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Objectives: To study the effect of mycophenolate mofetil (MMF) on various vaccination responses in kidney transplant recipients., Methods: In a randomized controlled trial (EudraCT nr.: 2014-001372-66), low immunologically risk kidney transplant recipients were randomized to TAC/MMF or TAC-monotherapy (TACmono), six months post-transplantation. One year after transplantation, in a pre-specified sub-study, recipients were vaccinated against pneumococcus, tetanus and influenza. Blood was sampled before and 21 days after vaccination. Adequate vaccination responses were defined by international criteria. A post-hoc analysis was conducted on SARS-CoV-2 vaccination responses within the same cohort., Results: Seventy-one recipients received pneumococcal and tetanus vaccines (TAC/MMF: n = 37, TACmono: n = 34), with 29 also vaccinated against influenza. When vaccinated, recipients were 60 (54-66) years old, with median eGFR of 54 (44-67) ml/min, tacrolimus trough levels 6.1 (5.4-7.0) ug/L in both groups and TAC/MMF daily MMF dose of 1000 (500-2000) mg. Adequate vaccination responses were: pneumococcal (TAC/MMF 43%, TACmono 74%, p = 0.016), tetanus (TAC/MMF 35%, TACmono 82%, p < 0.0001) and influenza (TAC/MMF 20%, TACmono 71%, p = 0.0092). Only 7% of TAC/MMF responded adequately to all three compared to 36% of TACmono (p = 0.080). Additionally, 40% of TAC/MMF responded inadequately to all three, whereas all TACmono patients responded adequately to at least one vaccination (p = 0.041). Lower SARS-CoV-2 vaccination antibody responses correlated with lower pneumococcal antibody vaccination responses (correlation coefficient: 0.41, p = 0.040)., Conclusions: MMF on top of tacrolimus severely hampers antibody responses to a broad range of vaccinations., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Here we assessed a possible relationship between baseline TGF-β concentrations and acquisition of sterile immunity after Plasmodium falciparum sporozoite immunization., Methods: TGF-β concentrations were determined in samples of 65 malaria-naive volunteers in 4 studies either prior to and after challenge infection, or prior to and after first immunizing infection under chemoprophylaxis with P. falciparum sporozoites., Results: High baseline TGF-β concentrations were associated with rapid acquisition of sterile protection (p = 0.028)., Conclusion: Baseline TGF-β concentrations predict the efficiency of acquisition of sterile immunity following sporozoite immunization and may represent a steady-state regulatory mechanism to keep in check immune systems with a low threshold for activation., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2023. Published by Elsevier B.V.)

Background and Aims: High-density lipoproteins (HDL) of patients with type 2 diabetes mellitus (T2DM) have impaired anti-inflammatory activities. The anti-inflammatory activity of HDL has been determined ex vivo after isolation by different methods from blood mostly obtained after overnight fasting. We first determined the effect of the HDL isolation method, and subsequently the effect of food intake on the anti-inflammatory function of HDL from T2DM patients., Methods: Blood was collected from healthy controls and T2DM patients after an overnight fast, and from T2DM patients 3 h after breakfast ( n  = 17 each). HDL was isolated by a two-step density gradient ultracentrifugation in iodixanol (HDL DGUC2 ), by sequential salt density flotation (HDL SEQ ) or by PEG precipitation (HDL PEG ). The anti-inflammatory function of HDL was determined by the reduction of the TNFα-induced expression of VCAM-1 in human coronary artery endothelial cells (HCAEC) and retinal endothelial cells (REC)., Results: HDL isolated by the three different methods from healthy controls inhibited TNFα-induced VCAM-1 expression in HCAEC. With apoA-I at 0.7 μM, HDL DGUC2 and HDL SEQ were similarly effective (16% versus 14% reduction; n  = 3; p  > 0.05) but less effective than HDL PEG (28%, p  < 0.05). Since ultracentrifugation removes most of the unbound plasma proteins, we used HDL DGUC2 for further experiments. With apoA-I at 3.2 μM, HDL from fasting healthy controls and T2DM patients reduced TNFα-induced VCAM-1 expression in HCAEC by 58 ± 13% and 51 ± 20%, respectively ( p  = 0.35), and in REC by 42 ± 13% and 25 ± 18%, respectively ( p  < 0.05). Compared to preprandial HDL, postprandial HDL from T2DM patients reduced VCAM-1 expression by 56 ± 16% (paired test: p  < 0.001) in HCAEC and by 34 ± 13% (paired test: p  < 0.05) in REC., Conclusions: The ex vivo anti-inflammatory activity of HDL is affected by the HDL isolation method. Two-step ultracentrifugation in an iodixanol gradient is a suitable method for HDL isolation when testing HDL anti-inflammatory function. The anti-inflammatory activity of HDL from overnight fasted T2DM patients is significantly impaired in REC but not in HCAEC. The anti-inflammatory function of HDL is partly restored by food intake., Competing Interests: The authors declare that they have no conflict of interest., (© 2021 The Authors.)

A soluble form of the interleukin-2 receptor (sIL-2R) is secreted upon T-cell activation. Increased blood levels of sIL-2R occur in a variety of immunological diseases. Although the biological function of sIL-2R is incompletely understood, both in health and disease, sIL-2R serum measurements are commonly conducted in clinical practice as it may help to facilitate diagnosis of specific immune-mediated diseases, such as haemophagocytic lymphohistiocytosis and sarcoidosis. In these, and in other immune-diseases, sIL-2R levels may be used as a biomarker to monitor/predict disease activity and treatment response. In this review, we will give a brief overview of the biology of the IL-2/IL-2R system and will subsequently discuss the clinical utility of sIL-2R measurement, especially in the context of haemophagocytic lymphohistiocytosis, sarcoidosis, rheumatoid arthritis, systemic lupus erythematosus, juvenile idiopathic arthritis, adult-onset Still's disease, ANCA-associated vasculitis, and IgG4-related disease.

Background: Since the late '90s, infliximab (Remicade ® ) is being used successfully to treat patients with several non-infectious immune mediated inflammatory diseases (IMIDs). In recent years, infliximab biosimilars, including Remsima ® were introduced in clinical practice. Aim: To investigate the interchangeability of Remicade ® (originator infliximab) and its biosimilar Remsima ® in patients with rare immune-mediated inflammatory diseases (IMIDs). Methods: This two-phased prospective open label observational study was designed to monitor the transition from Remicade ® to Remsima ® in patients with rare IMIDs. All included patients were followed during the first 2 years. The primary endpoint was the demonstration of non-difference in quality of life and therapeutic efficacy, as measured by parameters including a safety monitoring program, physicians perception of disease activity (PPDA) and patient self-reported outcomes (PSROs). Secondary outcomes included routine blood analysis, pre-infusion serum drug concentration values and anti-drug antibody formation. Results: Forty eight patients treated with Remicade ® were switched to Remsima ® in June-July 2016 and subsequently monitored during the first 2 years. The group consisted of patients with sarcoidosis ( n = 17), Behçet's disease ( n = 12), non-infectious uveitis ( n = 11), and other diagnoses ( n = 8). There were no significant differences in PPDA, PSROs, clinical and laboratory assessments and pre-infusion serum drug concentrations between the groups. De novo anti-drug antibodies were observed in two patients. Seven patients with sarcoidosis and five with another diagnosis developed a significant disease relapse ( n = 7) or adverse events ( n = 5) within 2 years; 10 of these patients discontinued Remsima ® treatment, one withdrew from the study and one received additional corticosteroid therapy. Conclusions: We observed no significant differences in PSROs, PPDA and laboratory parameters after treatment was switched from Remicade ® to Remsima ® . However, disease relapse or serious events were observed in 12 out of 48 patients when treatment was switched from Remicade ® to Remsima ® . The choice to switch anti-TNF alpha biologics in patients with rare IMIDs, particularly in sarcoidosis, requires well-considered decision-making and accurate monitoring due to a possibly higher incidence of disease worsening., (Copyright © 2020 Xue, van Bilsen, Schreurs, van Velthoven, Missotten, Thiadens, Kuijpers, van Biezen, Dalm, van Laar, Hermans, Dik, van Daele and van Hagen.)

Background & Aims: Overweight and obesity increase cardiovascular mortality in patients with type 2 diabetes (T2D). In a recent trial, however, diet-induced weight loss did not reduce the cardiovascular risk of patients with T2D, possibly due to the parallel intensive medical treatment. We investigated the effect of diet-induced weight loss on cardiovascular risk factors in overweight and obese patients with T2D, and whether this effect was influenced by the use of statins, ACE inhibitors, metformin and duration of T2D., Methods: Patients with T2D and BMI >27 were subjected to an energy-restricted diet during 4 months. Before and after intervention, plasma levels of sICAM-1, sVCAM-1, hsCRP, vWF and classical biomarkers were measured. The association of the change in biomarker levels with medication use and T2D history, corrected for age, sex and change in insulin dose, was tested by matched linear regression analyses., Results: In 131 patients, the diet resulted in weight loss of 10.2 kg (95%CI 9.2, 11.3; p < 0.001), improved median levels of HbA1 c (-7.0 mmol/mol (95%CI -8.5, -5.0); p < 0.001), LDL cholesterol (-0.2 mmol/L (95%CI -0.4, -0.1); p < 0.001), sICAM-1 (-22.4 ng/mL (95%CI -37.1, -8.7); p = 0.001), vWF (-3.9 IU/mL (95%CI -6.4, -1.4); p = 0.003) and hs-CRP (-0.6 mg/L (95%CI -1.2, -0.2); p = 0.007), but did not affect sVCAM-1 levels (1.6 ng/mL (95%CI -41.5, 48.6); p = 0.949). Duration of T2D and medical treatment were not associated with these effects, except for an association between statin use and change in sVCAM-1, where statin users improved more., Conclusion: Diet-induced weight loss reduced the levels of biomarkers of endothelial dysfunction and inflammation in overweight and obese patients with T2D independently of medication use and T2D duration. Even on intensive medical drug treatment as well as after a long history of T2D, patients may still profit from diet-induced weight reduction., (Copyright © 2016 European Society for Clinical Nutrition and Metabolism. Published by Elsevier Ltd. All rights reserved.)

Background: In up to 20% of patients with renal cell cancer (RCC) an inflammatory response consisting of low-grade fever, weight loss and an elevated ESR and CRP may occur with modest granulocytosis and thrombocytosis. Clinical and experimental data suggest a pathogenic role for tumour-derived cytokine production, especially interleukin-6., Case Report: A 79-year-old female with RCC presented with low-grade fever, weight loss and overt granulocytosis and thrombocytosis. Radiological examination revealed a right-sided renal tumour. During nephrectomy a gradient between the IL-6 levels in the renal artery and vein was demonstrated, providing direct evidence for in vivo production of IL-6 by the tumour affected kidney, which was confirmed by the demonstration of IL -6 in the tumour cells by immunohistochemical staining and in the supernatant of the homogenised tumour. Cytogenetic examination revealed complex abnormalities including a gain of chromosome 7. In addition we demonstrated production of IL-1alpha, IL-1beta, IL-8 and ICAM-1 in the tumour with systemic elevated levels of IL-6 and IL-8 with secondary increased serum G-CSF and TPO levels., Conclusion: We have provided direct evidence for the production of pro-inflammatory cytokines by renal cancer cells in a patient with RCC and a profound inflammatory response, with a central role of IL-6, probably due to a gain of chromosome 7. The extreme granulocytosis and thrombocytosis may have resulted from the secondary systemic production of G-CSF and TPO.

Pulmonary fibrosis results from excessive fibroblast proliferation and increased collagen deposition and occurs in chronic lung disease of prematurity (CLD). Platelet-derived growth factor (PDGF)-BB is mitogenic for fibroblasts and levels are increased in fibrotic lung disorders. Systemic dexamethasone (DEX) treatment improves pulmonary function and reduces inflammation in infants with or at risk of CLD. However, the effect of DEX treatment on fibroblast activity, PDGF-BB and collagen synthesis in the lungs of CLD patients is uncertain. Bronchoalveolar lavage (BAL) fluids, obtained from 15 infants at risk of CLD before and after DEX treatment, were analysed for fibroblast mitogenicity, PDGF-BB, N-terminal propeptide of collagen type III (PIIINP) and interleukin (IL)-1beta levels and inflammatory cell numbers. After DEX treatment, the mitogenic activity of BAL fluid for fibroblasts was not reduced but increased. The change in mitogenicity correlated with a change in BAL fluid PDGF-BB levels. Furthermore, BAL fluid-induced fibroblast proliferation was blocked using an inhibitor of the PDGF receptor. DEX treatment did not influence PIIINP levels, but reduced IL-1beta levels and inflammatory cell numbers in BAL fluid. This study suggests that dexamethasone treatment does not reduce fibroblast proliferation despite apparent downregulation of inflammation. The present findings do not support the use of dexamethasone for prevention of the fibrotic response in infants at risk of chronic lung disease of prematurity.

Bronchopulmonary dysplasia (BPD) can evolve in prematurely born infants who require mechanical ventilation because of hyaline membrane disease (HMD). The development of BPD can be divided in an acute, a regenerative, a transitional, and a chronic phase. During these different phases, extensive remodeling of the lung parenchyma with re-epithelialization of the alveoli and formation of fibrosis occurs. Matrix metalloproteinase-1 (MMP-1) is an enzyme that is involved in re-epithelialization processes, and dysregulation of MMP-1 activity contributes to fibrosis. Localization of MMP-1 and its inhibitors, tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2, were investigated in lung tissue obtained from infants who died during different phases of BPD development. In all studied cases (n = 50) type-II pneumocytes were found to be immunoreactive for MMP-1, TIMP-1, and TIMP-2. During the acute and regenerative phase of BPD, type-II pneumocytes re-epithelialize the injured alveoli. This may suggest that MMP-1 and its inhibitors, expressed by type-II pneumocytes, play a role in the re-epithelialization process after acute lung injury. Although MMP-1 staining intensity remained constant in type-II pneumocytes during BPD development, TIMP-1 increased during the chronic fibrotic phase. This relative elevation of TIMP-1 compared with MMP-1 is indicative for reduced collagenolytic activity by type-II pneumocytes in chronic BPD and may contribute to fibrosis. Fibrotic foci in chronic BPD contained fibroblasts immunoreactive for MMP-1 and TIMP-1 and -2. This may indicate that decreased collagen turnover by fibroblasts contributes to fibrosis in BPD development.

The coagulation cascade protease thrombin is a fibroblast mitogen, but the proliferative potential of other coagulation proteases is not known. In this study we show that factor Xa stimulated human fetal lung fibroblast DNA synthesis in a concentration-dependent manner from 1 nM onward with a fourfold increase at 200 nM. The mitogenic effect of factor Xa was confirmed using a colorimetric proliferation assay and direct cell counting. Factor Xa and thrombin had equivalent potencies, and their stimulatory effects followed a similar time course. Comparable results were also obtained with primary human adult fibroblasts derived from lung, kidney, heart, skin, and liver. Factor VIIa also stimulated fibroblast proliferation, but only at concentrations >10 nM, whereas factor IXa had no effect. To begin to address the mechanism by which factor Xa is acting, we show that human fibroblasts express effector-cell protease receptor-1 and that blocking antibodies to this receptor and the catalytic site of factor Xa inhibited its mitogenic effect. Furthermore, factor Xa upregulated platelet-derived growth factor-A (PDGF-A) mRNA expression, whereas PDGF-B could not be detected, and a blocking antibody to PDGF inhibited the mitogenic effect of factor Xa. We conclude that factor Xa acts as a fibroblast mitogen via binding to effector-cell protease receptor-1 and the autocrine release of PDGF.