Author: Garssen, Johan ; Redegeld, Frank A. ; Bezemer, Gillina F. G. ; Kormelink, Tom Groot ; Braber, Saskia ; Blokhuis, Bart R. ; Postma, Dirkje S. ; Folkerts, Gert ; Kraneveld, Aletta D. ; Koelink, Pim J. ; Kerstjens, Huib A. M. ; Thio, Marco ; Henricks, Paul A. J.

RATIONALENeutrophils are key players in chronic obstructive pulmonary disease (COPD), and increased numbers of neutrophils are present in sputum and lung tissue of patients with COPD. Interestingly, immunoglobulin free light chains (IgLC) are able to prolong the life of neutrophils; therefore, IgLC may contribute to the chronic state of inflammation.OBJECTIVESIn this study, the relation between IgLC and COPD has been investigated.METHODSWe investigated the presence of IgLC in different murine lung emphysema models. IgLC levels in serum from mice and patients with COPD were examined by Western blot analysis and ELISA, respectively. IgLC levels in lung tissue were determined by immunohistochemistry. Fluorescence-activated cell sorter and immunofluorescent analysis were used to detect binding between IgLC and human neutrophils. Interleukin-8 (CXCL8) release by neutrophils after IgLC incubation was measured by ELISA. The effect of F991, an IgLC antagonist, was examined on the neutrophil influx in murine lungs after 5 days of smoke exposure.MEASUREMENTS AND MAIN RESULTSIncreased levels of IgLC in serum of cigarette smoke-exposed and cigarette smoke extract-treated mice compared with control mice were observed. Patients with COPD showed increased serum IgLC and expression of IgLC in lung tissue compared with healthy volunteers. Interestingly, IgLC bound to neutrophils and activated neutrophils to release CXCL8. F991 inhibited the IgLC binding to neutrophils and reduced the smoke-induced neutrophil influx in murine lungs after smoke exposure.CONCLUSIONSThis study describes for the first time an association between neutrophils and IgLC in the pathophysiology of COPD, which could open new avenues to targeted treatment of this chronic disease.

01 Sep 2010·Clinical & Experimental AllergyQ2 · MEDICINE

Depletion of CD4⁺CD25⁺ T cells switches the whey‐allergic response from immunoglobulin E‐ to immunoglobulin free light chain‐dependent

Q2 · MEDICINE

Article

Author: van Esch, B. C. A. M. ; Redegeld, F. A. ; Garssen, J. ; Willemsen, L. E. M. ; Blokhuis, B. R. J. ; Knippels, L. M. J. ; Boon, L. ; Hofman, G. A. ; Schouten, B.

SummaryBackground Symptoms of allergy are largely attributed to an IgE‐mediated hypersensitivity response. However, a considerable number of patients also exhibit clinical features of allergy without detectable systemic IgE. Previous work showed that Ig‐free light chains (IgLC) may act as an alternate mechanism to induce allergic responses. CD4+CD25+ T cells are crucial in the initiation and regulation of allergic responses and compromised function might affect the response to allergens.Objective To examine the contribution of CD4+CD25+ T cells and IgLC towards the whey‐allergic response.Methods Mice were sensitized orally with whey using cholera toxin as an adjuvant. CD25+ T cells were depleted in vivo using a CD25 mAb. The acute allergic skin response to whey and ex vivo colon reactivity was measured in the presence or absence of F991, a specific inhibitor of IgLC. Serum whey‐specific antibodies and IgLC in serum and mesenteric lymph node (MLN) supernatants were measured. Depletion of CD4+CD25+ T cells was confirmed in the spleen.Results Anti‐CD25 treatment strongly reduced whey‐specific antibody levels and resulted in a partial depletion of effector T cells and a major depletion of Foxp3+ regulatory T cells. Surprisingly, despite the abolished specific IgE response, the acute allergic skin response to whey was not affected. IgLC levels were enhanced in the serum and MLN supernatants of CD25‐depleted sensitized mice. F991 inhibited the acute skin response and colon hyperreactivity in anti‐CD25‐treated mice, indicating that these responses were mainly IgLC dependent.Conclusions Depletion of CD4+CD25+ T cells resulted in a switch from an IgE‐ to an IgLC‐dependent acute skin response and functional hyperresponsiveness of the colon. Our data suggest that CD25+ T cells play a crucial role in balancing cow's milk allergy between IgE and IgE‐independent responses and both mechanisms might play a role in allergic responses to the same allergen.Cite this as: B. C. A. M. van Esch, B. Schouten, B. R. J. Blokhuis, G. A. Hofman, L. Boon, J. Garssen L. M. J. Knippels, L. E. M. Willemsen and F. A. Redegeld, Clinical & Experimental Allergy, 2010 (40) 1414–1421.

01 Jul 2010·The Journal of ImmunologyQ2 · MEDICINE

Ig-Free Light Chains Play a Crucial Role in Murine Mast Cell-Dependent Colitis and Are Associated with Human Inflammatory Bowel Diseases

Q2 · MEDICINE

Article

Author: Nijkamp, Frans P. ; Redegeld, Frank A. ; Kraneveld, Aletta D. ; Rijnierse, Anneke ; Blokhuis, Bart R. ; Koster, Andries S. ; Pronk, Inge ; Van der Heijden, Maurice W. ; Te Velde, Anje A. ; Hommes, Daniel W.

AbstractTraditionally, mast cells were regarded as key cells orchestrating type I hypersensitivity responses. However, it is now recognized that mast cells are widely involved in nonallergic (non-IgE) chronic diseases. Also, in inflammatory bowel disease (IBD), a disease not associated with increased IgE concentrations, clear signs of activation of mast cells have been found. In this study, we investigated if Ig-free L chain-induced hypersensitivity-like responses through activation of mast cells could contribute to the pathophysiology of IBD. As a mast cell-dependent model for IBD, mice were skin-sensitized with dinitrofluorobenzene followed by intrarectal application of the hapten. In this murine IBD model, F991 prevented mast cell activation and also abrogated the development of diarrhea, cellular infiltration, and colonic lymphoid follicle hyperplasia. Furthermore, passive immunization with Ag-specific Ig-free L chains (IgLCs) and subsequent rectal hapten challenge elicited local mast cell activation and increased vascular permeability in the colon of mice. Clinical support is provided by the observation that serum concentrations of IgLCs of patients suffering from Crohn’s disease are greatly increased. Moreover, increased presence of IgLCs was evident in tissue specimens from colon and ileum tissue of patients with IBD. Our data suggest that IgLCs may play a role in the pathogenesis of IBD, which provides novel therapeutic means to prevent or ameliorate the adverse gastrointestinal manifestations of IBD.

100 Deals associated with F-991

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Indication	Highest Phase	Country/Location	Organization	Date
Allergic asthma	Phase 2	NL	-	-
Asthma	Phase 2	-	University College Utrecht Alumni Association	-
Asthma	Phase 2	-	Fornix BioSciences NV	-
Crohn Disease	Phase 2	NL	-	-
Multiple Sclerosis	Phase 2	NL	-	-
Skin Diseases	Phase 2	-	University College Utrecht Alumni Association	-
Skin Diseases	Phase 2	-	Fornix BioSciences NV	-
Skin Diseases	Phase 2	NL	-	-
Skin Diseases	Phase 2	-	Clinquest, Inc.	-
Asthma	Preclinical	-	Clinquest, Inc.	-

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