IntroductionMultipotent human mesenchymal stromal cells (MSCs) are plasticadherent cells with triangular and fibroblastoid morphologic features, which have the capacity to differentiate into osteoblasts, adipocytes, and chondrocytes. Furthermore, they express the cell-surface markers CD73, CD90, and CD105, while being negative for CD34, CD45, and human leukocyte antigen (HLA-DR). 1 Various tissues including bone marrow, fat, umbilical cord blood, or fetal tissues have been used as sources for MSCs. 2 Not only are MSCs immunoprivileged because they are poorly lysed by T cells, but they also have strong immunosuppressive effects. [3][4][5][6] Therefore, MSCs are of clinical interest for both regenerative medicine and immune suppression. MSCs have been used successfully for treatment of graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation. 7 In addition, data from mouse models for rheumatoid arthritis or multiple sclerosis suggest that MSCs may be effective in the treatment of autoimmune diseases. 8 In vitro studies have analyzed the immunomodulatory effects of MSCs in detail and showed that MSCs inhibit the proliferation of T cells independent of the T-cell stimulus (ie, the suppression was observed when T cells were activated by alloantigens, mitogens, or through T-cell receptor engagement by anti-CD3 in combination with anti-CD28 antibodies). [4][5][6] Moreover, the inhibition is MHC independent. 9,10 MSCs do not only inhibit T-cell proliferation directly, but also impair dendritic cell function (ie, MSCs interfere with dentritic cell [DC] differentiation, maturation, and activation), which is shown by compromised antigen presentation and altered cytokine release. [11][12][13][14] MSCs also suppress the proliferation of NK cells and modulate the functions of B cells. 2 Most studies agree in that no cell-cell contact is required for the MSC-mediated immunosuppressive effects. 15 Instead, soluble molecules are thought to mediate this inhibition. Possible candidate molecules include transforming growth factor-␤ (TGF␤), hepatocyte growth factor, 5 indoleamine-2,3-dioxygenase (IDO), 16 prostaglandin E2 (PGE2), 11,17,18 insulin-like growth factorbinding proteins, 19 heme oxygenase-1 (HO), 20 and HLA-G5. 21 Moreover, the mechanism of the suppressive effects may be species dependent, as some molecules were described to be involved in suppressive effects of mouse MSCs such as nitric oxide (NO). 22 Another novel candidate molecule recently described to be involved in suppressive effects of mouse MSCs is the MSC-derived CC chemokine ligand CCL2; the proteolytically processed form of CCL2 modulates immunoglobulin production by plasma cells and is involved in the beneficial effects of MSCs in experimental autoimmune encephalomyelitis. 23,24 However, blocking any single one of these molecules did not completely abrogate the immuno suppressive functions of MSCs, indicating that several signaling pathways are involved and some important mediators may have not been identified yet. Several a...

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Objective:To compare disease progression between different onset forms of Metachromatic Leukodystrophy (MLD) and to investigate the influence of the type of first symptoms on the natural course and dynamic of disease progression.Methods:Clinical, genetic and biochemical parameters were analyzed within a nationwide study of patients with late-infantile (LI, onset ≤ 2.5 years), early-juvenile (EJ, onset 2.6 - < 6 years), late-juvenile (LJ, onset 6 – < 16 years), and adult (onset ≥ 16 years) forms of MLD. First symptoms were categorized as motor symptoms only, cognitive symptoms only, or both.. Standardized clinical endpoints included loss of motor and language functions, as well as dysphagia/tube feeding.Results:97 Patients with MLD were enrolled. Patients with LI (n=35) and EJ (n=18) MLD exhibited similarly rapid disease progression, all starting with motor symptoms (with or without additional cognitive symptoms). In LJ (n=38) and adult-onset (n=6) patients, the course of the disease was as rapid as in the early-onset forms, when motor symptoms were present at disease onset, while patients with only cognitive symptoms at disease onset exhibited significantly milder disease progression, independent of their age at onset. A certain genotype-phenotype correlation was observed.Conclusions:In addition to age at onset, the type of first symptoms predicts the rate of disease progression in MLD. These findings are important for counselling and therapy.Classification of Evidence:This study provides Class II evidence that in patients with MLD, age at onset and the type of first symptoms predict the rate of disease progression.