Browsing by Author "Jijon, Humberto"

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    Crohn’s-like disease in a patient exposed to anti-Interleukin-17 blockade (Ixekizumab) for the treatment of chronic plaque psoriasis: a case report
    (2019-09-05) Smith, Matthew K; Pai, Jay; Panaccione, Remo; Beck, Paul; Ferraz, Jose G; Jijon, Humberto
    Abstract Background Plaque psoriasis and inflammatory bowel disease (IBD) are both chronic immune-mediated inflammatory diseases with an overlapping genetic profile and have been linked in epidemiological studies. Psoriasis and IBD share similar components in their inflammatory pathways and animal and human studies have suggested a potential role for targeting interleukin (IL)-17 with novel antibody therapies in the treatment of these diseases. These studies, while promising for psoriasis, have been associated with deterioration in patients with IBD. Post-hoc analyses of clinical trials involving Ixekizumab revealed adverse outcomes in a small cluster of patients with IBD, prompting recommendations to monitor this population with the use of this drug. Case presentation Forty-two year old Caucasian male with treatment-refractory chronic plaque psoriasis who developed new onset diarrheal illness and rectal bleeding following a 12 week induction period with Ixekizumab (anti-IL-17 neutralizing antibody). Colonoscopy revealed severe ulceration throughout the ascending and transcending colon. Histopathology, combined with endoscopic findings, led to a diagnosis of Crohn’s-like colitis. The patient’s anti-IL-17 medication was discontinued and endoscopic remission was induced with the use of corticosteroids, escalated anti-TNF therapy and eventually anti IL-12/23 neutralizing antibody (ustekinumab). Conclusion Murine studies implicate IL-17 and the downstream effects of its inhibition, in the breakdown of the gut epithelial layer, the disruption of normal host immune responses and the propagation of intestinal inflammation. The increasing use of IL-17 inhibitors has led to reports of exacerbation and potential development of inflammatory bowel disease. While clinical trials have revealed clusters of new inflammatory bowel disease cases amongst psoriasis patients using an IL-17 inhibitor, there remains a lack of evidence to suggest a causal relationship. This is the first case report of de-novo severe Crohn’s-like IBD in association with the use of Ixekizumab requiring rescue with escalated dosing of anti-TNF therapy and highlights the importance of close monitoring in patients being treated with IL-17 inhibitors, especially in those patients with known risk factors for inflammatory bowel disease.
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    Regulation of Intestinal Epithelial Thymic Stromal Lymphopoietin Gene Expression by Retinoic Acid Receptor Alpha
    (2021-08-23) Mahmood, Ramsha; Jijon, Humberto; Beck, Paul; Hirota, Simon; McCafferty, Donna-Marie; Dufour, Antoine
    Inflammatory bowel disease is characterized by chronic inflammation of the gastrointestinal tract. The pathogenesis is thought to be due to a dysregulated immune response to intestinal microbiota. Approximately 15% of the risk is genetically linked and approximately 85% is attributed to environmental exposures. Dietary factors like retinoic acid (RA), a vitamin A metabolite, have been linked to the onset of IBD by influencing intestinal immune function. RA induces Tregs and inhibits the actions of proinflammatory Th-17 cells. We have previously described decreased CD103+ DCs numbers in the intestinal compartments of RARα-deficient mice (RARαvillin mice). We sought to generate an experimental system to identify signaling pathway(s) or mechanism(s) that might be governing these effects, specifically RA signaling, as this data suggested there might be contributing factors intrinsic to IECs. We chose to establish a knockout cell line using the CRISPR/Cas9 system, given its affordability and efficiency compared to other in vitro models, and used it to study the effects of RAR⍺ ablation in IECs. Thus, our hypothesis was that RA signaling regulates the expression of lymphokines and other immune mediators (e.g., TSLP) by IECs, which then modulate the intestinal immune compartment. We hypothesized TSLP could be contributing to the decrease in CD103+ DCs as it is an important cytokine involved in TH2-type immunity and plays a key role in the maintenance of peripheral CD4+ T cell homeostasis by modulating the activation/maturation of myeloid cells. We used the CRISPR/Cas9 system to examine the effects of RARα ablation and its role in regulating intestinal epithelial TSLP expression. We found that TSLP expression is controlled by RARα in IECs where it may act as a repressor of TSLP promoter transactivation. This suggests an important role for RA signaling on myeloid/T cell function via effects on TSLP gene expression.
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    The Human Interleukin-4 Treated Macrophage and Epithelial Wound Repair
    (2018-04-17) Jayme, Timothy; McKay, Derek; Beck, Paul; Jijon, Humberto; Yates, Robin; Hanington, Patrick
    The murine interleukin-4 (IL-4) treated alternatively activated macrophage (M(IL4)) is known to have key roles in wound repair. Given that mucosal wound healing is the best indicator of long term remission for patients with inflammatory bowel disease (IBD), adoptive transfer of the M(IL4) in mice has been extensively studied as a therapeutic, and its beneficial outcome may be induced, in part, by M(IL4)s inducing wound healing. However, research has been extremely limited in translating these findings into human studies. Furthermore, helminth-derived soluble products can induce and enhance the M(IL4) phenotype in both mice and humans, however, its ability to enhance M(IL4) function is unknown. Therefore, my MSc research was designed to test the hypotheses that: 1) the human blood-derived M(IL4) can be an autologous cell immunotherapy for IBD by inducing mucosal wound repair; and, 2) in vitro treatment of M(IL4)s with an extract of the rat tapeworm, Hymenolepis diminuta (HdE), can enhance its capacity to wound repair. To my knowledge this is the first time that a human blood-derived M(IL4) (CD206highCCL18+CD14low) has been reported to promote colonic epithelial wound repair in an in vitro scratch assay: an ability dependent on TGF and prostaglandins. Furthermore, cryopreservation of human M(IL4)s, which could be an important process if used therapeutically, did not lose their ability to promote wound repair, although decreased M(IL4) markers were noted. Monocytes from patients with inactive Crohn’s disease or ulcerative colitis could be differentiated into M(IL4)s with the capacity to promote epithelial wound repair. Interestingly, M(IL4)s from patients with active Crohn’s disease and ulcerative colitis were more variable in their response to IL-4, and impaired M(IL4) activation (CD206lowCCL18+CD14low) correlated with an impaired ability to promote epithelial wound repair. This suggests that in vivo, M(IL4)s may have an important role in the resolution of inflammation by inducing mucosal wound repair in patients with active IBD. Finally, I could not find any direct evidence, in vitro, that HdE enhances the capacity of M(IL4)s to promote wound repair. Having defined the ability of the monocyte-derived M(IL4)s from healthy volunteers and patients with IBD to promote epithelial wound healing, my research lays the foundation for a more extensive investigation of the anti-inflammatory/pro-resolution activity of the human M(IL4), which could be used as an autologous transplant in a personalized medicine approach to IBD or other enteropathies.