| 1. |
- Alyamani, Manar, et al.
(författare)
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Alkaline sphingomyelinase (NPP7) impacts the homeostasis of intestinal T lymphocyte populations
- 2023
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Ingår i: Frontiers in Immunology. - : Frontiers Media SA. - 1664-3224. ; 13
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Tidskriftsartikel (refereegranskat)abstract
- Background and aim: Alkaline sphingomyelinase (NPP7) is expressed by intestinal epithelial cells and is crucial for the digestion of dietary sphingomyelin. NPP7 also inactivates proinflammatory mediators including platelet-activating factor and lysophosphatidylcholine. The aim of this study was to examine a potential role for NPP7 in the homeostasis of the intestinal immune system. Methods: We quantified the numbers of B-lymphocytes, plasma cells, T-lymphocytes including regulatory T-lymphocytes (Tregs), natural killer cells, dendritic cells, macrophages, and neutrophils, in the small and large intestines, the mesenteric lymph nodes and the spleens of heterozygous and homozygous NPP7 knockout (KO) and wildtype (WT) mice. Tissues were examined by immunohistochemistry and stainings quantified using computerized image analysis. Results: The numbers of both small and large intestinal CD3ε+, CD4+, and CD8α+ T-lymphocytes were significantly higher in NPP7 KO compared to WT mice (with a dose-response relationship in the large intestine), whereas Treg numbers were unchanged, and dendritic cell numbers reduced. In contrast, the numbers of CD3ε+ and CD4+ T-lymphocytes in mesenteric lymph nodes were significantly reduced in NPP7 KO mice, while no differences were observed in spleens. The numbers of B-lymphocytes, plasma cells, natural killer cells, macrophages, and neutrophils were similar between genotypes. Conclusion: NPP7 contributes to the regulation of dendritic cell and T-lymphocyte numbers in mesenteric lymph nodes and both the small and large intestines, thus playing a role in the homeostasis of gut immunity. Although it is likely that the downstream effects of NPP7 activity involve the sphingomyelin metabolites ceramide and spingosine-1-phosphate, the exact mechanisms behind this regulatory function of NPP7 need to be addressed in future studies.
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| 2. |
- Bergqvist, Viktoria, et al.
(författare)
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Switching from originator infliximab to the biosimilar CT-P13 in 313 patients with inflammatory bowel disease
- 2018
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Ingår i: Therapeutic Advances in Gastroenterology. - : SAGE Publications. - 1756-283X .- 1756-2848. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: As the patents of originator biologics are expiring, biosimilar versions are becoming available for the treatment of inflammatory bowel disease (IBD). However, published switch studies of the first infliximab biosimilar, CT-P13, have delivered ambiguous results that could be interpreted as showing a trend towards inferior effectiveness in Crohn's disease (CD) compared with ulcerative colitis (UC). The aim of this study was to investigate the effectiveness and safety of switching IBD patients from treatment with Remicade to CT-P13.METHODS: In this prospective observational cohort study, all adult IBD patients on Remicade treatment, at four hospitals, were switched to CT-P13. The primary endpoint was change in clinical disease activity at 2, 6, and 12 months after the switch. Secondary endpoints were subgroup analyses of patients with and without concomitant immunomodulators; changes in biomarkers, quality of life, drug trough levels and anti-drug antibodies (ADAbs); and adverse events.RESULTS: A total of 313 IBD patients were switched (195 CD; 118 UC). There were no significant changes in clinical disease activity, quality of life, biomarkers (except a small but significant increase in albumin in CD) including F-calprotectin, drug trough levels, or proportion of patients in remission. Disease worsening rates were 14.0% for CD and 13.8% for UC; and 2.7% developed ADAbs and 2.2% developed serious adverse events.CONCLUSIONS: This is the largest study of switched IBD patients published to date, and it demonstrates that switching from Remicade to CT-P13 may be done with preserved therapeutic effectiveness and safety in both CD and UC.
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| 3. |
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| 4. |
- Kadivar, Mohammad, et al.
(författare)
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CD8αβ+ γδ T cells : A novel T cell subset with a potential role in inflammatory bowel disease
- 2016
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Ingår i: Journal of Immunology. - : The American Association of Immunologists. - 0022-1767 .- 1550-6606. ; 197:12, s. 4584-4592
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Tidskriftsartikel (refereegranskat)abstract
- γδ T cells have been attributed a wide variety of functions, which in some cases may appear as contradictory. To better understand the enigmatic biology of γδ T cells it is crucial to define the constituting subpopulations. γδ T cells have previously been categorized into two subpopulations: CD8aa+ and CD8- cells. In this study we have defined and characterized a novel subset of human γδ T-cells expressing CD8ab. These CD8αβ+ γδ T cells differed from the previously described γδ T cell subsets in several aspects, including the degree of enrichment within the gut mucosa, the activation status in blood, the type of TCRd variant used in blood, and small but significant differences in their response to IL-2 stimulation. Furthermore, the novel subset expressed cytotoxic mediators and CD69, and produced IFN-γ and TNF-α. In patients with active inflammatory bowel disease the mucosal frequencies of CD8αβ+ γδ T cells were significantly lower as compared with healthy controls, correlated negatively with the degree of disease activity, and increased to normal levels as a result of anti-TNF-a therapy. In conclusion, our results demonstrate that CD8αβ+ γδ T cells constitute a novel lymphocyte subset, which is strongly enriched within the gut and may play an important role in gut homeostasis and mucosal healing in inflammatory bowel disease.
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| 5. |
- Kadivar, Mohammad
(författare)
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Immunopathology of Inflammatory Bowel Disease
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Inflammatory bowel disease (IBD) is a chronic inflammatory condition affecting the gastrointestinal tract, with a remitting and relapsing course. There are two main forms of IBD: Crohn’s disease (CD) and ulcerative colitis (UC). The etiology of IBD is not fully understood, however both CD and UC thought to be closely associated with dysregulated innate and adaptive immune responses. The aim of this thesis was to investigate the immunopathology of CD and UC with particular focus on T cell subsets, the cellular and molecular effects of anti-TNFα treatment in CD; and to develop a tool to monitor the disease activity in both CD and UC based on immunological alterations.In the first paper, we described an optimized method for isolating immune cells separately from epithelium and lamina propria of human intestinal biopsies. We identified the distinct T cell compartments of epithelium and lamina propria in the normal gut, and showed that the T cell compartment of the small bowel differed from the colon in healthy gut. Importantly, we demonstrated that intestinal T cell profile changed in patients with CD and UC compared to healthy controls, in which the intestinal T cell compartment of CD and UC patients differed. These data might be used for in- depth IBD phenotyping, potentially defining new subgroups of the two diseases, and for differentiating between aggressive versus mild disease phenotypes. Finally, it could be used for prognosis of responders and non-responders to various therapies.In the second paper we identified a novel, distinct, and functionally active γδ T cell subpopulation in human expressing CD8αβ heterodimer. Only two subsets of γδ T cells have been previously characterized based on the expression of co- receptors. We showed that CD8αβ+ γδ T cells were enriched in the gut particularly in the epithelial layer. Moreover, we showed that the frequency of CD8αβ+ γδ T cells were reduced in the gut of patients with active IBD, correlated negatively with disease activity, and their frequency normalized after IBD therapy, suggesting a protective role for this subset in IBD. By improved subset delineation these results could contribute to the development of immunotherapy strategies.In the third paper, we performed a comprehensive evaluation of the cellular and molecular effects of anti-TNFα treatment in CD patients. Results from the study allow us to propose the following model that both molecular and cellular proinflammatory/harming and anti-inflammatory/repair components are present and upregulated during active inflammation, but tissue-destructive forces overpower the anti-inflammatory and repairing efforts. Interestingly, anti- TNFα treatment downregulated both of these arms, especially with an emphasis on the proinflammatory/tissue- destruction mediators. This allows the anti-inflammatory/healing mechanisms to become fully effective, imparting mucosal healing. Thus, it could be beneficial to administrate selected growth factors and repair mediators for a limited time during the induction phase of anti-TNFα therapy, to further enhance the healing process, which also would help to seal a leaky barrier that allows loss of drug into the lumen and penetration of microbes into the gut tissues.In the forth paper, we developed a new validated and unbiased immunohistological index to assess the disease activity uniformly in both CD and UC, Quantitative Immunohistochemical Computerized Crohn’s and Colitis (QiC3) index. We formulated this objective index based on the number of some immune cells to achieve the best sensitivity and specificity for separating normal and inflamed tissues. Our results showed that the QiC3 index correlated strongly with histopathological scores and gene expression levels of proinflammatory mediators in IBD patients. The QiC3 index works for both ileal and colonic mucosal samples and can be used in clinical management and clinical trials for IBD, in human and animals’ basic researches, and in intestinal infectious diseases.
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| 6. |
- Löfroos, Ann-Britt, et al.
(författare)
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Colorectal cancer-infiltrating T lymphocytes display a distinct chemokine receptor expression profile
- 2017
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Ingår i: European Journal of Medical Research. - : Springer Science and Business Media LLC. - 0949-2321 .- 2047-783X. ; 22:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: T lymphocytes exert important homeostatic functions in the healthy intestinal mucosa, whereas in case of colorectal cancer (CRC), infiltration of T lymphocytes into the tumor is crucial for an effective anti-tumor immune response. In both situations, the recruitment mechanisms of T lymphocytes into the tissues are essential for the immunological functions deciding the outcome. The recruitment of T lymphocytes is largely dependent on their expression of various chemokine receptors. The aim of this study was to identify potential chemokine receptors involved in the recruitment of T lymphocytes to normal human colonic mucosa and to CRC tissue, respectively, by examining the expression of 16 different chemokine receptors on T lymphocytes isolated from these tissues. Methods: Tissues were collected from patients undergoing bowel resection for CRC. Lymphocytes were isolated through enzymatic tissue degradation of CRC tissue and nearby located unaffected mucosa, respectively. The expression of a broad panel of chemokine receptors on the freshly isolated T lymphocytes was examined by flow cytometry. Results: In the normal colonic mucosa, the frequencies of cells expressing CCR2, CCR4, CXCR3, and CXCR6 differed significantly between CD4+ and CD8+ T lymphocytes, suggesting that the molecular mechanisms mediating T lymphocyte recruitment to the gut differ between CD4+ and CD8+ T lymphocytes. In CRC, the frequencies of cells expressing CCR2 and CXCR5 were significantly lower in both the CD4+ and CD8+ T lymphocyte populations compared to unaffected colonic mucosa, and the frequency of CCR9+ cytotoxic T lymphocytes was significantly decreased in CRC tissue. Conclusions: With regard to the normal gut mucosa, the results suggest that the molecular mechanisms mediating T lymphocyte recruitment differ between CD4+ and CD8+ T lymphocytes, which are important for understanding gut homeostasis. Importantly, T lymphocytes from CRC compared to normal colonic tissue displayed a distinct chemokine receptor expression profile, suggesting that mechanisms for recruitment of T lymphocytes to CRC tissue are skewed compared to normal colonic mucosa. Understanding these mechanisms could help in developing new strategies in cancer immunotherapy and to optimize already available alternatives such as immune checkpoint inhibitors.
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| 7. |
- Siddhuraj, Premkumar, et al.
(författare)
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Lung Mast Cells Have a High Constitutive Expression of Carboxypeptidase A3 mRNA That Is Independent from Granule-Stored CPA3
- 2021
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Ingår i: Cells. - : MDPI AG. - 2073-4409. ; 10:2
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Tidskriftsartikel (refereegranskat)abstract
- The mast cell granule metalloprotease CPA3 is proposed to have important tissue homeostatic functions. However, the basal CPA3 mRNA and protein expression among mast cell populations has remained poorly investigated. Using a novel histology-based methodology that yields quantitative data on mRNA and protein expression at a single-cell level, the present study maps CPA3 mRNA and protein throughout the MCT and MCTC populations in healthy skin, gut and lung tissues. MCTC cells had both a higher frequency of CPA3 protein-containing cells and a higher protein-staining intensity than the MCT population. Among the tissues, skin MCs had highest CPA3 protein intensity. The expression pattern at the mRNA level was reversed. Lung mast cells had the highest mean CPA3 mRNA staining. Intriguingly, the large alveolar MCT population, that lack CPA3 protein, had uniquely high CPA3 mRNA intensity. A broader multi-tissue RNA analysis confirmed the uniquely high CPA3 mRNA quantities in the lung and corroborated the dissociation between chymase and CPA3 at the mRNA level. Taken together, our novel data suggest a hitherto underestimated contribution of mucosal-like MCT to baseline CPA3 mRNA production. The functional consequence of this high constitutive expression now reveals an important area for further research.
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