Targeting tumor necrosis factor alpha. New drugs used to modulate inflammatory diseases.

Since its discovery, the understanding of the roles for TNF-alpha in human biology and disease has grown. Receptors for TNF are found on virtually all cell types, and many physiologic processes seem to be altered by TNF-alpha. The understanding of how TNF-alpha is involved in the pathophysiology of diseases, such as inflammatory diseases, has allowed the development of new drugs that can interfere with excess TNF-alpha and thus has allowed novel therapies for rheumatoid arthritis and Crohn's disease. As the role of TNF-alpha in other diseases becomes better understood, such TNF-alpha-modulating drugs may find further applications. In the skin, TNF-alpha is prominent cytokine that seems to be important in allergic and irritant contact dermatitis and inflammatory skin conditions. Modulating TNF-alpha activity in the skin may provide therapeutic benefits for a variety of skin conditions (Table 4). Tumor necrosis factor-alpha levels are elevated in skin lesions of psoriasis. A few reports have already suggested that etanercept and infliximab may offer a therapeutic effect in patients with psoriasis. Clinical studies evaluating the true efficacy of these drugs in psoriasis are under way. Specifically, the authors and others are involved in a double-blind, placebo-controlled study to assess the efficacy of etanercept for psoriasis. Thalidomide has been used off-label with some success to treat a number of dermatologic diseases, including several inflammatory skin conditions. Etanercept and infliximab might perhaps prove efficacious for inflammatory skin conditions as well. Finally, it is possible that drugs targeting TNF-alpha may have yet-unrecognized serious side effects. Because TNF-alpha seems to be a central cytokine in UVR-induced apoptosis, the chronic use of TNF-alpha-altering drugs might increase the risk for skin cancers. Tumor necrosis factor-alpha also plays some role in cutaneous wound healing; the effect these drugs might have on this process is also unknown at this time. Certainly, much is already [table: see text] known about TNF-alpha and how it plays many central roles. This understanding has allowed the development of useful new drugs for intractable disease. As the understanding of TNF-alpha and other cytokine biology increases, so will the number of potential therapeutic agents.

CADASIL: the dermatologic diagnosis of a neurologic disease. Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy.

Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an increasingly recognized neurologic disease characterized by pathognomonic changes to the small vessels, particularly in the brain and skin. Although much has recently been written about this disease in the neuropathology literature, to our knowledge nothing has appeared in the dermatology literature. We wish to call attention to the unique role dermatologists and dermatopathologists can play in the diagnosis of this disease. We review the condition's clinical, histologic, and ultrastructural features.

Detection of human herpesvirus 8 DNA sequences in tissues and bodily fluids.

Human herpesvirus 8 (HHV-8) has been proposed as a sexually transmitted etiologic agent of Kaposi's sarcoma (KS). In this study, by use of a sensitive polymerase chain reaction assay, HHV-8 DNA was detected in the skin lesions (92%), normal skin (23%), peripheral blood mononuclear cells (PBMC) (46%), plasma (7%), saliva (37%), and semen (12%) but not stool samples from KS patients. The average number of HHV-8 copies per microgram of positive target DNA was 64, 000, 9000, 40, 33,000, and 300 for skin, PBMC, plasma, saliva, and semen samples, respectively. Only 1 non-KS donor sample, of saliva, was positive for HHV-8. Sequencing showed 5% divergence among HHV-8 strains. The data suggest that saliva may be more important than semen or stool in the sexual transmission of HHV-8. The relatively high prevalence of HHV-8 in PBMC raises the question as to why there is no evidence for bloodborne virus transmission.

Tumorigenesis of rat mammary epithelial cells by N-nitroso-N-methylurea in an in vitro system: characterization of the microtumors.

Chemical carcinogenesis is a lengthy process that involves the rather loosely defined stages of initiation, promotion, and progression. Several model systems of mammary carcinogenesis have been designed to elucidate the mechanisms of chemical carcinogenesis. Most of these systems have included animal models. While organ specific chemical carcinogenesis can be initiated in these systems, the subsequent stages of promotion and progression are difficult to study in detail. Investigations on in vitro carcinogenesis have shown transformation of mammalian cells in culture; the transformational event, however, is difficult to discern within the monolayer culture. We have recently reported the development of an in vitro carcinogenesis system that allows both the initiation as well as the progression of mammary cells in a collagen gel matrix culture system. The cells transformed by a chemical carcinogen develop into discernible microtumors within the three dimensions of a collagen gel culture. Isolation of these microtumors from the collagen gel and subsequent culture in monolayer has produced cells capable of colony formation in soft agar. The present study further characterizes these microtumors originated in vitro by analysis of cell growth kinetics versus parallel control cells. In addition, flow cytometric and cytogenetic studies have been performed to investigate the chromosomal stability of these cells. It was also observed that the microtumors, produced in vitro from mammary epithelial cells of an inbred strain of rats, show the ability to form tumors upon transplantation into the fat pad of syngeneic hosts.

In vitro carcinogenesis of mammary epithelial cells by N-nitroso-N-methylurea using a collagen gel matrix culture.

Carcinogenesis is a lengthy process which eventually culminates in the transformed phenotype, cancer. However, much remains to be defined about the process of transformation. In vivo models for the study of the carcinogenic process present limitations because it is not possible to detect the premalignant stages in the animals. An in vitro model, on the other hand, facilitates the study of the carcinogenic process because it enables one to dissect out the crucial events required for carcinogenesis to occur. As carcinogenesis is believed to be a multistep process; initiation, promotion, and progression, a multistep, in vitro system has been devised in our laboratory to mimic each of these stages. We have previously shown the formation of "microtumors" in collagen gels, induced by 7,12-dimethylbenz(a) anthracene. In the present study the direct acting water soluble, mammary carcinogen, N-nitroso-N-methylurea (NMU) was used for tumorigenesis of mammary epithelial cells in culture. Mammary epithelial cells from virgin Sprague-Dawley rats were propagated and exposed to single or multiple doses of NMU while growing as a monolayer in glass petri dishes (initiation). Initiation cells were then plated into a collagen gel matrix culture. Prolonged growth in the collagen gels afforded for the progression of the transformed cells into discernable microtumors in the three-dimensional matrix of the collagen. The morphology of these "tumors" was determined by histologic sections of the gels. Fewer, if any, such structures existed in the untreated gels.