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Regulating the regulators – monitoring immune mechanisms in targeted therapies


Thesis by Aukelise Charlotte Madeleine Theodora de Wolf


Chapter 1. General introduction

Part I. Monitoring the effects of preventive immunomodulatory therapies on regulatory T cells

Chapter 2. Regulatory T cell frequencies and phenotypes following antiviral vaccination

Part II. Monitoring the effects of non-cell-based medicinal products on regulatory T cells

Chapter 3. An arthritis-suppressive and Treg cell-inducing CD4+ T cell epitope is functional in the context of HLA-restricted T cell responses

Chapter 4. Development of an in vitro assay to test B29 peptide responsiveness in peripheral blood samples

Chapter 5. Dawn of monitoring regulatory T cells in (non-)clinical studies: their relevance is slowly recognised

Part III. Regulating in vitro functionality testing of cell-based medicinal products

Chapter 6. Regulatory perspective on in vitro potency assays for human mesenchymal stromal cells used in immunotherapy

Chapter 7. Regulatory perspective on in vitro potency assays for human T cells used in anti-tumour immunotherapy

Chapter 8. Regulatory perspective on in vitro potency assays for human dendritic cells used in anti-tumour immunotherapy

Chapter 9. Summarising discussion

Chapter 10. Addendum

© 2018 Charlotte de Wolf

All rights reserved. Published manuscripts and figures were reprinted in this thesis with permission from the publishers. No part of this thesis may be reproduced or transmitted in any form or by any means, electronical or mechanical, without prior permission of the author.

ISBN: 978-90-393-7039-1

The research described in this thesis was carried out at:

– the Department of Infectious Diseases and Immunology, Division of Immunology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.

– the Department of Quality, Division of Biological Medicinal Products, Medicines Evaluation Board, Utrecht, The Netherlands. The research described in Chapter 2 was performed within the framework of the European Union’s Seventh Framework Programme BioVacSafe.

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Review: Autoinflammatory/autoimmunity syndrome induced by adjuvants (ASIA; Shoenfeld’s syndrome): A new flame


Autoimmunity Reviews, Available online 12 October 2018

Jan Willem Cohen Tervaert


In the present review, recent findings regarding autoimmune/inflammatory syndrome by adjuvants (ASIA) are described. Patients with ASIA present with complaints such as fatigue, cognitive impairment, arthralgias, myalgias, pyrexia, dry eyes and dry mouth. During the last few years, it has been postulated that these symptoms in patients with foreign body implants are due to a chronic inflammatory process and an adjuvant effect of the implanted biomaterial. Ultimately, these inflammatory reactions result in (an increase of) allergies, autoimmune diseases, immune deficiency and/or lymphomas.

Pre-existent allergic disease has been found to be an important risk factor for the development of ASIA after foreign body implantation. Explantation of the foreign body results in the majority of patients in an amelioration of the symptoms. There is an urgent need to start adequately adjusted epidemiological studies to obtain better evidence which percentage of patients does develop symptoms and/or diseases such as ASIA, immune deficiency, and/or autoimmune diseases after implant surgery.


ASIA- autoimmune/inflammatory syndrome by adjuvants Immune deficiency Silicone breast implants Mesh implants ALCL – Anaplastic large cell lymphoma Explantation

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Differential diagnosis of late-type reactions to injected local anaesthetics: Inflammation at the injection site is the only indicator of allergic hypersensitivity


Axel Trautmann, Johanna Stoevesandt

Contact Dermatitis, First published: 11 October 2018. https://doi.org/10.1111/cod.13130



Anaphylaxis‐like reactions developing within a few minutes are the most frequent complications of subcutaneous or submucosal injections of local anaesthetics (LAs), and topically applied LAs are potential contact allergens. In addition, injected LAs have been reported to induce delayed reactions, including local inflammation at the injection site, and various general symptoms.


To assess the frequency and symptoms of late‐type hypersensitivity occurring several hours after LA injections.


We retrospectively evaluated clinical data and test results from all patients referred to our allergy clinic in a period of 20 years for diagnostic work‐up of LA‐associated late‐type reactions.


Of 202 patients reporting symptoms with onset at least 1 hour after LA injection, 40 had cutaneous inflammation confined to the injection site, and 162 reported various systemic symptoms. LA hypersensitivity could be excluded in all patients with systemic complaints by means of skin testing and subsequent subcutaneous provocation. In 8 of the 40 patients (20%) with local inflammatory reactions, late‐type allergic LA hypersensitivity was confirmed.


Late‐type LA allergy commonly causes inflammatory skin reactions confined to the injection site. Conversely, LAs are highly unlikely to trigger delayed systemic symptoms such as urticarial or exanthematous skin eruptions.

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Association of histamine with hypertension-induced cardiac remodeling and reduction of hypertrophy with the histamine-2-receptor antagonist famotidine compared with the beta-blocker metoprolol


Hypertension Research (2018) | Published: 11 October 2018

Ajay Godwin Potnuri, Lingesh Allakonda, Arulvelan Appavoo, Sherin Saheera & Renuka R. Nair


The association of histamine with adverse cardiac remodeling in chronic pressure overload has not received much attention. A pilot study in spontaneously hypertensive rats (SHRs) indicated a reduction of left ventricular hypertrophy (LVH) with a histamine-2-receptor (H2R) antagonist (famotidine). This finding prompted a detailed investigation of temporal variation in myocardial histamine and H2R expression and the cardiovascular response to H2R antagonism compared with that of the conventional beta-blocker metoprolol. Reduction of LVH is known to reduce the risk of adverse cardiovascular events. The myocardial histamine content and H2R expression increased with age in SHRs but not in normotensive Wistar rats. The cardiovascular response to famotidine (30 mg kg−1) was compared with that of metoprolol (50 mg kg−1) in 6-month-old male SHRs treated for 60 days. The decrease in diastolic blood pressure and improvement in cardiac function induced by famotidine and metoprolol were comparable. Both treatments caused the regression of LVH as assessed from the hypertrophy index, histomorphometry, B type natriuretic peptide (BNP), pro-collagen 1, and hydroxyproline levels. Calcineurin-A expression (marker of pathological remodeling) decreased, and Peroxiredoxin-3 expression (mitochondrial antioxidant) increased in response to the treatments. The myocardial histamine levels decreased with the treatments. The age-dependent increase in myocardial histamine and H2R in the SHRs signifies their association with progressive cardiac remodeling. The regression of LVH and improvement in cardiac function by famotidine further demonstrates the role of histamine in cardiac remodeling. Hypertrophy of cultured cardiac cells upon exposure to histamine and the H2R agonist amthamine substantiates the role of histamine in cardiac remodeling. The cardiovascular response to famotidine is comparable to that of metoprolol, suggesting repurposing of H2R antagonists for the management of hypertensive heart disease.

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Rocuronium hypersensitivity: Does off-target occupation of the MRGPRX2 receptor play a role?


The Journal of Allergy and Clinical Immunology, Published online: October 10, 2018

Athina L. Van Gasse, MD, Jessy Elst, MSc, Chris H. Bridts, MLT, Christel Mertens, MLT, Margaretha Faber, MD, PhD, Margo M. Hagendorens, MD, PhD, Luc S. De Clerck, MD, PhD, Vito Sabato, MD, PhD, Didier G. Ebo, MD, PhD

Key words: basophil, CD63, hypersensitivity, mast cell activation, MRGPRX2, rocuronium, skin test, specific IgE, tryptase

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Degranulation of mast cells induced by gastric cancer-derived adrenomedullin prompts gastric cancer progression


Cell Death & Disease volume 9, Article number: 1034 (2018)

Yi-pin Lv, Liu-sheng Peng, Qi-hong Wang, Na Chen, Yong-sheng Teng, Ting-ting Wang, Fang-yuan Mao, Jin-yu Zhang, Ping Cheng, Yu-gang Liu, Hui Kong, Xiao-long Wu, Chuan-jie Hao, Weisan Chen, Jiang Zhu, Bin Han, Qiang Ma, Ke Li, Quanming Zou & Yuan Zhuang


Mast cells are prominent components of solid tumors and exhibit distinct phenotypes in different tumor microenvironments. However, their precise mechanism of communication in gastric cancer remains largely unclear. Here, we found that patients with GC showed a significantly higher mast cell infiltration in tumors. Mast cell levels increased with tumor progression and independently predicted reduced overall survival. Tumor-derived adrenomedullin (ADM) induced mast cell degranulation via PI3K-AKT signaling pathway, which effectively promoted the proliferation and inhibited the apoptosis of GC cells in vitro and contributed to the growth and progression of GC tumors in vivo, and the effect could be reversed by blocking interleukin (IL)-17A production from these mast cells. Our results illuminate a novel protumorigenic role and associated mechanism of mast cells in GC, and also provide functional evidence for these mast cells to prevent, and to treat this immunopathogenesis feature of GC.

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Leukocyte CD300a Contributes to the Resolution of Murine Allergic Inflammation


Laila Karra, Roopesh Singh Gangwar, Revital Shamri, Pier Giorgio Puzzovio, Shahar Cohen-Mor, Bruce D. Levy and Francesca Levi-Schaffer

J Immunol October 12, 2018, ji1801000; DOI: https://doi.org/10.4049/jimmunol.1801000


CD300a is an inhibitory receptor for mast cells and eosinophils in allergic inflammation (AI); however, the spatiotemporal expression of CD300a and its potential roles in the resolution of AI are still to be determined. In this study, employing a mouse model of allergic peritonitis, we demonstrate that CD300a expression on peritoneal cells is regulated from inflammation to resolution. Allergic peritonitis–induced CD300a−/− mice had a rapid increase in their inflammatory cell infiltrates and tryptase content in the peritoneal cavity compared with wild type, and their resolution process was significantly delayed. CD300a−/− mice expressed lower levels of ALX/FPR2 receptor on peritoneal cells and had higher levels of LXA4 in the peritoneal lavage. CD300a activation on mouse bone marrow–derived mast cells regulated ALX/FPR2 expression levels following IgE-mediated activation. Together, these findings indicate a role for CD300a in AI and its resolution, in part via the specialized proresolving mediator LXA4 and ALX/FPR2 receptor pathway activation.

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