In situ depletion of CD4+ T cells in human skin by Zanolimumab.

CD4(+) T cells, in activated or malignant form, are involved in a number of diseases including inflammatory skin diseases such as psoriasis, and T cell lymphomas such as the majority of cutaneous T cell lymphomas (CTCL). Targeting CD4 with an antibody that inhibits and/or eliminates disease-driving T cells in situ may therefore be a useful approach in the treatment of inflammatory and malignant skin diseases. Depletion of CD4(+) T cells in intact inflamed human skin tissue by Zanolimumab, a fully human therapeutic monoclonal antibody (IgG1, kappa) against CD4, was studied in a human psoriasis xenograft mouse model. Zanolimumab treatment was shown to induce a significant reduction in the numbers of inflammatory mononuclear cells in upper dermis. This reduction in inflammatory mononuclear cells in situ was primarily due to a significant reduction in the numbers of skin-infiltrating CD4(+), but not CD8(+) CD3(+) T cells. The capacity of Zanolimumab to deplete the CD4(+) T cells in the skin may be of importance in diseases where CD4(+) T cells play a central role. Indeed, in a phase II clinical trial Zanolimumab has shown a dose-dependent clinical response in patients with CTCL and the antibody is currently in a phase III clinical trial for CTCL, a disease for which there is no safe and effective treatment available today.

[Biotechnological pharmaceuticals and their potential use in inflammatory skin diseases]. / Bioteknologiske farmaka. Og deres mulige anvendelse ved inflammatoriske hudsygdomme.

In recent years, a more detailed understanding of the pathogenesis of several inflammatory skin diseases, and developments in biotechnology, have made it possible to design specific response modifiers, which hold a potential for greater effectiveness and fewer side effects than do the systemic therapies in current use in cases of severe psoriasis, contact dermatitis and atopic dermatitis. The immune system plays a pivotal role in the pathogenesis of inflammatory skin diseases, and this is where such biological response modifiers as monoclonal antibodies, recombinant cytokines, or fusion proteins may be effective. Several biological response modifiers have already shown positive results in phase II clinical trials; phase III trials are being carried out.

Long-wave UVA offers partial protection against UVB-induced immune suppression in human skin.

Ultraviolet-B (UVB, 280-320 nm) interferes with the generation of cell-mediated immunity to contact allergens applied epicutaneously on the irradiated site. To investigate whether pretreatment with UVA-1 (340-400 nm) protects against the UVB-induced immune suppression we sensitized human volunteers with diphenylcyclopropenone (DPCP) on normal buttock skin (n= 12), on UVB-irradiated buttock skin (n=21), on buttock skin pretreated with UVA-1 (n= 12), and on buttock skin pretreated with UVA-1 and thereafter irradiated with UVB (n=22). Sensitization on UVB-irradiated skin reduced the immunization rate to DPCP compared with sensitization on non-irradiated skin (p<0.01) and skin pretreated with UVA-1 (p<0.01). In contrast, the immunization rate in the group of volunteers sensitized on skin pretreated with UVA-1 before UVB irradiation was significantly higher than the immunization rate in the group of volunteers sensitized on UVB-irradiated skin alone (p<0.05). These results indicate that pretreatment with UVA-1 under certain conditions offers partial protection against the UVB-induced reduction in the immunization rates to epicutaneous allergens.

Contrasting effects of ultraviolet A1 and ultraviolet B exposure on the induction of tumour necrosis factor-alpha in human skin.

Ultraviolet B (UVB) irradiation of the skin causes immunosuppression which is relevant to the induction of skin cancer. The mechanism of this immunomodulation is unclear but various regulatory molecules have been implicated, including cis-urocanic acid (cis-UCA) and the cytokines tumour necrosis factor-alpha (TNF-alpha) and interleukin 10 (IL-10). Whether ultraviolet A (UVA) induces similar changes has not been investigated fully. We studied the effect of in vivo UVB and long-wave UVA (UVA1) exposure on the induction of TNF-alpha, IL-10 and cis-UCA in human skin. Volunteers were irradiated with three minimal erythema doses (MED) of UVB or UVA1. At different times after irradiation, suction blisters were raised from irradiated and from non-irradiated (control) skin. The TNF-alpha and IL-10 protein concentration, and the percentage of cis-UCA in the blister fluid, were then determined. UVB irradiation of human skin led to a rapid and significant increase in TNF-alpha concentration in suction-blister fluid, with maximal values 6 h after irradiation (n = 6, P < 0.05). In contrast, UVA1 irradiation led to a decrease in TNF-alpha concentration in the suction-blister fluid compared with non-irradiated skin, with the lowest values 6 h after irradiation (n = 6, P < 0.05). Both UVB and UVA1 exposure of the skin induced a slight increase in IL-10 concentration. However, the increase in IL-10 was only significant after UVB irradiation (UVB, n = 6, P < 0.05; UVA, n = 7, P < 0.1). As previously shown, both UVB and UVA1 result in the photo-isomerization of trans-UCA and an increased percentage of cis-UCA was found in the suction-blister fluid. Thus the results show differential effects of UVB and UVA1 irradiation on the induction of immunoregulatory molecules, which may help to explain the variation in immune responses after UVB and UVA1 exposure of human skin.