Wolf-Henning Boehncke

Proteasome inhibition: a new anti-inflammatory strategy

The ubiquitin-proteasome pathway has a central role in the selective degradation of intracellular proteins. Among the key proteins modulated by the proteasome are those involved in the control of inflammatory processes, cell cycle regulation, and gene expression. Consequently proteasome inhibition is a potential treatment option for cancer and inflammatory conditions. Thus far, proof of principle has been obtained from studies in numerous animal models for a variety of human diseases including cancer, reperfusion injury, and inflammatory conditions such as rheumatoid arthritis, asthma, multiple sclerosis, and psoriasis. Two proteasome inhibitors, each representing a unique chemical class, are currently under clinical evaluation. Velcade (PS-341) is currently being evaluated in multiple phase II clinical trials for several solid tumor indications and has just entered a phase III trial for multiple myeloma. PS-519, representing another class of inhibitors, focuses on the inflammatory events following ischemia and reperfusion injury. Since proteasome inhibitors exhibit anti-inflammatory and antiproliferative effects, diseases characterized by both of these processes simultaneously, as is the case in rheumatoid arthritis or psoriasis, might also represent clinical opportunities for such drugs.

Proteasome inhibition reduces superantigen-mediated T cell activation and the severity of psoriasis in a SCID-hu model.

There is increasing evidence that bacterial superantigens contribute to inflammation and T cell responses in psoriasis. Psoriatic inflammation entails a complex series of inductive and effector processes that require the regulated expression of various proinflammatory genes, many of which require NF-kappa B for maximal trans-activation. PS-519 is a potent and selective proteasome inhibitor based upon the naturally occurring compound lactacystin, which inhibits NF-kappa B activation by blocking the degradation of its inhibitory protein I kappa B. We report that proteasome inhibition by PS-519 reduces superantigen-mediated T cell-activation in vitro and in vivo. Proliferation was inhibited along with the expression of very early (CD69), early (CD25), and late T cell (HLA-DR) activation molecules. Moreover, expression of E-selectin ligands relevant to dermal T cell homing was reduced, as was E-selectin binding in vitro. Finally, PS-519 proved to be therapeutically effective in a SCID-hu xenogeneic psoriasis transplantation model. We conclude that inhibition of the proteasome, e.g., by PS-519, is a promising means to treat T cell-mediated disorders such as psoriasis.

Efomycine M, a new specific inhibitor of selectin, impairs leukocyte adhesion and alleviates cutaneous inflammation

Specific interference with molecular mechanisms guiding tissue localization of leukocytes may be of great utility for selective immunosuppressive therapies. We have discovered and characterized efomycines, a new family of selective small-molecule inhibitors of selectin functions. Members of this family significantly inhibited leukocyte adhesion in vitro. Efomycine M, which was nontoxic and showed the most selective inhibitory effects on selectin-mediated leukocyte-endothelial adhesion in vitro, significantly diminished rolling in mouse ear venules in vivo as seen by intravital microscopy. In addition, efomycine M alleviated cutaneous inflammation in two complementary mouse models of psoriasis, one of the most common chronic inflammatory skin disorders. Molecular modeling demonstrated a spatial conformation of efomycines mimicking naturally occurring selectin ligands. Efomycine M might be efficacious in the treatment of human inflammatory disorders through a similar mechanism.

Is psoriasis a T-cell disease?

Abstract: The etiology and pathogenesis of psoriasis – one of the most common chronic, inflammatory, hyperproliferative skin disorders of man – have long fascinated dermatologists, pathologists and biologists alike. Here, we have a model disease that offers to study neuroectodermal‐mesenchymal interactions in the widest sense possible. Epithelial, endothelial, and hematopoietic cells as well as neurons projecting into the skin apparently all interact with each other to generate the characteristic psoriatic lesion. For decades, the ongoing controversy on the molecular nature, choreography and hierarchy of these complex interactions e.g. between epidermal keratinocytes, T cells, neurotrophils, endothelial cells and sensory nerves has served as a driving force propelling investigative dermatology to ever new horizons. This debate has not only been at the heart of our quest to develop more effective forms of therapy for this socially crippling disease, but it also has profoundly influenced how we view the skin as a whole: the numerous competing theories on the pathogenesis of psoriasis published so far also are reflections on the evolution of mainstream thought in skin biology over the last decades. These days, conventional wisdom – infatuated with a T‐cell‐centered approach to inflammatory skin diseases – portrays psoriasis as an autoimmune disease, where misguided T lymphocyte activities cause secondary epithelial abnormalities. And yet, as this CONTROVERSIES feature reminds us, some authoritative “pockets of academic resistance” are still quite alive, and interpret psoriasis e.g. as a genetically determined, abnormal epithelial response pattern to infectious and/or physicochemical skin insults. Weighing the corresponding lines of argumentation is not only an intriguing, clinically relevant intellectual exercise, but also serves as a wonderful instrument for questioning our own views of the skin universe and its patterns of deviation from a state of homeostasis.

Selection of conserved TCR VDJ rearrangements in chronic psoriatic plaques indicates a common antigen in psoriasis vulgaris.

Psoriasis vulgaris is a common HLA‐associated inflammatory skin disease. Although its etiology is still unknown, it is thought to involve T cell‐mediated inflammatory mechanisms. In examining the lesional psoriatic TCR β chain (TCRB) usage in a pair of identical twins concordant for psoriasis, we observed repetitive TCR VDJ rearrangements which indicated antigen‐specific oligoclonal T cell expansion. Several of these TCRB rearrangements were identical or highly homologous in the amino acid composition of the complementarity determining region 3 (CDR3), suggesting that T cells with these TCR might be important for disease manifestation. This conclusion was strengthened by TCR analysis of other psoriasis patients. Several repetitive lesional TCRB rearrangements were found that were similar to the conserved CDR3 seen in the twins. Since TCR antigen specificity is largely determined by the β chain CDR3, selection of T cells with conserved TCRB CDR3 motifs could indicate the presence of a common antigen as a major target of the lesional psoriatic immune response.

Photodynamic therapy in psoriasis: suppression of cytokine production in vitro and recording of fluorescence modification during treatment in vivo

Photodynamic therapy (PDT) consists of the combination of photosensitizers absorbing light mainly in the red spectral region and irradiation with light of corresponding wavelengths. We analysed its effects on the cytokine secretion (IL-1Β, TNFα, IL-6) of freshly isolated peripheral mononuclear cells from six patients with chronic plaque-stage psoriasis in comparison with PUVA. PUVA treatment resulted in a decreased production of all three cytokines, but most pronounced in the case of IL-6. PDT caused a similar change in the cytokine pattern, but its effectiveness was lower. In vivo fluorescence recordings were performed on psoriatic plaque lesions after topical application of the photosensitizer Photosan-3. Under irradiation, progressive photobleaching was noted with increasing radiation dosage. This is the first reported study of photochemical reactions using on-line fluorescence recordings during PDT of psoriatic lesions in vivo. Our results demonstrate the capacity of PDT to cause immunomodulatory effects similar to PUVA, thus indicating its potential application to the treatment of this common disease.

Association between interleukin-1 receptor antagonist (IL-1ra) gene polymorphism and early and late-onset psoriasis

Association between interleukin-1 receptor antagonist (IL-1ra) gene polymorphism and early and late-onset psoriasis

Narrowband UV-B phototherapy in the treatment of cutaneous graft versus host disease.

Graft versus host disease (GVHD) is an important problem following allogenic bone marrow transplantation (BMT). The beneficial effects of photochemotherapy with psoralens plus UVA irradiation (PUVA) have been described repeatedly; however, PUVA is limited by a wide range of unwanted effects. A novel improved form of UV-B phototherapy, narrowband UV-B, has been proven to be very effective in T-cell mediated dermatoses. Therefore, we investigated the effect of narrowband UV-B phototherapy (5 times per week) in 10 patients with cutaneous GVHD (grade 2-3) resistant to standard immunosuppressive drugs. It was tolerated well by all patients, and no side effects were observed. Skin lesions showed complete clearance in 7 out of 10 patients within 3 to 5 weeks. 3 patients showed significant improvement of GVHD. We suggest that narrowband UV-B phototherapy is a nonaggressive treatment that may benefit patients with cutaneous GVHD who already take high doses of immunosuppressive drugs.

PSORIASIFORM ARCHITECTURE OF MURINE EPIDERMIS OVERLYING HUMAN PSORIATIC DERMIS TRANSPLANTED ONTO SCID MICE

Preliminary observations in a xenogeneic SCID mouse transplantation model indicated that murine epidermis overgrows human dermis from psoriatic skin but not that form normal skin. To investigate the effect of peripheral blood mononuclear cells on the differentiation of murine keratinocytes, we transplanted involved and uninvolved full-thickness skin from patients with psoriasis onto SCID mice and followed this with repeated subcutaneous injections of cells suspended in patient serum. After 6 weeks grafts were analysed morphologically and immunohistochemically. The epidermis in grafts from clinically uninvolved skin appeared normal. The persistence of a psoriasiform epidermis was noted in all grafts from affected sites despite a lack of lymphocytic infiltration. Staining for human and mouse MHC class I antigens revealed the murine origin of keratinocytes forming the psoriasiform epidermis, while the human dermis was retained. Our observations indicate that the defect underlying the pathogenesis of psoriasis is most likely located in the dermal rather than the epidermal compartment. This xenogeneic transplantation model may be useful for future studies of the pathogenesis and treatment of psoriasis.

Leg ulcers in Klinefelter's syndrome – further evidence for an involvement of plasminogen activator inhibitor‐1

An abnormality in platelet aggregability or fibrinolysis, namely elevated activity of plasminogen activator inhibitor‐1 (PAI‐1), has been recently documented in patients suffering from Klinefelters syndrome associated with leg ulceration without underlying venous insufficiency. To determine whether increased PAI‐1 activity is a general feature of Klinefelters syndrome, or more specifically associated with leg ulceration, we investigated PAI‐1 influencing parameters and PAI‐1 activity in two groups of patients: (i) Klinefelter patients suffering from leg ulceration (n=7); and (ii) Klinefelter patients without leg ulceration (n=6). On analysing PAI‐1 influencing parameters such as age, body mass index, triglycerides, C‐reactive protein, testosterone, smoking behaviour, the presence of diabetes mellitus, and artierial hypertension, respectively, we found no statistically significant differences between the two groups. However, PAI‐1 activity in group 1 was highly significantly elevated compared with that in group two patients (P<0.005). We conclude that (i) PAI‐1 activity is not elevated in Klinefelters syndrome in general; (ii) elevation of PAI‐1 activity in patients suffering from Klinefelters syndrome does not appear to be secondary to PAI‐1 influencing parameters; and (iii) elevation of PAI‐1 activity may play a crucial role in the pathogenesis of leg ulceration in Klinefelters syndrome. Therefore, a therapy for leg ulceration in Klinefelters syndrome that aims to return the elevated PAI‐1 activity to normal should be explored.