Treatment of immune-mediated skin diseases: future perspectives

ARTICLE

Advances in our understanding of the cellular and molecular mechanisms involved in inflammatory and immune-mediated skin diseases as well as the new and exciting discoveries in biotechnology have led to the development of several novel immunomodulating and antiinflammatory drugs. New therapies have been developed by either using existing or newly made classes of immunomodulating drugs. On the other hand as a consequence of the improved understanding of the molecular mechanism of these diseases, several new targets have been identified leading to the development of specific agonists or antagonists. Moreover, new strategies using in vitro modified antigen-presenting cells, antisense oligonucleotides as well as gene therapy are currently being developed. The following review will briefly discuss some of the new immunomodulating strategies for the treatment of skin diseases.

Non-specific immunomodulating strategies

Among non-specific immunomodulating drugs cyclosporin A (CyA) is widely used for the treatment of psoriasis, atopic dermatitis and autoimmune diseases of the skin [1]. In dermatology CyA is usually used in a dose of 2.5-5 mg/kg daily. CyA binds to the immunophilin termed cyclophilin. The drug-receptor-complex inhibits the protein phosphatase, calcineurin and thus interrupts the nuclear translocation of the cytoplasmic subunit of the nuclear factor of activated T-cells (NF-AT). As a consequence the transcription of cytokine genes (IL-2) is blocked which results in immunosuppression [2]. However, the use of CyA for the treatment of skin diseases is limited because of the occurrence of sometimes severe side effects such as nephrotoxicity, hypertension and an increased incidence of malignancies especially in combination with UV-light [3].

Tacrolimus (FK506), like CyA, via inhibiting the phosphatase calcineurin causes a downregulation of IL-2 production [2]. The doses used for the treatment of skin diseases range from 0.05 mg/kg to 0.15 mg/kg daily. Side effects are similar to those seen with CyA. Currently the systemic use of tacrolimus is limited to the treatment of severe T-cell mediated skin diseases such as psoriasis, atopic dermatitis, a.o. [4, 5].

Recently, tacrolimus was developed for topical use and tacrolimus ointment has been shown to be very effective in the treatment of inflammatory skin diseases [6]. Moreover, there is evidence from animal studies indicating that topical application of tacrolimus may be useful for the treatment of alopecia areata [7]. Treatment of atopic dermatitis with a 0.01% tacrolimus ointment twice daily for 3 weeks resulted in a significant improvement of inflammatory skin lesions as well as itching [8]. In contrast to corticosteroids, tacrolimus does not cause skin atrophy. No severe systemic side effects have been reported. The most common application site adverse effect was skin burning within the first week of treatment [8]. In some patients low levels of tacrolimus have been detected during topical treatment [9]. The efficacy and safety of topically applied tacrolimus as a treatment of atopic dermatitis in adult and pediatric patients has been confirmed recently in long-term clinical trials [10, 11].

Ascomycin derivatives such as pimecrolimus (ASM 981) are currently being developed for the treatment of inflammatory skin diseases. ASM 981, like tacrolimus and CyA inhibits calcineurin and has similar immunomodulating effects [12]. However, in animal models systemic application of ASM 981 did not cause toxic adverse events such nephrotoxicity, hepatotoxicity or hypertension [12]. Moreover, the immunosuppressing capacity of ASM 981 is significantly weaker when compared to that of CyA and tacrolimus. ASM 981 effectively inhibits the elicitation phase of a contact hypersensitivity reaction but in contrast to CyA and tacrolimus, does not impair the sensitization phase [13]. In an animal transplantation model, significantly higher amounts of ASM 981 are required to prevent organ rejection than with CyA or tacrolimus [14]. According to a first clinical trial systemic application of ASM 981 was highly and dose-dependently effective in the treatment of patients with moderate to severe plaque psoriasis resulting in PASI-reduction of 60 to 75% after 4 weeks of treatment. No serious adverse events such as nephrotoxicity, hepatotoxicity, hypertension or myelotoxicity have been observed. The only notable side effect was a transient feeling of warmth after drug intake [15]. These promising clinical data need to be confirmed in further controlled clinical trials.

ASM 981 also has been developed for topical treatment of inflammatory skin diseases [12]. In several clinical trials the topical application of 1% ASM 981 cream twice daily within 3 weeks significantly improved eczematous lesions as well as itching. Long-term studies in adults and children are currently being performed [16, 17]. In addition ASM 981 cream proved to be an effective treatment for chronic irritant hand dermatitis and allergic contact dermatitis [12]. Like tacrolimus ASM 981 does not cause skin atrophy and with the exception of initial mild burning does not cause severe adverse events. In contrast to tacrolimus, topical application of ASM 981 in patients with atopic dermatitis did not lead to the occurrence of significant serum levels [17]. Treatment of plaque type psoriasis either with tacrolimus or ASM 981 was only effective when applied under occlusion [18, 19].

Other specific immunomodulatory drugs which may be useful for the treatment of skin diseases include fumaric acid, mycophenolat mofetil (MMF), rapamycin, leflunomide and others [5, 20, 21]. Several clinical studies have demonstrated that fumaric acid because of its immunomodulating and possibly IL-10 inducing capacity, is very effective for the treatment of psoriasis. Side effects include flush, gastrointestinal symptoms as well as mild myelotoxicity [22]. Mycophenolat mofetil (MMF) inhibits the enzyme ionosine monophosphate dihydrogenase (IMPDH) which is required for the de novo pathway of guanosine nucleotides needed for DNA and RNA synthesis. In contrast to other cell types which may also use salvage pathways to synthesize guanosine, lymphocytes are primarily dependent on the de novo pathway and therefore their activation and proliferation is selectively impaired by MMF. There is recent evidence that MMF by inhibiting HIV-replication ­ guanosine nucleotides serve as substrate for reverse transcriptase ­ and by depleting activated CD4⁺ cells could be an additional effective treatment of HIV infection [23]. Several clinical reports have been published on the successful treatment of bullous pemphigoid, pemphigus, psoriasis, pyoderma gangraenosum, atopic dermatitis and others with MMF [5, 21, 24, 25]. For the treatment of skin diseases MMF is usually used in a dose of 2 x 1 g daily. Although, there are no controlled clinical trials comparing the efficacy of MMF to other immunomodulatory drugs one advantage of MMF seems to be its improved tolerability associated with a low toxicity profile [21]. However, controlled clinical trials which are currently being performed will reveal the safety and efficacy of MMF in the treatment of inflammatory, autoimmune and allergic diseases.

Cytokines play a crucial role in the pathogenesis of inflammatory and immune mediated diseases and apparently have an enormous therapeutic potential. Some cytokines such as interferons (IFN) are already widely used for the treatment of skin diseases and represent the current standard therapy for high risk melanoma and cutaneous T cell lymphoma [26]. More recently the use of cytokine inhibitors has gained increasing attention for the treatment of inflammatory skin diseases. Accordingly, the Th2 type cytokine interleukin-10 (IL-10) that is able to inhibit the expression of Th1 type cytokines appears to be a useful approach for the treatment of Th1 mediated diseases such as psoriasis. In the first clinical trials subcutaneous application of IL-10 resulted in a significant drop of the PASI score. Although IL-10 was well tolerated more clinical trials are needed to evaluate the efficacy and possible long-term side effects of this treatment [27].

An interesting alternative to cytokine therapy is the use of synthetic low molecular weight compounds which function as cytokine inhibitors or inducers. Suplatast tonsilate is a selective Th2 cytokine inhibitor that suppresses the synthesis of IL-4 and IL-5 in vitro [28]. Treatment with suplatast tosilate recently has been shown to improve pulmonary function and steroid intake in steroid dependent asthma [29]. Systemic or topical application of the nucleoside analogon imiquimod induces the production of cytokines such as IL-1, TNFalpha, IFNalpha and IL-12 which result in the generation of a Th1 immune response with antiviral and antitumoral activity [30]. Several clinical trials have proved the efficacy of imiquimod in the treatment of anogenital warts resulting in remission rates up to 75% [31]. There is also evidence from preliminary studies demonstrating that imiquimod is very effective in the treatment of actinic keratosis, basal cell carcinomas, squamous cell carcinomas, lentigo maligna and melanoma metastasis [32-34]. The efficacy of this promising new approach in the treatment of tumors and perhaps other Th2 mediated diseases needs to be evaluated in further clinical trials.

There is evidence that bacterial DNA and synthetic oligodeoxynucleotides containing unmethylated CpG motifs (CpG ODN) are potent immunostimulatory agents. In animal models CpG ODN have been shown to enhance Th1 immune-responses. Preliminary results in animals and humans indicate that CpG ODN enhance innate immunity and also may be used as an adjuvant for immunization as well as to stimulate anti-tumor immunity. CpG ODN via inducing Th1 responses also could be useful for the treatment of Th2 mediated diseases such as asthma and atopic dermatitis [35].

Specific immunomodulating strategies

Advances in the understanding of the complex molecular mechanisms of immune reactions have led to the identification of several new targets such as cytokine-receptors, adhesion molecules and transcription factors that may result in novel antiinflammatory and immunomodulating strategies. Approaches to block these specific targets are: humanized antibodies directed against cytokines or their receptors, soluble receptors that bind to secreted cytokines, receptor antagonists, fusion protein constructs targeting cytokines or cell surface molecules and transcription factor inhibitors. Clinical studies which are currently being performed use humanized antibodies against cytokines (IL-2, TNFalpha), cytokine receptors (IL-2R, TNFalphaR), Tcell markers (CD3, CD4, CD44), B-cell markers (CD20), costimulatory molecules on antigen presenting cells (CD11, CD80), the high affinity IgE receptor (FcepsilonRI), epidermal growth factor and virus (respiratory syncytial virus) [36]. Most of these antibodies were primarily developed to prevent transplant rejection or to treat autoimmune diseases and tumors. Recently, in a murine model of alopecia areata treatment with an antibody directed against a form of the lymphocyte homing receptor (anti-CD44v10) has been shown to inhibit the onset of the disease [37]. Treatment of CD20 expressing B-cell lymphomas with anti-CD20 appears to be promising according to the first clinical studies [38]. Antibodies directed against T cell surface molecules (anti-CD4) and costimulatory molecules (anti-CD11a, anti-CD80) in preliminary clinical trials appear to be effective for the treatment of psoriasis as well as atopic dermatitis [39-42]. Several clinical trials are currently being performed using different humanized antibodies directed against the high affinity IL-2 receptor (CD25) to investigate their efficacy in T cell-mediated diseases such as cutaneous T cell lymphoma and psoriasis [36, 43]. To neutralize the proinflammatory cytokine TNFalpha in addition to humanized antibodies fusion proteins containing the TNFalpha receptor (TNFalphaRII) and a humanized immunoglobulin fragment are currently investigated. Anti-TNFalpha therapy appears to be effective in the treatment of psoriasis and psoriatic arthritis [44, 45]. Strategies to block IgE using humanized murine antibodies directed against the high affinity IgE receptor in patients with moderate and severe asthma as well as in birch pollen-induced seasonal allergic rhinitis have demonstrated significant clinical improvement and rescue medication sparing effects [46, 47]. Treatment with monoclonal antibodies is usually well tolerated, the most common side effects were flu-like symptoms. However, an increased incidence of infectious diseases or tumors following long-term treatment has to be considered [36].

Another strategy for a specific immuno-therapy is the use of fusion proteins consisting of cytokines, receptors or adhesion molecules linked with immunoglobulin fragments or toxins. CTLA-4 Ig is a recombinant fusion protein that contains the extracellular domain of the human CTLA-4 fused to human IgG₁ thereby functioning as a high affinity CD28/CTLA-4 antagonist. CTLA-4 Ig appears to be useful in inhibiting T cell activation by binding to B7 on antigen-presenting cells and thus blocking T cell activation. Preliminary data indicate that treatment with CTLA-4 Ig appears to be effective in psoriasis and atopic diseases [5, 48]. LFA₃TIP is a human fusion protein in which the CD2 binding domain of LFA₃ has been linked to the Fc portion of human IgG₁, leading to functional blockade of the LFA₃/CD2 pathway. Thus LFA₃TIP by binding to CD2 inhibits the function of CD4 and CD8 Tcells. Indeed, treatment with LFA₃TIP led to prolonged graft survival in transplantation medicine and also was very effective in the treatment of psoriasis. LFA₃TIP was well tolerated without any serious short-term side effects [5, 49]. DAB₃₈₉IL-2 is an IL-2 receptor specific fusion protein in which the receptor binding domain of the diphteria toxin has been replaced by human IL-2 and the membrane translocating and cytotoxic domains have been retained. Clinical and laboratory investigations have demonstrated a selective destruction of IL-2 receptor expressing T lymphocytes and DAB₃₈₉IL-2 successfully has been used in clinical trials for the treatment of cutaneous T cell lymphomas and psoriasis. The most common side effects observed were flu-like symptoms with severity increasing at higher doses [50, 51]. First clinical studies with immuno-cytokines being fusion proteins of IL-2 with tumor antigens have yielded promising results in the treatment of melanoma [52].

Inhibition of transcription factors such as NFkappaB which plays an important role in the regulation of inflammatory signals is of particular interest. Recently, a protein consisting of the amino terminal region of the regulatory protein NEMO (NFkappaB essential modifier) which is required for the activation of NFkappaB has been found to selectively inhibit NFkappaB as thus may be developed as an antiinflammatory compound [53]. Moreover, the carboxy terminal tripeptide of alpha melanocyte stimulating hormone (alphaMSH) also was found to block NFkappaB activation and to have in vivo antiiflammatory activities [54]. Other interesting targets are MAP-kinases which are involved in the expression of proinflammatory genes and chronic inflammation [55].

Restricted T cell receptor (TCR) gene use has been reported in populations of activated T cells isolated from autoimmune diseases such as rheumatoid arthritis, multiple sclerosis and psoriasis. One possible strategy for treating psoriasis was therefore to target the appropriate TCR on auto-reactive T cells. Vaccine based upon these TCR have been developed and their safety has already been demonstrated in first clinical trials using Vbeta3 and Vbeta13.1 TCR peptides [5].

There are several vaccination strategies which are currently being investigated for their clinical anti-tumor efficacy. These include tumor cell based vaccines such as those based on the transfection of (tumor)-cells with cytokine genes (IL-2, IL-4, IL-7), tumor cell/antigen presenting cell hybrids, tumor antigen-derived peptides, recombinant viral vectors engineered to encode tumor antigens, plasmid (naked) DNA-based vaccines and dendritic cell vaccines [56]. Vaccination using autologous mature dendritic cells pulsed with tumor antigens and/or transfected with cytokine genes in order to activate cytotoxic cells are currently being investigated in several clinical trials for the treatment of advanced melanoma [57, 58]. The value of vaccination strategies using DNA vaccines are investigated in several clinical trials in the treatment of tumors. For example in a murine model an autologous DNA vaccine containing the murine ubiquitin gene fused to murine melanoma antigens was found to break peripheral T cell tolerance and to protect against melanoma [59]. In another approach of a DNA vaccine, the gene for the antigen of interest is cloned into a bacterial plasmid that will stimulate the expression of the inserted gene in mammalian cells. After injection into the host the plasmid enters a cell, where it remains in the nucleus and is not integrated into the cell's DNA. Subsequently, the plasmid DNA will direct the synthesis of the antigen it encodes. In addition, together with DNA, immunostimulatory desoxynucleotides (CPG ODN) may be inserted into the plasmid. These CPG ODN motifs will induce a Th1 immune response and thus further stimulate the activation of cytotoxic cells [60].

The enormous developments in the search for new and more effective treatments together with a low profile of side effects are exciting and suggest a promising future for the treatment of inflammatory, autoimmune, allergic and neoplastic skin diseases.

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