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Madame Curie Bioscience Database [Internet]. Austin (TX): Landes Bioscience; 2000-2013.

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Interleukin-10 and Psoriasis

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Interleukin (IL)-10 is an important immunoregulatory cytokine. One of its main biological function seems to be the limitation and termination of inflammatory responses. Remarkably, a relative deficiency in IL-10 expression is found in psoriasis, a frequent inflammatory skin disease, characterized by a type 1 cytokine pattern. Induction of IL-10 expression was found by conventional antipsoriatic therapies, suggesting that IL-10 may be a key cytokine in psoriasis and that application of this cytokine may have therapeutic effects. In first clinical trials over 3-7 weeks in patients with established psoriasis IL-10 was well tolerated and clinical efficient. In a long term trial in patients with psoriasis in remission, IL-10 therapy decreased the incidence of relapse and prolonged the disease free interval. Laboratory investigations suggest that IL-10 exerts its antipsoriatic activity by effects on different cell populations including antigen pre-senting cells and T-cells. IL-10 led to a lasting type 1/ type 2 cytokine balance shift. Direct effects of IL-10 on keratinocytes, however, are unlikely to have contributed to the clinical response, since IL-10 unresponsiveness of keratinocytes was found in vitro. IL-10 seems to have major importance in psoriasis. Further investigations are necessary to determine whether its application may represent a promising new therapeutic approach.

Pathophysiology of Psoriasis

Psoriasis is a multigenic, cutaneous disorder characterized by inflammation and abnormal epidermal proliferation with a prevalence of 2-3% in the general population. It is defined as a clinical entity affecting skin, nails, and in approx. 5% of the patients joints. Typical findings are keratinocyte hyperproliferation with hyper- and parakeratotic differentiation, epidermal influx of polymorphonuclear leukocytes, and the presence of a mononuclear infiltrate in the papillary dermis and in the epidermis. In contrast to type 2, psoriasis type 1 psoriasis is characterized by early onset (before age 40) and a positive family history.

Several observations indicate that T lymphocytes and cytokines are of major importance in the pathogenesis of this chronic skin disease. These observations are supported by the beneficial effects of systemic administration of immunosuppressive drugs like cyclosporine A, FK506, DAB389IL-2, and anti-T-cell antibodies, known to act on T-cells and to influence the cytokine pattern. Finally, recent investigations using SCID mice demonstrated a central role of immunocytes, in particular T cells, in the pathophysiology of psoriasis. Table 1 summerizes the arguments for considering psoriasis a T-cell mediated dermatosis.1

Table 1. Arguments for considering psoriasis a T cell mediated dermatosis.

Table 1

Arguments for considering psoriasis a T cell mediated dermatosis.

All in all, based on the current knowledge, psoriasis is considered to be probably initiated by presentation of so far unknown "psoriasis-related antigens" by specialized cutaneous APC. Presentation of these antigens and/or superantigens activates T-effector lymphocytes leading to enhanced cytokine formation. These activated T-cells are considered to change epidermal growth homeostasis, leading to increased keratinocyte proliferation and abnormal differentiation. The cutaneous and systemic over-expression of several proinflammatory cytokines, in particular type 1 cytokines, has been demonstrated in psoriasis. This includes interleukin (IL-)2, IL-6, IL-8, IL-12, interferon (IFN-)γ, tumor necrosis factor (TNF)-α. Considering all data and the evidences that “classical” type-1 and type-2 patterns only mark extremes in a wide variety of motifs, the cytokine profile in psoriasis can be considered as “proinflammatory, type 1-like”. The resulting immunological dysbalance is shown in (Fig. 1) Beside the regulatory effects of cytokines on inflammation which seems to be crucial, several out of them might directly enhance the keratinocyte proliferation. So, it has been shown that IL-1 and IL-6 are mitogenic for keratinocytes. However, several other factors are involved into the control of keratinocyte growth as well. It is important to notice that there might be a special mix of factors responsible for the keratinocyte hyperproliferation and that other factors not identified so far might be involved, too.

Figure 1. Effects of IL-10 on the T-helper (Th)1/Th2 dysbalance in psoriasis.

Figure 1

Effects of IL-10 on the T-helper (Th)1/Th2 dysbalance in psoriasis.18 An immune deviation towards a type 1 cytokine aptetrn is a typical finding in several indications such as psoriasis, rheumatoid arthrism, inflammatory bowel disease, transplant rejection, (more...)

IL-10 Expression in Psoriasis

Its considerable anti-inflammatory effects and its ability to act as a main suppresser of cellular immunity2 raises the question of the IL-10 expression under pathophysiological conditions, including in psoriasis.

Immunohistochemical investigations suggested a low cutaneous IL-10 protein expression.3 Similar results were found by quantification of IL-10 protein in blister fluids.4 We found that the cutaneous IL-10 mRNA expression in psoriasis was significantly lower than in atopic dermatitis or cutaneous T-cell lymphoma. The level of IL-10 mRNA expression did not differ from healthy skin, even though numerous pro-inflammatory cytokines are overexpressed. These results are in particular remarkable since TNF, a major inducer of IL-10 was highly expressed. All in all this indicates a relative IL-10 deficiency in psoriasis5 which might have a genetic background.

Remarkably, well established antipsoriatic therapies such as UV radiation or vitamin D analogues are leading to an increase of IL-10 expression in vitro and in vivo.5

IL-10 and IL-10 Receptor Polymorphisms in Psoriasis

Genetic markers in cytokine genes are becoming widely used in studies of immune-mediated disease and it is becoming apparent that they can be markers of disease susceptibility as well as of disease severity.6 When the two known polymorphic microsatellite markers in the human IL-10 promoter IL10.G and IL10.R. were investigated in psoriasis patients, no difference was noted in comparison to the control group. Also, no difference in allele distribution was observed when the psoriasis patients were stratified according to age of onset. However, a clear differential distribution was revealed when patients were grouped according to whether they had a positive family history of psoriasis. In this case, allele IL10.G13 was positively associated with familial psoriasis and this was also true when younger patients were considered; patients with age-of-onset of less than forty were three-fold more likely to have a psoriatic family background if they carried this allele. Thus, it appears that the IL-10 locus contributes to the genetic background in familial psoriasis.7 More recent investigations in a larger population, however, do not support this.8 Further investigations are necessary to determine whether the relative IL-10 deficiency in psoriasis has a genetic origin.

Clinical Effects of IL-10 Therapy in Psoriasis

The powerful immunomodulatory properties of IL-10 and the promising results from IL-10 delivery on the course of several inflammatory diseases in experimental models induced the interest on clinical application of recombinant human (rh) IL-10 (ilodecakin / Tenovil; Schering-Plough Corp., USA) After promising data from phase 1 trials in was used in several indications including in psoriasis. The first administration of human recombined IL-10 in human was performed in 1995.9 Overall, these studies showed that IL-10 is well tolerated without serious side effects at doses up to 25 μg/kg; mild to moderate flu-like symptoms were observed in a fraction of recipients at doses up to 100 μg/kg.10 Therapeutic effects of IL-10 in psoriatic patients has been studied in 7 trials so far (Table 2).

Table 2. Clinical effects of IL-10 therapy in psoriasis.

Table 2

Clinical effects of IL-10 therapy in psoriasis.

In our pilot trial starting in 1997, daily injections of 8 μg rhIL-10 /kg body weight directly under a psoriatic plaque over a 24 day period led to complete clearance of the plaque in one of two patients.5 Moreover, some systemic antipsoriatic effects were observed in all 3 patients treated in this pilot trial (subcutaneous injections under nonlesional skin in the third patient).

In a second trial (open-label phase II), ten psoriatic patients received subcutaneously rhIL-10 over a 7 week period in a dosage of 8 μg/kg daily (n=5) or 20 μg/kg three times per week (n=5), respectively.11 Patients were followed up for an additional 7 weeks. The treatment was well tolerated. We found antipsoriatic effects in 9 out of 10 patients resulting in a significant decrease of the psoriasis area and severity index (PASI) by 55.3 ± 11.5 % (mean ± SEM, p<0.02). The antipsoriatic effect was confirmed by histological examination. Heterogeneity in the effec-tiveness was found among the patients, but seemed to be independent of the dosage regime11 (Fig. 2).

Figure 2. Clinical effects of short course IL-10 therapy in established psoriasis.

Figure 2

Clinical effects of short course IL-10 therapy in established psoriasis. Example of a patient showing good response towards IL-10 therapy. Typical skin lesions before (A), during (B - day 15) and at the end of therapy (C- day 50) are shown. The patient (more...)

Similar clinical effectiveness of IL-10 application has been reported by Reich et al.12 In this open-label phase II trial ten patients were treated subcutaneously with 4 μg/kg rhIL-10 daily. The mean of the disease activity score PASI decreased by 67.9% after 6 weeks of treatment and was associated with improvement of histological parameters.13 The clinical response was asso-ciated with a significant decrease of cutaneous cell infiltration and the lesional expression of type1 cytokines (IFNg, TNF), IL-17 IL-8, and IL-8 receptor CXCR2. There was some evidence that genetic factors are involved in the response to IL-10.13

In a more recent study14 28 patients with moderate-to-severe psoriasis received rhIL-10 (20 μg/kg) or placebo subcutaneously 3 times weekly for 12 weeks in a randomized, double-blind manner. Remarkably, treatment with rhIL-10 resulted in only temporary clinical improvement after 6 and 8 weeks, despite sustained systemic decreases in proinflammatory and type 1 cytokine production.

The effect of IL-10 in psoriatic arthritis patients has been investigated by McInnnes and coworkers. IL-10 was given sc for 28 consecutive days in a double blind, placebo-controlled study including 29 patients (0, 1, 5, or 10 μg/kg). Modest, but significant clinical improvement in skin, but not articular disease activity scores with only minor adverse effects was observed.15

More recently, we investigated the effects of long-term IL-10 application on the immune system and duration of psoriasis remission.16 We performed a placebo-controlled, double-blind, phase II trial using IL-10 in patients with chronic plaque psoriasis in remission. Patients re-ceived subcutaneous injections with either IL-10 (10 μg/kg body weight; n=7) or placebo (n=10) 3 times per week until relapse or study termination after 4 months. The treatment was well tolerated. In the placebo group almost all patients (90%) showed a relapse during the observation period. In contrast to this, only 2 out of 7 patients (28.6%) relapsed in the IL-10-treated group. Kaplan Meier analysis revealed a significantly lower relapse incidence in the IL-10 than in the placebo group (p=0.02). The mean relapse-free interval time was 101.6±12.6 days in the IL-10 group in comparison to 66.4±10.4 days in the placebo group (Fig. 3).

Figure 3. Clinical effects of long term IL-10 therapy in psoriasis.

Figure 3

Clinical effects of long term IL-10 therapy in psoriasis. A) Individual courses of psoriatic disease under long term IL-10 application to prevent the reoccurenace of disease. The patients dropped out of the analysis when fulfilling the criteria for psoriasis (more...)

Immunological Effects of IL-10 Therapy in Psoriasis

Analysing the immunological effects of IL-10 therapy in psoriasis should lead to an better understanding of its antipsoriatic mode of action. It seems that IL-10 exerts its antipsoriatic activity by effects on different cell populations including T-cells and APCs as well as their mutual interaction. IL-10 is able to suppress the APC activity of monocytes/macrophages and the development of dendritic cells. In fact, depressed monocytic HLA-DR and CD86 expres-sion as well as TNF-α and IL-12 secretion capacities were observed by us during IL-10 therapy. Moreover, IL-10 led to a lasting type 1/ type 2 shift (increasing proportion of IL-4, IL-5, and IL-10 producing T-cells, selective increase in IgE serum levels).17 A significant negative corre-lation was demonstrated between the IL-4 secretion capacity and Psoriasis Area and Severity Index score was found in our long term trial. The physiological significance of these findings was reflected by the depressed DTH reaction to recall antigens during IL-10 therapy.11,18 Interestingly, IL-10 therapy led to a decrease in cutaneous IL-8 and an increase in IL-4 expression, both of which might contribute to the antipsoriatic effect.13,19 This is supported by the recently reported antipsoriatic effects of IL-4 itself.20 Direct effects of IL-10 on keratinocytes, however, are unlikely to have contributed to the clinical response, since the IL-10 unrespon-siveness of keratinocytes has been demonstrated by us recently.21,22

Perspectives

Some effectiveness of IL-10 application for the therapy of established, exacerbated psoriasis has been demonstrated by the majority of early phase II trials. Further investigations, in particular multicenter, placebo-controlled, double blind trials, however, are required to better determine the therapeutic potential of this cytokine. This will lead to the answer whether IL-10 could finally become an approved, successful antipsoriatic drug. Independent from this, the effects of IL-10 in psoriasis are contributing to an better pathopysiological understanding of this immune skin disease.1

Regarding the clinical response the picture is already emerging that the potency of this treatment seems to be overall below that of other promising approaches such as the anti-TNF-α strategies. Thus, a complete disease clearance is usually a rare event after IL-10 application, suggesting a relatively low anti-inflammatory potential for this therapy. Moreover, a recent report23 and our recent unpublished observations suggest even pro-inflammatory properties of IL-10. In agreement with this we observed an increase of the sIL-2R levels in IL-10 long-term-treated patients. Therefore, we speculate that IL-10 might not be the major “break through” in anti-inflammatory therapy of exacerbated disease. In contrast, impressive clinical effects with regard to prevention of psoriasis relapse, were found in a single study, rather reflect-ing long-term immunomodulatory than anti-inflammatory properties of IL-10. It might be that not anti-inflammatory but complex immunomodulatory effects might be primarily responsible for the prolongation of the disease-free interval we observed in psoriasis. Such a hypothesis is supported by recent data from animal and in vitro experiments, demonstrating that IL-10 can induce the formation of regulatory T-cells with major impact on the immunoregulation.24,25 Taken together, both first clinical and immunological data suggest that IL-10 application seems to be even more attractive in a secondary prophylactic (prevention of relapse) than in a therapeutic approach in psoriasis. It might be speculated, that IL-10 long term therapy could be equally effective in other entities as inflammatory bowel diseases or rheumatoid arthritis and transplantation.

If it could be determined why certain patients show a good response whereas other do not respond at all, this may lead to the identification of patients suitable for IL-10 therapy. Determining the cytokine and cytokine receptor pattern might be an approach. Currently, however, no real predictive test parameter is available.

So far, IL-10 as a cytokine is therapeutically has been used as a recombinant protein i.e., a large molecule. Therefore its quite expensive to produce, must be administered by injection, which is quite inconvenient for the patient, and the induction of neutralizing antibodies, which might limit their effect, has to be excluded for long term application. Identification of molecules mediating the effects of this cytokine which are suitable for pharmacological interven-tion with small molecules will, therefore, of increasing interest. Interference of protein–protein interaction with small molecules, however, is almost impossible. Therefore, it is unlikely that IL-10 receptor agonists suitable for oral application will be discovered. Molecules acting down-stream of the cytokine receptors targeting for example certain kinases or phosphatases or signal transduction molecules might represent much better “drugable” approaches. The problem here, however, is the specificity, since the known IL-10 signal transduction molecules are shared by different cytokines. Induction of cytokine production with low molecular weight compounds may represent novel approaches. In any case, further investigations on the regulation of IL-10 expression and signalling are of major importance and may lead to better therapeutic approaches.

References

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