Interleukin 10 Treatment of Psoriasis

Asadullah, Khusru; Döcke, Wolf‐Dietrich; Ebeling, Merle; Friedrich, Markus; Belbe, Gudrun; Audring, Heike; Volk, Hans‐Dieter; Sterry, Wolfram

doi:10.1001/archderm.135.2.187

Cited by 143 publications

(23 citation statements)

References 29 publications

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“…Increased IL-10 and GM-CSF levels have been reported to be beneficial in the treatment of inflammatory disease [30], [31]. Clinical efficacy with IL-10 treatment in psoriasis patients was reported, with immunohistologic improvement [32], [33], as well as lowered incidence of relapse and prolonged disease-free interval [34]. Thus, the enhanced IL-10 effects of apilimod are expected to add benefit to clinical outcome.…”

Section: Discussionmentioning

confidence: 99%

Apilimod Inhibits the Production of IL-12 and IL-23 and Reduces Dendritic Cell Infiltration in Psoriasis

et al. 2012

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Psoriasis is characterized by hyperplasia of the epidermis and infiltration of leukocytes into both the dermis and epidermis. IL-23, a key cytokine that induces T H 17 cells, has been found to play a critical role in the pathogenesis of psoriasis. Apilimod is a small-molecule compound that selectively suppresses synthesis of IL-12 and IL-23. An open-label clinical study of oral administration of apilimod was conducted in patients with psoriasis. Substantial improvements in histology and clinical measurements were observed in patients receiving 70mg QD. The expression of IL-23p19 and IL-12/IL-23p40 in skin lesions was significantly reduced in this dose group, with a simultaneous increase in IL-10 observed. A decrease in the levels of T H 1 and T H 17 cytokines/chemokines in skin lesions followed these p19 and p40 changes. In parallel, a reduction in skin-infiltrating CD11c + dendritic cells and CD3 + T cells was seen, with a greater decrease in the CD11c + population. This was accompanied by increases in T and B cells, and decreases in neutrophils and eosinophils in the periphery. This study demonstrates the immunomodulatory activity of apilimod and provides clinical evidence supporting the inhibition of IL-12/IL-23 synthesis for the treatment of T H 1- and T H 17-mediated inflammatory diseases.

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Section: Discussionmentioning

confidence: 99%

Apilimod Inhibits the Production of IL-12 and IL-23 and Reduces Dendritic Cell Infiltration in Psoriasis

et al. 2012

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“…IL-6 induces an acute inflammatory reaction and supports the activation of lymphocytes, myeloid cells and keratinocytes in the epidermis, which may increase the serum level of IL-6, leading to increased inflammation. Relative deficiency of IL-10 is also seen in psoriatic patients and may be important in the development of this disease [55], [56], [57]. However, no significant differences were found in the polymorphisms of IL-6 and IL-10 promoter genes between patients with psoriasis and healthy controls [58].…”

Section: Discussionmentioning

confidence: 99%

Sleep Loss and Cytokines Levels in an Experimental Model of Psoriasis

et al. 2012

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Up to 80% of people develop a cutaneous condition closely connected to their exposure to stressful life events. Psoriasis is a chronic recurrent inflammatory skin disorder with multifactorial etiology, including genetic background, environmental factors, and immune system disturbances with a strong cytokine component. Moreover, psoriasis is variably associated with sleep disturbance and sleep deprivation. This study evaluated the influence of sleep loss in the context of an animal model of psoriasis by measuring cytokine and stress-related hormone levels. Male adult Balb/C mice with or without psoriasis were subjected to 48 h of selective paradoxical sleep deprivation (PSD). Sleep deprivation potentiated the activities of kallikrein-5 and kallikrein-7 in the skin of psoriatic groups. Also, mice with psoriasis had significant increases in specific pro-inflammatory cytokines (IL-1β, IL-6 and IL-12) and decreases in the anti-inflammatory cytokine (IL-10) after PSD, which were normalized after 48 h of sleep rebound. Linear regression showed that IL-2, IL-6 and IL-12 levels predicted 66% of corticosterone levels, which were selectively increased in psoriasis mice subject to PSD. Kallikrein-5 was also correlated with pro-inflammatory cytokines, explaining 58% of IL-6 and IL-12 variability. These data suggest that sleep deprivation plays an important role in the exacerbation of psoriasis through modulation of the immune system in the epidermal barrier. Thus, sleep loss should be considered a risk factor for the development of psoriasis.

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“…A likely reason is the direct access and injection of IL-10 into the target organ, the skin, thereby bypassing to some extent the complex regulatory network that controls IL-10 biology. Determination of definitive clinical efficacy of IL-10 in psoriasis, however, awaits the results of phase III studies [90–91]. …”

Section: Il-10 and Pathogenesis Of Autoimmune Diseasesmentioning

confidence: 99%

“…Thus, effective delivery is apparently a major obstacle hampering IL-10 immunotherapies. Emphasizing this notion are the encouraging outcomes of the psoriasis studies where IL-10 was injected directly into the psoriatic lesions [90, 135]. We believe that strategies to improve delivery via using innovative time course, multiple injections and/or various dosage, alternate mode and site of administration of IL-10, co-stimulation blockade along with IL-10 therapy, use of small molecule mimics of IL-10 are unlikely to solve this complex problem.…”

Section: Challenges Facing Effective Therapeutic Utilization Of Ilmentioning

confidence: 99%

Interleukin-10 paradox: A potent immunoregulatory cytokine that has been difficult to harness for immunotherapy

et al. 2015

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Interleukin-10 (IL-10) is arguably the most potent anti-inflammatory cytokine. It is produced by almost all the innate and adaptive immune cells. These cells also serve as its targets, indicating that IL-10 secretion and action is highly regulated and perhaps compartmentalized. Consistent with this notion, various efforts directed at systemic administration of IL-10 to modulate autoimmune diseases (type 1 diabetes, multiple sclerosis, rheumatoid arthritis, psoriasis) have produced conflicting and largely inconsequential effects. On the other hand, IL-10 can promote humoral immune responses, enhancing class II expression on B cells and inducing immunoglobulin (Ig) production. Consequently, the high IL-10 level in systemic lupus erythematosus (SLE) patients is considered pathogenic and its blockade ameliorates the disease. In this perspective, we review preclinical findings and results of recent clinical studies using exogenous IL-10 to treat the aforementioned autoimmune diseases. In addition, given the limited success of IL-10 supplementation, we suggest that future studies should be expanded beyond modulating the delivery modes to include developing new strategies to protect and replenish the endogenous sources of IL-10. As an example, we provide evidence that aberrant Fas-mediated deletion of IL-10-producing B cells subverts the immunoregulatory role of IL-10 in autoimmune diabetes and that modulation of the Fas pathway preserves the IL-10-producing B cells and completely protects NOD mice from developing the disease.

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Interleukin 10 Treatment of Psoriasis

Cited by 143 publications

References 29 publications

Apilimod Inhibits the Production of IL-12 and IL-23 and Reduces Dendritic Cell Infiltration in Psoriasis

Apilimod Inhibits the Production of IL-12 and IL-23 and Reduces Dendritic Cell Infiltration in Psoriasis

Sleep Loss and Cytokines Levels in an Experimental Model of Psoriasis

Interleukin-10 paradox: A potent immunoregulatory cytokine that has been difficult to harness for immunotherapy

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