Localized Delivery of Interferon-β by Lactobacillus Exacerbates Experimental Colitis

Abstract

BackgroundThere have been conflicting reports of the role of Type I interferons (IFN) in inflammatory bowel disease (IBD). Clinical trials have shown potent efficacy of systemic interferon-beta (IFN-β) in inducing remission of ulcerative colitis. Likewise, IFNAR1−/− mice display an increased sensitivity to dextran sulfate sodium (DSS)-induced colitis, suggesting Type I IFN play a protective role during inflammation of the gut. Curiously, however, there have also been reports detailing the spontaneous development of IBD in patients receiving systemic IFN-β therapy for multiple sclerosis or hepatitis.Methodology/Principal FindingsTo investigate the effects of local administration of IFN-β on a murine model of colitis, we developed a transgenic Lactobacillus acidophilus strain that constitutively expresses IFN-β (La-IFN-β). While pretreatment of mice with control Lactobacillus (La-EV) provided slight protective benefits, La-IFN-β increased sensitivity to DSS. Analysis showed colitic mice pretreated with La-IFN-β had increased production of TNF-α, IFN-γ, IL-17A and IL-13 by intestinal tissues and decreased regulatory T cells (Tregs) in their small intestine. Examination of CD103+ dendritic cells (DCs) in the Peyer's patches revealed that IFNAR1 expression was dramatically reduced by La-IFN-β. Similarly, bone marrow-derived DCs matured with La-IFN-β experienced a 3-fold reduction of IFNAR1 and were impaired in their ability to induce Tregs.Conclusions/SignificanceOur IFNAR1 expression data identifies a correlation between the loss/downregulation of IFNAR1 on DCs and exacerbation of colitis. Our data show that Lactobacillus secreting IFN-β has an immunological effect that in our model results in the exacerbation of colitis. This study underscores that the selection of therapeutics delivered by a bacterial vehicle must take into consideration the simultaneous effects of the vehicle itself.

Review: New Anti-Cytokines for IBD: What is in the Pipeline?

“…Though in all of the conducted trials, IFNβ revealed to be safe and well tolerable there are recent case reports that IFNβ treatment in patients with multiple sclerosis was associated with development of IBD [147]. Recent data suggested that IFNγ administration exacerbated colitis in a mouse model of colitis [148]. While the data of the two most recent trials using IFNβ in patients with UC have not been published to date, their results will be of great interest.…”

Genetically Engineered Lactobacilli for Technological and Functional Food Applications

“…Another non desired effect of a recombinant Lactobacillus was found when L. acidophilus was engineered to express the interferon- to study the local delivery of this molecule in a colitis mouse model. Surprisingly the administration of the recombinant bacteria secreting IFN- has an immunological effect that resulted in the exacerbation of colitis in this model (McFarland et al, 2011).…”

Multiple sclerosis and inflammatory bowel disease: what implications in therapeutic decisions?

“…INF-B1a has different anti-inflammatory mechanisms of action, such as: inhibiting expression of adhesion molecules leading to reduced adhesion of leukocytes and attenuation of inflammatory reactions, downregulation of matrix metalloproteinases, which are implicated in the immunopathogenesis of MS [11][12][13][14][15] and finally inhibiting Th17 cell differentiation known to be a pivotal cell in MS pathogenesis [16]. Conflicting data and paradoxical effects of INF-beta are described in the literature, since in spite of several clinical trials showing promising results in the treatment of UC with INF-B [13], there are various reports of development of UC in patients with MS treated with this drug [17][18][19]. Some authors think that the role of Type I IFN in controlling or exacerbating gut inflammation may be dependent upon factors intrinsic to the patients and this would explain spontaneous development of IBD in some patients receiving IFN-b therapy for MS or hepatitis [13].…”

“…Conflicting data and paradoxical effects of INF-beta are described in the literature, since in spite of several clinical trials showing promising results in the treatment of UC with INF-B [13], there are various reports of development of UC in patients with MS treated with this drug [17][18][19]. Some authors think that the role of Type I IFN in controlling or exacerbating gut inflammation may be dependent upon factors intrinsic to the patients and this would explain spontaneous development of IBD in some patients receiving IFN-b therapy for MS or hepatitis [13]. Taking into account all these facts, natalizumab, a humanized monoclonal antibody against alfa 4 integrin, was started since this drug is effective in the treatment of either MS and IBD [20,21].…”