Immunoregulatory T cells of CD4 + CD25 + phenotype suppress T cell function and protect rodents from organ-specific autoimmune disease. The human counterpart of this subset of T cells expresses high levels of CD25 and its role in human autoimmune disorders is currently under intense investigation. In multiple sclerosis (MS), a chronic inflammatory disease of the central nervous system (CNS), the activation of circulating self-reactive T cells with specificity for myelin components is considered to be an important disease initiating event. Here, we investigated whether MS is associated with an altered ability of CD4 + CD25 high regulatory T cells (T reg ) to confer suppression of myelin-specific immune responses. Whereas T reg frequencies were equally distributed in blood and cerebrospinal fluid of MS patients and did not differ compared to healthy controls, the suppressive potency of patient-derived CD4 + CD25 high T lymphocytes was impaired. Their inhibitory effect on antigen-specific T cell proliferation induced by human recombinant myelin oligodendrocyte protein as well as on immune responses elicited by polyclonal and allogeneic stimuli was significantly reduced compared to healthy individuals. The effect was persistent and not due to responder cell resistance or altered survival of T reg , suggesting that a defective immunoregulation of peripheral T cells mediated by CD4 + CD25 high T lymphocytes promotes CNS autoimmunity in MS.

The suppressive function of regulatory T cells (Treg) is impaired in multiple sclerosis (MS) patients. The mechanism underlying the Treg functional defect is unknown. Treg mature in the thymus and the majority of cells circulating in the periphery rapidly adopt a memory phenotype. Because our own previous findings suggest that the thymic output of T cells is impaired in MS, we hypothesized that an altered Treg generation may contribute to the suppressive deficiency. We therefore determined the role of Treg that enter the circulation as recent thymic emigrants (RTE) and, unlike their CD45RO+ memory counterparts, express CD31 as typical surface marker. We show that the numbers of CD31+-coexpressing CD4+CD25+CD45RA+CD45RO−FOXP3+ Treg (RTE-Treg) within peripheral blood decline with age and are significantly reduced in MS patients. The reduced de novo generation of RTE-Treg is compensated by higher proportions of memory Treg, resulting in a stable cell count of the total Treg population. Depletion of CD31+ cells from Treg diminishes the suppressive capacity of donor but not patient Treg and neutralizes the difference in inhibitory potencies between the two groups. Overall, there was a clear correlation between Treg-mediated suppression and the prevalence of RTE-Treg, indicating that CD31-expressing naive Treg contribute to the functional properties of the entire Treg population. Furthermore, patient-derived Treg, but not healthy Treg, exhibit a contracted TCR Vβ repertoire. These observations suggest that a shift in the homeostatic composition of Treg subsets related to a reduced thymic-dependent de novo generation of RTE-Treg with a compensatory expansion of memory Treg may contribute to the Treg defect associated with MS.

The term 'regenerative medicine' refers to a new and expanding field in biomedical research that focuses on the development of innovative therapies allowing the body to replace, restore and regenerate damaged or diseased cells, tissues and organs. It combines several technological approaches including the use of soluble molecules, biomaterials, tissue engineering, gene therapy, stem cell transplantation and the reprogramming of cell and tissue types. Because of its easy accessibility, skin is becoming an attractive model organ for regenerative medicine. Here, we review recent developments in regenerative medicine and their potential relevance for dermatology with a particular emphasis on biomaterials, tissue engineering, skin substitutes and stem cellbased therapies for skin reconstitution in patients suffering from chronic wounds and extensive burns.

CD44 proteins are cell surface receptors for hyaluronic acid (HA), a component of the extracellular matrix that has multiple effects on cell behavior. CD44 can be shed from the cell surface by proteolytic cleavage. The resulting soluble form can interfere with the interaction between HA and membrane-bound CD44. Soluble CD44 can abolish the cell proliferation-promoting effect of HA on melanoma cell lines, suggesting that a better understanding of the shedding process might identify ways of blocking tumor cell proliferation. ADAM10, ADAM17, and MMP14 have previously been implicated in the shedding of CD44 from various tumor cells. Using immunohistochemistry we demonstrate that ADAM10 and ADAM17 but not MMP14 are significantly expressed on melanoma cells in histological sections. In human melanoma cell lines expression of these proteases could be blocked by transfection with appropriate siRNAs. However, only blocking of ADAM10 expression led to decreased shedding of CD44. In parallel, cell proliferation was promoted. Confocal microscopy demonstrated that ADAM10 and CD44 colocalize on the cell surface. We conclude that ADAM10 is the predominant protease involved in the constitutive shedding of endogenous CD44 from melanoma cells, and that enhancement of ADAM10 activity could be an approach to decrease the proliferation of melanoma cells.

Hair root harbours a complex cell pool with an immense developmental potential. Several lineages, including skin, can be differentiated from the multipotent to pluripotent cells of outer root sheath (ORS) of hair follicle. Outer root sheath presents the most opulent non-invasively gained adult stem cell source known. For the purposes of cultivating melanocytes designated for graft-based treatments of depigmentation disorders, we have established an ex vivo/in vitro cultivation method by introducing several methodological improvements to the ORS explant method of Dieckmann. As a result, we gained a higher, purer yield of differentiated melanocytes in half the time (at least 10 6 of 95% pure cells in 4 weeks). This reliable cultivation procedure begins with the epilation of 60 hairs and yields high numbers of ORS melanocytes that could be used for grafting applications. The procedure not only utilises the developmental potential of hair root cell pool and favors differentiation into melanocytes, but also contributes to the general trend of minimal-to-non-invasive strategies for regenerative medicine.