Scientists at the Johns Hopkins University (MD, USA) have discovered how a chemical found in broccoli may help to prevent the severe blistering and skin breakage observed in patients with epidermolysis bullosa simplex (EBS). The chemical (sulforaphane) is present at high levels in a precursor form in broccoli and related vegetables, such as cauliflower and brussel sprouts.
EBS is a rare, potentially fatal, genetic disease that is typified by the dysfunction of intermediate filaments in basal keratinocytes of the epidermis. It is usually caused by mutations in one of two genes (keratin 5 [K5] or 14 [K14]).
Pierre Coulombe and colleagues (Johns Hopkins University School of Medicine, MD, USA) used topical sulforaphane to treat newborn mice that had a severe form of EBS. The team observed a marked improvement in the treated mice.
Coulombe explains that the two specific gene products (of K5 and K14) usually join together to form highly resilient fibers in a deeper layer of the skin to make the skin durable. A defect in either keratin causes the skin to become fragile as the two keratins cannot mesh.
“Humans have around 54 distinct keratins, many of which are similar in structure and function”, says Coulombe. “We figured we might be able to exploit this similarity and dial up a replacement by triggering the activation of a suitable signaling pathway in skin”. He had hoped that he could use sulforaphane to stimulate alternative keratin productin in order to replace the defective one.
Paul Talalay, coauthor of the study, adds “this is the first suggestion that we may be able to treat this terrible disease, and we didn’t need to invent a new drug; sulforaphane is naturally found in our diet.”
There is an arduous task ahead to adapt this chemical into a topical form that would be effective on human skin.
Coulombe is hopeful that this can be achieved eventually, “if we can clear these important hurdles, then sulforaphane can potentially be a tremendous therapeutic, with the added benefit of having anticancer properties”. He adds, “And when you consider that the only current option for EBS is wrapping gauze around trauma-prone areas to minimize breakage, and otherwise avoiding infection and making sure blisters heal properly, then even a mild success would be a significant benefit for these patients.”
Source: Kerns ML, Depianto D, Dinkova-Kostova AT, Talalay P, Coulombe PA. Reprogramming of keratin biosynthesis by sulforaphane restores skin integrity in epidermolysis bullosa simplex. Proc. Natl Acad. Sci. USA 104(36), 14460–14465 (2007).
Synthetic lipids may help treat skin diseases
Synthetic lipids, known as pseudoceramides, have been created by researchers and it is hoped that they can be utilized to treat skin diseases, such as atopic dermatitis, psoriasis and glucocorticoid-induced epidermal atrophy. The lipids are involved with skin cell growth and, potentially, may be used to treat diseases in which this process malfunctions and the skin cells grow abnormally.
The outermost skin layer, which serves as a physical barrier (the stratum corneum), contains ceramides. The primary function of ceramides is to control growth and differentiation in skin cells. Scientists have recently created a synthetic form of these ceramides and observed their effects on skin cells.
The series of ceramides were created by Jeung-Hoon Lee and colleagues (Chungnam National University, Daejeon, South Korea). The research group found that K6PC-4, -5 and -9 all markedly increased the amount of certain proteins (keratin 1 and involucrin) expressed in normal human epidermal keratinocytes cultured in vitro.
Protein levels (specifically of keratin 1) were also seen to increase in a reconstituted epidermis model with the addition of K6PC-4, -5 and -9.
It is hoped that these novel synthetic ceramide derivatives have the potential to treat skin diseases involving abnormal keratinocyte differentiation.
Source: Kwon YB, Kim CD, Youm JK et al. Novel synthetic ceramide derivatives increase intracellular calcium levels and promote epidermal keratinocyte differentiation. J. Lipid Res. 48(9), 1936–1943 (2007).
Cannabis substance may be useful for the treatment of allergic skin disease
The body’s natural defense to allergic contact dermatitis may be aided by a substance from the cannabis plant, a recent study shows.
Allergic contact dermatitis occurs when sensitive or allergic skin comes into contact with an allergen and has a reaction to it, resulting in a rash. It affects 5% of men and 11% of women in industrialized countries.
The recent study, published in Science, demonstrated that the endocannabinoid system is a major regulator of cutaneous contact hypersensitivity in mice. They also demonstrated that mice deficient in cannabinoid receptors showed an increased cutaneous inflammatory response to allergens.
The team administered tetrahydrocannabinol (THC) and other cannabinoids to the animals to see if they reduced the observed allergic response. The results demonstrated that THC significantly decreased the allergic reaction in comparison with untreated mice.
After a series of experiments they found that the mice skin cells produced a chemokine which is involved in the cutaneous response reaction. They also found that when the skin is exposed to an allergen and the endocannabinoid system is activated, the allergic response is reduced as the production of the chemokine is being modulated.
It is hoped that these results will help in the development of a therapeutic treatment for contact dermatitis based on activation of the endocannabinoid system.
Source: Karsak M, Gaffal E, Date R et al. Attenuation of allergic contact dermatitis through the endocannabinoid system. Science 316(5830), 1494–1497 (2007).
Manipulating melanin to treat skin pigment disorders
New research from the University of Cincinnati (OH, USA) has demonstrated that keratinocytes, and not just melanocytes, contribute to variations in skin pigmentation. The results could potentially aid in the development of new treatments for pigmentation disorders.
Raymond Boissy and his team discovered that keratinocytes may be able to control pigmentation in the skin in their 2-year, preclinical study.
Boissy believes that his findings could help in the development of treatments for pigment diseases, such as vitiligo and melasma. He explains, “we’ve isolated specific physiological properties that regulate the melanocytes’ functional abilities. This is an important discovery because many pigment diseases are the result of deregulation of the melanocyte.”
He adds, “now we have a new set of molecules to investigate that may help create uniform skin color – both for patients with pigment disorders or serious burn wounds as well as those seeking improved cosmetic skin appearance.”
This is the first study to identify a specific model for manipulating melanin production in the body by utilizing keratinocytes. It had previously been found that melanocytes deliver melanosomes to keratinocytes, which are then dispersed in those with dark skin. This dispersion throughout the cell results in a larger surface area being capable of absorbing more light than in lighter skin.
“This was the first clue that keratinocytes played a role in skin coloration outside of genetic factors regulating the melanocyte”, explains Boissy. “Further study showed there was no informational difference between the melanosomes in keratinocytes for dark and light skin responsible for sorting within the keratinocyte. The cells sorted themselves based on ethnic background, so we wanted to learn more about the factors that influence skin pigmentation.”
Boissy and his team used a combination of keratinocytes and melanocytes, from both dark and light skin to create a substitute for human skin. The cells were then grown in a mouse model for approximately 3 months.
“We found that by transplanting keratinocytes from light-skinned individuals to bioengineered skin substitutes produced a lightening effect”, Boissy comments. “The same effect resulted when keratinocytes from dark-skinned individuals were transplanted into the skin substitute, creating a darkening effect.”
When cells from a mixture of light and dark skin were used, an intermediate skin color was achieved.
The researchers believe that the discovery that ketarinocytes also influence the amount of pigment produced is important. Although Boissy believes that their influence is subtle, he believes it clearly demonstrates that it is not only the genetics of melanocytes that determines the coloration of the skin.
Source: Yoshida Y, Hachiya A, Sriwiriyanont P et al. Functional analysis of keratinocytes in skin color using a human skin substitute model composed of cells derived from different skin pigmentation types. FASEB J. 1(11), 2829–2839 (2007).
Blood chemicals associated with itching
There are increases in the levels of two blood chemicals when we scratch our skin report scientists from the Chinese University of Hong Kong (P.R. China). They are hopeful that this new information could lead to new treatments for childhood atopic dermatitis and the associated itching.
Atopic dermatitis affects up to 20% of children and although treatments are available that help alleviate the symptoms, very little is understood about what causes the accompanying pruritis.
The study authors monitored itching in 28 children with atopic dermatitis, while they slept, with the use of a DigiTrac monitor device on their dominant arm. The device monitored and recorded the amount that the children scratched from 10pm until 8am. The children had previously been assessed for diseases severity and quality of life using the Scoring Atopic Dermatitis (SCORAD) index and the Children’s Dermatology Life Quality Index (CDLQI), respectively.
It was found that the amount that the child scratched was linked with the amount of brain-derived neurotrophic factor (BDNF) and Substance P. This finding helps to sheds light on the cause of itching in patients with eczema.
Researcher Kam-lun Ellis Hon of the Hong Kong team reports, “as far as we are aware, this is the first report to demonstrate that BDNF and Substance P are significantly linked to disease activity, quality of life, as well as the levels of scratching as recorded by the wrist monitor.”
The study authors conclude, “the strong correlations with nocturnal wrist movements suggest that they [BDNF and Substance P] may be the pathogenic factors of the annoying symptoms of scratching.”
Source: Hon KL, Lam MC, Wong KY, Leung TF, Ng PC. Pathophysiology of nocturnal scratching in childhood atopic dermatitis: the role of brain-derived neurotrophic factor and Substance P. Br. J. Dermatol. (2007) (Epub ahead of print).
ImmuFact® IMP321 enters Phase I trial for metastatic melanoma
Immutep SA, a French-based biopharmaceutical company, has announced that its lead product ImmuFact® IMP321 has entered an open-label, single-arm, Phase I clinical trial in patients with advanced melanoma.
ImmuFact IMP321 is a highly potent T-cell immunostimulatory factor that can enhance T-cell responses. It is the soluble form of CD223, a natural lymphocyte receptor that binds to MHC class II molecules on antigen-presenting cells. This binding enhances cross-presentation of antigens to T-cells, resulting in strong and long-lasting antitumor or antiviral cytotoxic T cell responses when IMP321 is used alone or as an adjuvant coinjected with antigens.
This new trial involves melanoma patients who have received adoptive T-cell transfer after immunosuppression by chemotherapy. The patients will receive IMP321 as an adjuvant to a therapeutic cancer vaccine containing a peptide melanoma antigen (Melan-A/MART1). The main aim is to evaluate safety and efficacy of the combined treatment. This is the sixth clinical trial with ImmuFact IMP321 in the last 30 months and will be carried out in the Fondation du Centre Pluridisciplinaire d’Oncologie and the Ludwig Institute for Cancer Research (Lausanne, Switzerland).
“We are delighted to announce another cancer vaccine trial using our immunopotentiator agent IMP321”, said Frederic Triebel, Immutep’s scientific and medical director. “This new class of non-Toll-like receptor agonist may represent the extra boost that peptide antigens need for a strong and prolonged cytotoxic T-cell activity.”
Serge Leyvraz and Verena Voelter will lead the Lausanne researchers as two principal investigators of this study. “We are very pleased to start this trial in metastatic melanoma patients, which should provide information about the potency of IMP321 as an adjuvant for the induction of specific antitumor CD8 T-cell responses after lymphodepletion and adoptive T-cell transfer”, said Voelter. “The concept of transient immunosuppression combined with the stimulation of an antigen-specific antitumor response during the immune reconstitution period has been shown to be very promising in preclinical animal models as well as in first clinical trials run in melanoma patients in the USA.”
Previously, two randomized, single-blind, dose-escalating Phase I studies have been completed in 108 healthy individuals using IMP321 alone and in combination with two standard antigens to demonstrate IMP321’s safety and efficacy as an adjuvant in therapeutic vaccines. The product is currently being tested in four clinical trials in different cancers, including this new study.
Source: Immutep SA, France: www.immutep.com