Psoriasis is one of the common skin diseases that individuals infected with the AIDS virus develop, although Kaposi's sarcoma (KS) remains as the hallmark for the cutaneous recognition and diagnosis of AIDS in young patients. The basis for this proposal is centered around our novel observation, that a specific type of skin-related macrophage called the dermal dendrocyte, is dramatically increased in AIDS patients with psoriasis and KS, as well as in another AIDS related skin disease, granuloma annulare (GA). While prior to the AIDS epidemic there was no apparent link between psoriasis, KS and GA, their relatively selective increase in AIDS patients can be understood by our observation that in both AIDS and non-AIDS patients, they all share a common cellular denominator, which is the dermal dendrocyte. This discovery strongly suggests a key pathophysiological role for the dermal dendrocyte, and in this proposal we will evaluate the role of the dermal dendrocyte in the context of HIV infection, as well as in idiopathic, or non-AIDS-related, psoriasis patients. The thrust of this proposal is to determine how dermal dendrocytes in skin can be targeted for activation by HIV, and once activated, how this becomes translated into producing a disordered cutaneous cytokine network (involving interleukin- 1, IL- 1, granulocyte- monocyte colony stimulating factor, GM-CSF, tumor necrosis factor, TNF-alpha, and basic fibroblast growth factor, bFGF) which is ultimately responsible for the histological features including angiogenesis, epidermal keratinocyte hyperproliferation, and T cell infiltration. This study will bring into clear focus the cascade of molecular events that we currently postulate to be of major importance in AIDS-related psoriasis, which is: HIV -> T Cell -> lymphokines -> dermal dendrocyte -> IL-1, GM-CSF, TNF-alpha, bFGF -> psoriasis. Our experimental approach includes: identification of dermal dendrocytes in tissue sections with correlation to disease activity; isolation and characterization of dermal dendrocytes in vitro; examination of how dermal dendrocytes influence other indigenous cell types of the skin in both in-vitro and in-vivo experiments; characterization of the interaction between HIV and dermal dendrocytes. Techniques used in these experiments include: cell culture; differential centrifugation; immunohistochemical staining, in-vitro macrophage and lymphocyte functional studies; bioassays and Northern blot analysis animal studies and various molecular biological studies of the HIV virus/dermal dendrocyte interaction. We will examine the role of activated dermal dendrocytes in producing psoriasiform changes in rabbit skin. These model systems, together with descriptive in-vitro results, will substantially advance our understanding of the complex immunoregulatory dysfunction characteristic of AIDS-related skin diseases, such as psoriasis. Such new knowledge will lead to therapeutic strategies targeted at HIV activated dermal dendrocytes, and the consequent disordered cytokine network for the treatment of KS and psoriasis in AIDS patients.
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