Heat-shock proteins as drugs: potential applications in cancer, infections, and autoimmune and atopic diseases.

Heat-shock proteins (HSPs) serve as both a valuable target as well as a potent tool in the therapy of melanoma and human papillomavirus infections. HSPs have been found to associate with key pathogenic antigens and, under different circumstances, activate or suppress both innate and adaptive immunity via several mechanisms. The dominant mechanism of HSP is as a chaperonin to upregulate antigens on antigen-presenting cell surfaces. While no HSP-based therapies are currently FDA approved, several are currently in phase III clinical trials. This study reviews the current literature on therapeutic studies of HSP and the significant role these proteins are likely to play in future therapeutic approaches to neoplasms, infections, and inflammatory diseases of the skin.

Topical diphenylcyclopropenone as a measure of immune competence in HIV-seropositive subjects.

BACKGROUND: CD4 T cell counts are recognized as the standard method for monitoring HIV-seropositive patients and, along with viral load, are clinically important as indicators for initiating highly active antiretrovival therapy (HAART). Skin reaction scores following topical application of diphenylcyclopropenone (DPC) also demonstrate diagnostic utility as a functional measure of immune competence. METHODS: We used low sensitizing doses of DPC in 40 patients applied in a non-volatile, non-irritating topical delivery system to assess immune competence in 40 HIV-seropositive subjects with a range of CD4 T cell counts. Standardized patch test reading scores were used, with 2+ or greater scores (erythema and induration) indicative of a positive response. The patch test scores were then compared with CD4 counts. RESULTS: Application of DPC in concentrations of 0.4% and 0.2% successfully resulted in 90% sensitivity skin reaction scores in subjects with >300 CD4 T cells/microL, following a single 0.1 mL application to the inner aspect of the arm. Lower DPC concentrations of 0.1% and 0.05% were too low for initial sensitization reactions. Three subjects with CD4 counts between 150 and 300 cells/microL showed positive skin reactions indicating that this DPC test gives the clinician information on cellular immunity beyond the CD4 count. CONCLUSION: We conclude that a single topical application of DPC at concentrations between 0.2% and 0.4% can serve as a measure of immune competence in HIV-seropositive patients. As a functional measure of immunocompetence, this DPC test provides information beyond a CD4 count, which is particularly relevant to HIV-positive subjects with CD4 counts between 200 and 350 cells/microL.

Haptens as drugs: contact allergens are powerful topical immunomodulators.

For the past 40 years, dermatologists have safely used contact sensitizers such as dinitrochlorobenzene (DNCB), diphenylcyclopropenone (DPCP), and squaric acid dibutylester (SADBE) for the treatment of warts, alopecia areata, and even skin cancers. Most of these studies have utilized these powerful topical immunomodulators in acetone, a volatile solvent that precludes development of contact sensitizers as products. We have overcome these problems and stabilized these topical immunomodulators in a non-volatile, nonirritating GRAS (generally regarded as safe) vehicle. The current review article covers the traditional use of contact sensitizers for a variety of benign and malignant conditions and discusses possible mechanisms in relation to developments in modem molecular immunodermatology.

Resolution of odontogenic keratocysts of the jaw in basal cell nevus syndrome with GDC-0449.

BACKGROUND: Odontogenic keratocysts of the jaw are a central feature of basal cell nevus syndrome (BCNS) and arise from the basal cell layer of the surface epithelium. Although they are benign, they tend to be aggressive, with local invasion of bony structures, extensive growth, and potential for substantial disfigurement and speech dysfunction. Complete surgical resection is the current standard of care; however, the procedures are often technically challenging and are followed by high recurrence rates. OBSERVATIONS: We report the case of a 55-year-old man with a long-standing history of BCNS. Over a 25-year period, this patient had been treated for many basal cell carcinomas (BCCs). He also had multiple large odontogenic keratocysts in the mandible that had previously been treated using surgical, chemotherapeutic, and radiation treatment techniques. He had also undergone a right inguinal lymph node dissection after BCC metastasis was diagnosed within a lymph node. Owing to the recalcitrant nature of his condition and his history of BCC metastasis, the patient was started on a daily regimen of a new oral drug, GDC-0449, which inhibits the hedgehog signaling pathway, a key genetic contributor in the oncogenesis of BCCs. In addition to complete resolution of all his BCCs at 12-week follow-up, nearly complete resolution of 3 odontogenic keratocysts was documented by serial dental radiographs after 2 years of therapy. CONCLUSIONS: We report the nearly complete regression of multiple BCNS-associated odontogenic keratocysts following nonsurgical treatment with GDC-0449. This novel drug, useful for the treatment of BCC, also appears to be effective for treatment of odontogenic keratocysts.

The other end of the rainbow: infrared and skin.

Although infrared radiation (IRR) is ubiquitous in the terrestrial milieu, its effects on human skin have until now been largely ignored. Recent studies suggest an important role for infrared A (IRA) radiation (760-1440 nm) in dermal inflammation, photoaging, and photocarcinogenesis. In this issue, Calles et al. identify and analyze the IRA-induced transcriptome in human dermal fibroblasts. Their work paves the way for new research directions in IRA photobiology and raises important clinical questions regarding photoprotection and IRR-based dermatotherapy.

Role of extracellular adenosine triphosphate in human skin.

BACKGROUND: The nucleotide adenosine triphosphate (ATP) has long been known to drive and participate in countless intracellular processes. Extracellular ATP and its metabolite adenosine have also been shown to exert a variety of effects on nearly every cell type in human skin. Knowledge of the sources and effects of extracellular ATP in human skin may help shape new therapies for skin injury, inflammation, and numerous other cutaneous disorders. OBJECTIVE: The objective of this review is to introduce the reader to current knowledge regarding the sources and effects of extracellular ATP in human skin and to outline areas in which further research is necessary to clarify the nature and mechanism of these effects. CONCLUSION: Extracellular ATP seems to play a direct role in triggering skin inflammatory, regenerative, and fibrotic responses to mechanical injury, an indirect role in melanocyte proliferation and apoptosis, and a complex role in Langerhans cell-directed adaptive immunity.