Novel responses of human skin to intradermal recombinant granulocyte/macrophage-colony-stimulating factor: Langerhans cell recruitment, keratinocyte growth, and enhanced wound healing.

Abstract

StlmllrlaryRecombinant granulocyte/macrophage-colony-stimulating factor (rGM-CSF), prepared from Chinese hamster ovary (CHO) cells and Escherichia coli, was administered to 35 patients with the borderline and polar lepromatous forms of leprosy by the intradermal and subcutaneous routes at doses of 7.5-45.0/zg/d for 10 d. With each of these doses and routes, increases in the number of circulating eosinophils were noted. After the intradermal injection, the local skin sites demonstrated zones of roughening and micronod~arity that appeared within 2 A. AS h and persisted for more than 6 d. Reinjection of sites led to enhanced areas of epidermal reaction. GM-CSF prepared from CHO cells was a more potent inducer of this effect. GM-CSF given by the subcutaneous route, at higher doses, failed to initiate these changes. At the microscopic level, the epidermis became thickened (+ 75 %) with increased numbers and layers of enlarged keratinocyteg These contained increased numbers of ribosomes and prominent nucleoli, and were imbedded in a looser meshwork of the zona Pellucida. The modified keratinocytes remained MHC class II antigen negative throughout the course of the response. A major change in the dermis was the progressive accumulation of CDI+, Birbeck granule-positive cells. These Langerhans were recognizable at 48 h after intradermal injection and reached maximum numbers by 4 d. During this period the number of epidermal Langerhans cells remained relatively constant. No increment in dermal Langerhans cells occurred when GLM-CSF was injected by the subcutaneous route. No appreciable increase in the numbers of T cells and monocytes was noted, and granulocytes and eosinophils were largely present within the dermal microvasculature. 4-mm punch biopsies taken from injected sites and adjacent controls were compared in terms of the rapidity of wound healing. 22 of 26 sites demonstrated more rapid filling and hemostasis, whereas four were equivalent to controls. We conclude that rGM-CSF, when introduced into the skin, leads to enhanced keratinocyte growth, the selective recruitment of Langerhans cells into the dermis, and enhanced wound healing of the prepared site. There was no evidence of an enhanced ceU-mediated response to Mycobacterium leprae, and bacillary numbers remained unchanged.

The organotypic culture of HPV-transformed keratinocytes: an effective in vitro model for the development of new immunotherapeutic approaches for mucosal (pre)neoplastic lesions

“…We and other workers have observed that HPV + keratinocytes cell lines produce less GM-CSF than normal keratinocytes [29]. Since GM-CSF is an essential factor not only for the maturation and differentiation of DC but also for their motility [30], we tested the capacity of this cytokine to influence the ability of DC to colonize an in vitro formed (pre)neoplastic epithelium. Under basal conditions, the level of DC infiltration in cultures of normal keratinocytes was higher than that of HPV + cell lines cultures.…”

Arsenic Enhancement of Skin Neoplasia by Chronic Stimulation of Growth Factors

“…53 Direct intradermal injection of GM-CSF into human skin causes keratinocyte enlargement and thickening of the epidermis. 54 Recent studies have shown increased GM-CSF mRNA expression in lesional 55 and lesion-free 56 psoriatic skin as well as skin from patients with atopic dermatitis. 57 A role for GM-CSF in dermal carcinogenesis has also been postulated based on evidence that mice show dose-and timedependent increases in GM-CSF in the skin after topical treatment with tumor-promoting agents.…”

The Roles of Growth Factors in Keratinocyte Migration

“…[1][2][3] Identifying and determining the exact functions of the numerous growth factors and molecules that regulate or modulate growth factor-induced signaling in wounds, particularly those which contribute to the re-epithelialization The rise in metabolic diseases, such as type-2 diabetes, has led to a similar increase in comorbidities such as chronic leg and foot ulcers, which together affect more than 2.5 million Americans. 5 …”