ABSTRACT
Dysregulated angiogenesis is a hallmark of chronic inflammatory diseases, including psoriasis, a common skin disorder that affects approximately 2% of the population. Studying both human psoriasis in 2 complementary xenotransplantation models and psoriasis-like skin lesions in transgenic mice with epidermal expression of human TGF-ß1, we have demonstrated that antiangiogenic non-viral somatic gene therapy reduces the cutaneous microvasculature and alleviates chronic inflammatory skin disorders. Transient muscular expression of the recombinant disintegrin domain (RDD) of metargidin (also known as ADAM-15) by in vivo electroporation reduced cutaneous angiogenesis and vascularization in all 3 models. As demonstrated using red fluorescent protein-coupled RDD, the treatment resulted in muscular expression of the gene product and its deposition within the cutaneous hyperangiogenic connective tissue. High-resolution ultrasound revealed reduced cutaneous blood flow in vivo after electroporation with RDD but not with control plasmids. In addition, angiogenesis- and inflammation-related molecular markers, keratinocyte proliferation, epidermal thickness, and clinical disease scores were downregulated in all models. Thus, non-viral antiangiogenic gene therapy can alleviate psoriasis and may do so in other angiogenesis-related inflammatory skin disorders.
Subject(s)
Genetic Therapy , Neovascularization, Pathologic/therapy , Psoriasis/therapy , ADAM Proteins/genetics , Animals , Disease Models, Animal , Endothelial Cells/physiology , Female , Gene Expression , Humans , In Vitro Techniques , Male , Membrane Proteins/genetics , Mice , Mice, Transgenic , Neovascularization, Pathologic/genetics , Neovascularization, Pathologic/pathology , Neovascularization, Pathologic/physiopathology , Psoriasis/genetics , Psoriasis/pathology , Psoriasis/physiopathology , Recombinant Fusion Proteins/genetics , Transplantation, HeterologousSubject(s)
Agricultural Workers' Diseases/diagnosis , Ecthyma, Contagious/diagnosis , Adult , Agricultural Workers' Diseases/drug therapy , Animals , Anti-Bacterial Agents/therapeutic use , Dicloxacillin/therapeutic use , Ecthyma, Contagious/drug therapy , Female , Humans , Immunocompetence , Orf virus , SheepABSTRACT
Psoriasis is a chronic inflammatory disease of the skin characterized by epidermal hyperplasia, dermal angiogenesis, infiltration of activated T cells, and increased cytokine levels. One of these cytokines, IL-15, triggers inflammatory cell recruitment, angiogenesis, and production of other inflammatory cytokines, including IFN-gamma, TNF-alpha, and IL-17, which are all upregulated in psoriatic lesions. To investigate the role of IL-15 in psoriasis, we generated mAb's using human immunoglobulin-transgenic mice. One of the IL-15-specific antibodies we generated, 146B7, did not compete with IL-15 for binding to its receptor but potently interfered with the assembly of the IL-15 receptor alpha, beta, gamma complex. This antibody effectively blocked IL-15-induced T cell proliferation and monocyte TNF-alpha release in vitro. In a human psoriasis xenograft model, antibody 146B7 reduced the severity of psoriasis, as measured by epidermal thickness, grade of parakeratosis, and numbers of inflammatory cells and cycling keratinocytes. These results obtained with this IL-15-specific mAb support an important role for IL-15 in the pathogenesis of psoriasis.
Subject(s)
Interleukin-15/physiology , Psoriasis/immunology , Psoriasis/therapy , Animals , Antibodies, Monoclonal/immunology , Antibodies, Monoclonal/metabolism , Antigens, CD/immunology , Antigens, CD/metabolism , Disease Models, Animal , Epitope Mapping , Humans , Interleukin-15/immunology , Ki-67 Antigen/metabolism , Mice , Mice, SCID , Mice, Transgenic , Psoriasis/pathology , Receptors, Interleukin-15 , Receptors, Interleukin-2/immunology , Receptors, Interleukin-2/metabolism , Skin Transplantation , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , Transplantation, HeterologousABSTRACT
In recent years, a more detailed understanding of the pathogenesis of several inflammatory skin diseases, combined with the developments within biotechnology, has made it possible to design more selective response modifiers. Biological response modifiers hold the potential for greater effectiveness and fewer side-effects than the current systemic therapies now used for severe psoriasis, contact dermatitis and atopic dermatitis. In the pathogenesis of inflammatory skin diseases, the immune system plays a pivotal role, and this is where biological response modifiers such as monoclonal antibodies, recombinant cytokines, or fusion proteins may be effective. Several biological response modifiers have already shown positive results in phase II/III clinical trials in skin diseases, and many new biological response modifiers are in progress.
