-inflammatory cytokines. Mouse models have shown an association of schizophrenia with dysregulation of the CX3CL1-CX3CR1 and CXCL12-CXCR4 axes. Altogether, dysregulation in chemokine expression may contribute to neuroinflammation in schizophrenia. In conclusion, this evidence indicates the involvement of chemokines in the neurobiological processes associated with schizophrenia.
Topics: Animals; Mice; Schizophrenia; Neuroinflammatory Diseases; Chemokines; Cytokines; Chemokine CCL2; Chemokine CCL4; Chemotaxis, Leukocyte; Chemokine CCL5
PubMed: 36768537
DOI: 10.3390/ijms24032215 -
Frontiers in Oncology 2022Immune checkpoint molecule lymphocyte-activating gene-3 (LAG-3), which is expressed on active lymphocytes, has proven to be associated with immunosuppression and cancer...
PURPOSE
Immune checkpoint molecule lymphocyte-activating gene-3 (LAG-3), which is expressed on active lymphocytes, has proven to be associated with immunosuppression and cancer progression in a variety of solid tumors. However, the role of LAG-3 lymphocytes in human breast cancer (BC) is still not conclusive. We therefore performed a meta-analysis to clarify the role of these cells in prognosis prediction for BC.
METHODS
We searched PubMed, Embase, and EBSCO to identify the studies evaluating the association of LAG-3 lymphocyte infiltration and overall survival (OS) and/or disease-free survival (DFS) in BC patients, then combined extracted data with STATA 12.0.
RESULTS
Eight published studies involving 5,859 BC patients were incorporated into this meta-analysis. We noted that a high number of LAG-3 tumor-infiltrating lymphocytes were not appreciably associated with OS and DFS in BC patients. Strikingly, in stratified analyses based on the molecular type of BC, LAG-3 lymphocyte infiltration was remarkably associated with better OS rather than DFS in triple-negative breast cancer (TNBC), whereas it significantly influenced neither OS nor DFS in Her2-positive BC. However, an increased density of these lymphocytes indicated a trend for better OS in Her2-positive BC. In addition, we found that LAG-3 lymphocyte infiltration was also remarkably associated with prolonged OS in Her2-positive BC patients when they were measured by immunohistochemistry (IHC). In addition, an elevated number of these lymphocytes did not correlate with pathological complete response rate or clinicopathological features including lymph node metastasis.
CONCLUSION
The infiltration of LAG-3 lymphocytes ameliorates OS in TNBC and Her2-positive BC, implicating that it is a valuable prognostic biomarker, and applications of anti-LAG-3 antagonists may possibly be not a promising therapeutic strategy for human BC especially for TNBC.
PubMed: 36761428
DOI: 10.3389/fonc.2022.986903 -
International Journal of Molecular... Dec 2022Endometriosis is a chronic inflammatory disorder, characterized by the presence of endometrial cells outside the uterine cavity. An increasing number of studies... (Review)
Review
Endometriosis is a chronic inflammatory disorder, characterized by the presence of endometrial cells outside the uterine cavity. An increasing number of studies correlate the immune system with endometriosis, particularly NK receptors (NKR), which have been suggested to play an essential role in the pathogenesis of the disease. This systematic review aims to enlighten the role of NKR in endometriosis. A literature search was performed independently by two reviewers, to identify studies assessing the role of NKR in endometriosis. In total, 18 studies were included. Endometriosis pathogenesis seems to be marked by the overexpression of NK inhibitor receptors (KIRS), namely, CD158a+, KIR2DL1, CD94/NKG2A, PD-1, NKB1, and EB6, and inhibiting ligands such as PD-L1, HLA-E, HLA-G, and HLA-I. Concurrently, there is a decrease in NK-activating receptors and natural cytotoxicity receptors (NCRs), such as NKp46, NKp30, and NKG2D. The immune shift from NK surveillance to NK suppression is also apparent in the greater relative number of ITIM domains compared with ITAM domains in NKRs. In conclusion, NK receptor activity seems to dictate the immunocompetency of women to clear endometriotic cells from the peritoneal cavity. Future research could explore NKRs as therapeutic targets, such as that which is now well established in cancer therapy through immunotherapy.
Topics: Humans; Female; Receptors, Natural Killer Cell; Killer Cells, Natural; Endometriosis; Endometrium
PubMed: 36613776
DOI: 10.3390/ijms24010331 -
Frontiers in Immunology 2022Recovery from coronavirus disease 2019 (COVID-19) can be impaired by the persistence of symptoms or new-onset health complications, commonly referred to as Long COVID.... (Review)
Review
BACKGROUND
Recovery from coronavirus disease 2019 (COVID-19) can be impaired by the persistence of symptoms or new-onset health complications, commonly referred to as Long COVID. In a subset of patients, Long COVID is associated with immune system perturbations of unknown etiology, which could be related to compromised immunoregulatory mechanisms.
OBJECTIVE
The objective of this scoping review was to summarize the existing literature regarding the frequency and functionality of Tregs in convalescent COVID-19 patients and to explore indications for their potential involvement in the development of Long COVID.
DESIGN
A systematic search of studies investigating Tregs during COVID-19 convalescence was conducted on MEDLINE ( Pubmed) and Web of Science.
RESULTS
The literature search yielded 17 relevant studies, of which three included a distinct cohort of patients with Long COVID. The reviewed studies suggest that the Treg population of COVID-19 patients can reconstitute quantitatively and functionally during recovery. However, the comparison between recovered and seronegative controls revealed that an infection-induced dysregulation of the Treg compartment can be sustained for at least several months. The small number of studies investigating Tregs in Long COVID allowed no firm conclusions to be drawn about their involvement in the syndrome's etiology. Yet, even almost one year post-infection Long COVID patients exhibit significantly altered proportions of Tregs within the CD4+ T cell population.
CONCLUSIONS
Persistent alterations in cell frequency in Long COVID patients indicate that Treg dysregulation might be linked to immune system-associated sequelae. Future studies should aim to address the association of Treg adaptations with different symptom clusters and blood parameters beyond the sole quantification of cell frequencies while adhering to consensualized phenotyping strategies.
Topics: Humans; CD4-Positive T-Lymphocytes; COVID-19; Post-Acute COVID-19 Syndrome; T-Lymphocytes, Regulatory
PubMed: 36582234
DOI: 10.3389/fimmu.2022.1070994 -
Molecular Psychiatry Mar 2023Meta-analyses implicate immune dysfunction in depression confirming increased levels of circulating immune proteins (e.g., cytokines) in depression cases compared to... (Meta-Analysis)
Meta-Analysis
INTRODUCTION
Meta-analyses implicate immune dysfunction in depression confirming increased levels of circulating immune proteins (e.g., cytokines) in depression cases compared to controls. White blood cells (WBC) both produce and are influenced by cytokines, and play key roles in orchestrating innate and adaptive immune responses, but their role in depression remains unclear. Therefore, a systematic review of studies of various WBC subsets in depression is required for a greater understanding of the nature of immune dysfunction in this illness.
METHODS
We searched PubMed and PsycINFO databases (inception to 5 April 2022) and conducted a systematic review and meta-analysis of identified studies comparing absolute count and/or relative percentage of flow cytometry-derived WBC subsets between depression cases and controls. Selected studies were quality assessed. Random-effect meta-analysis was performed.
RESULTS
Thirty-three studies were included and 27 studies (n = 2277) were meta-analysed. We report an increase in mean absolute counts of WBC (seven studies; standardised mean difference [SMD] = 1.07; 95% CI, 0.61-1.53; P < 0.01; I = 64%), granulocytes (two studies; SMD = 2.07; 95% CI, 1.45-2.68; P < 0.01; I = 0%), neutrophils (four studies; SMD = 0.91; 95% CI, 0.23-1.58; P < 0.01; I = 82%), monocytes (seven studies; SMD = 0.60; 95% CI, 0.19-1.01; P < 0.01; I = 66%), CD4 helper T cells (11 studies; SMD = 0.30; 95% CI, 0.15-0.45; P < 0.01; I = 0%), natural killer cells (11 studies; SMD = 1.23; 95% CI, 0.38-2.08; P < 0.01; I = 95%), B cells (10 studies; SMD = 0.30; 95% CI, 0.03-0.57; P = 0.03; I = 56%), and activated T cells (eight studies; SMD = 0.45; 95% CI, 0.24-0.66; P < 0.01; I = 0%) in depression, compared to controls. Fewer studies reported relative percentage, indicating increased neutrophils and decreased total lymphocytes, Th1, and Th2 cells in depression.
CONCLUSIONS
Depression is characterised by widespread alterations in circulating myeloid and lymphoid cells, consistent with dysfunction in both innate and adaptive immunity. Immune cells could be useful biomarkers for illness subtyping and patient stratification in future immunotherapy trials of depression, along with cytokines, other biomarkers, and clinical measures.
Topics: Humans; Depression; Biomarkers
PubMed: 36577838
DOI: 10.1038/s41380-022-01919-7 -
Multiple Sclerosis and Related Disorders Jan 2023Treatment with cladribine tablets (CladT), an immune reconstitution therapy for relapsing multiple sclerosis (RMS), involves two short courses of treatment in Year 1 and... (Review)
Review
BACKGROUND
Treatment with cladribine tablets (CladT), an immune reconstitution therapy for relapsing multiple sclerosis (RMS), involves two short courses of treatment in Year 1 and Year 2. Most patients achieve sustained efficacy with CladT, but a small proportion may experience new disease activity (DA). Following completion of the indicated dose, physicians may have questions relating to the long-term management of these patients. Since the EU approval of CladT over 5 years ago, real-world evidence (RWE) is increasing and may provide some insights and guidance for clinical practice. We describe a systematic literature review (SLR) of RWE and provide expert opinions relating to six questions regarding the long-term use of CladT.
METHODS
Pertinent clinical questions were developed by a steering committee (SC) of 14 international multiple sclerosis (MS) experts regarding breakthrough DA in Year 1, new DA after 2 years or more of treatment, long-term management of stable patients, and whether additional courses of CladT may be required or safe. An SLR was performed in EMBASE and PubMed using the population, intervention, comparators, outcomes, study design (PICOS) framework to identify relevant studies within the last 15 years. Searches of key congress proceedings for the last 2-3 years were also performed. Following review of the results and RWE, the SC drafted and agreed on expert opinion statements for each question.
RESULTS
A total of 35 publications reporting RWE for CladT were included in this review. In the real world, breakthrough DA in Year 1 is of low incidence (1.1-21.9%) but can occur, particularly in patients switching from anti-lymphocyte trafficking agents. In most patients, this DA did not lead to treatment discontinuation. Reported rates of DA after the full therapeutic effect of CladT has been achieved (end of Year 2, 3 or 4) range from 12.0 to 18.7% in the few studies identified. No RWE was identified to support management decisions for stable patients in Year 5 or later. Views among the group were also diverse on this question and voting on expert opinion statements was required. Only two studies reported the administration of additional courses of CladT, but detailed safety outcomes were not provided.
CONCLUSIONS
RWE for the long-term use of CladT in the treatment of RMS is increasing, however, gaps in knowledge remain. Where possible, the RWE identified through the SLR informed expert statements, but, where RWE is still lacking, these were based solely on experiences and opinion, providing some guidance on topics and questions that occur in daily clinical practice. More real-world studies with longer-term follow-up periods are needed and highly anticipated.
Topics: Humans; Cladribine; Multiple Sclerosis; Expert Testimony; Lymphocytes; Tablets; Recurrence; Immunosuppressive Agents
PubMed: 36565573
DOI: 10.1016/j.msard.2022.104459 -
Blood Advances Dec 2022Patients with multiple myeloma (MM) have a diminished immune response to coronavirus disease 2019 (COVID-19) vaccines. Risk factors for an impaired immune response are... (Meta-Analysis)
Meta-Analysis
Patients with multiple myeloma (MM) have a diminished immune response to coronavirus disease 2019 (COVID-19) vaccines. Risk factors for an impaired immune response are yet to be determined. We aimed to summarize the COVID-19 vaccine immunogenicity and to identify factors that influence the humoral immune response in patients with MM. Two reviewers independently conducted a literature search in MEDLINE, Embase, ISI Web of Science, Cochrane library, and Clinicaltrials.gov from existence until 24 May 24 2022. (PROSPERO: CRD42021277005). A total of 15 studies were included in the systematic review and 5 were included in the meta-analysis. The average rate (range) of positive functional T-lymphocyte response was 44.2% (34.2%-48.5%) after 2 doses of messenger RNA (mRNA) COVID-19 vaccines. The average antispike antibody response rates (range) were 42.7% (20.8%-88.5%) and 78.2% (55.8%-94.2%) after 1 and 2 doses of mRNA COVID-19 vaccines, respectively. The average neutralizing antibody response rates (range) were 25% (1 study) and 62.7% (53.3%-68.6%) after 1 and 2 doses of mRNA COVID-19 vaccines, respectively. Patients with high-risk cytogenetics or receiving anti-CD38 therapy were less likely to have a humoral immune response with pooled odds ratios of 0.36 (95% confidence interval [95% CI], 0.18, 0.69), I2 = 0% and 0.42 (95% CI, 0.22, 0.79), I2 = 14%, respectively. Patients who were not on active MM treatment were more likely to respond with pooled odds ratio of 2.42 (95% CI, 1.10, 5.33), I2 = 7%. Patients with MM had low rates of humoral and cellular immune responses to the mRNA COVID-19 vaccines. Further studies are needed to determine the optimal doses of vaccines and evaluate the use of monoclonal antibodies for pre-exposure prophylaxis in this population.
Topics: Humans; COVID-19 Vaccines; Multiple Myeloma; COVID-19; SARS-CoV-2; Antibodies, Monoclonal
PubMed: 36538342
DOI: 10.1182/bloodadvances.2022008530 -
Frontiers in Physiology 2022Intensified training coupled with sufficient recovery is required to improve athletic performance. A stress-recovery imbalance can lead to negative states of...
Intensified training coupled with sufficient recovery is required to improve athletic performance. A stress-recovery imbalance can lead to negative states of overtraining. Hormonal alterations associated with intensified training, such as blunted cortisol, may impair the immune response. Cortisol promotes the maturation and migration of dendritic cells which subsequently stimulate the T cell response. However, there are currently no clear reliable biomarkers to highlight the overtraining syndrome. This systematic review and meta-analysis examined the effect of intensified training on immune cells. Outcomes from this could provide insight into whether these markers may be used as an indicator of negative states of overtraining. SPORTDiscus, PUBMED, Academic Search Complete, Scopus and Web of Science were searched until June 2022. Included articles reported on immune biomarkers relating to lymphocytes, dendritic cells, and cytokines before and after a period of intensified training, in humans and rodents, at rest and in response to exercise. 164 full texts were screened for eligibility. Across 57 eligible studies, 16 immune biomarkers were assessed. 7 were assessed at rest and in response to a bout of exercise, and 9 assessed at rest only. Included lymphocyte markers were CD3, CD4 and CD8 T cell count, NK cell count, NK Cytolytic activity, lymphocyte proliferation and CD4/CD8 ratio. Dendritic cell markers examined were CD80, CD86, and MHC II expression. Cytokines included IL-1β, IL-2, IL-10, TNF-α and IFN-γ. A period of intensified training significantly decreased resting total lymphocyte (0.57, 95% CI 0.30) and CD8 T cell counts (0.37, 95% CI 0.04), and unstimulated plasma IL-1β levels (0.63, 95% CI 0.17). Resting dendritic cell CD86 expression significantly increased ( 2.18, 95% CI 4.07). All other biomarkers remained unchanged. Although some biomarkers alter after a period of intensified training, definitive immune biomarkers are limited. Specifically, due to low study numbers, further investigation into the dendritic cell response in human models is required.
PubMed: 36439269
DOI: 10.3389/fphys.2022.998925 -
International Journal of Molecular... Nov 2022Autism spectrum disorder (ASD) is a neurodevelopmental condition with a so far unknown etiology. Increasing evidence suggests that a state of systemic low-grade... (Meta-Analysis)
Meta-Analysis Review
Activation of the Monocyte/Macrophage System and Abnormal Blood Levels of Lymphocyte Subpopulations in Individuals with Autism Spectrum Disorder: A Systematic Review and Meta-Analysis.
Autism spectrum disorder (ASD) is a neurodevelopmental condition with a so far unknown etiology. Increasing evidence suggests that a state of systemic low-grade inflammation may be involved in the pathophysiology of this condition. However, studies investigating peripheral blood levels of immune cells, and/or of immune cell activation markers such as neopterin are lacking and have provided mixed findings. We performed a systematic review and meta-analysis of studies comparing total and differential white blood cell (WBC) counts, blood levels of lymphocyte subpopulations and of neopterin between individuals with ASD and typically developing (TD) controls (PROSPERO registration number: CRD CRD42019146472). Online searches covered publications from 1 January 1994 until 1 March 2022. Out of 1170 publication records identified, 25 studies were finally included. Random-effects meta-analyses were carried out, and sensitivity analyses were performed to control for potential moderators. Results: Individuals with ASD showed a significantly higher WBC count (k = 10, g = 0.29, p = 0.001, I2 = 34%), significantly higher levels of neutrophils (k = 6, g = 0.29, p = 0.005, I2 = 31%), monocytes (k = 11, g = 0.35, p < 0.001, I2 = 54%), NK cells (k = 7, g = 0.36, p = 0.037, I2 = 67%), Tc cells (k = 4, g = 0.73, p = 0.021, I2 = 82%), and a significantly lower Th/Tc cells ratio (k = 3, g = −0.42, p = 0.008, I2 = 0%), compared to TD controls. Subjects with ASD were also characterized by a significantly higher neutrophil-to-lymphocyte ratio (NLR) (k = 4, g = 0.69, p = 0.040, I2 = 90%), and significantly higher neopterin levels (k = 3, g = 1.16, p = 0.001, I2 = 97%) compared to TD controls. No significant differences were found with respect to the levels of lymphocytes, B cells, Th cells, Treg cells, and Th17 cells. Sensitivity analysis suggested that the findings for monocyte and neutrophil levels were robust, and independent of other factors, such as medication status, diagnostic criteria applied, and/or the difference in age or sex between subjects with ASD and TD controls. Taken together, our findings suggest the existence of a chronically (and systemically) activated inflammatory response system in, at least, a subgroup of individuals with ASD. This might have not only diagnostic, but also, therapeutic implications. However, larger longitudinal studies including more homogeneous samples and laboratory assessment methods and recording potential confounding factors such as body mass index, or the presence of comorbid psychiatric and/or medical conditions are urgently needed to confirm the findings.
Topics: Humans; Monocytes; Autism Spectrum Disorder; Neopterin; Leukocytes; Lymphocyte Subsets; Th17 Cells; Macrophages
PubMed: 36430805
DOI: 10.3390/ijms232214329