thymosin and Multiple-Sclerosis

Multiple sclerosis (MS) afflicts more than 2.5 million individuals worldwide and this number is increasing over time. Within the past years, a great number of disease-modifying treatments have emerged; however, efficacious treatments and a cure for MS await discovery. Thymosins, soluble hormone-like peptides produced by the thymus gland, can mediate immune and non-immune physiological processes and have gained interest in recent years as therapeutics in inflammatory and autoimmune diseases.. Pubmed was searched with no time constraints for articles using a combination of the keywords "thymosin/s" or "thymus factor/s" AND "multiple sclerosis", mesh terms with no language restriction.. Here, we review the state-of-the-art on the effects of thymosins on MS and its experimental models. In particular, we describe what is known in this field on the roles of thymosin-α1 (Tα1) and -β4 (Tβ4) as potential anti-inflammatory as well as neuroprotective and remyelinating molecules and their mechanisms of action.. Based on the data that Tα1 and Tβ4 act as anti-inflammatory molecules and as inducers of myelin repair and neuronal protection, respectively, a possible therapeutic application in MS for Tα1 and Tβ4 alone or combined with other approved drugs may be envisaged. This approach is reasonable in light of the current clinical usage of Tα1 and data demonstrating the safety, tolerability and efficacy of Tβ4 in clinical practice.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Disease Models, Animal; Encephalomyelitis, Autoimmune, Experimental; Humans; Multiple Sclerosis; Neuroprotective Agents; Oligodendrocyte Precursor Cells; Thymosin; Translational Research, Biomedical; Treatment Outcome

Neurorestorative therapy targets multiple types of parenchymal cells in the intact tissue of injured brain tissue to increase neurogenesis, angiogenesis, oligodendrogenesis, and axonal remodeling during recovery from neurological injury. In our laboratory, we tested thymosin β4 (Tβ4) as a neurorestorative agent to treat models of neurological injury. This review discusses our results demonstrating that Tβ4 improves neurological functional outcome in a rat model of embolic stroke, a mouse model of multiple sclerosis, and a rat model of traumatic brain injury. Tβ4 is a pleiotropic peptide exhibiting many actions in several different types of tissues. One mechanism associated with improvement of neurological improvement from Tβ4 treatment is oligodendrogenesis involving the differentiation of oligodendrocyte progenitor cells to mature myelin-secreting oligodendrocytes. Moreover, our preclinical data provide a basis for movement of Tβ4 into clinical trials for treatment of these devastating neurological diseases and injuries.

Topics: Animals; Brain Injuries; Mice; Multiple Sclerosis; Rats; Stroke; Thymosin

Multiple sclerosis is a disease of the central nervous system characterized by recurrent inflammatory demyelinating lesions in the early disease stage. Lesion formation and mechanisms leading to lesion remyelination are not fully understood. Matrix Assisted Laser Desorption Ionisation Mass Spectrometry imaging (MALDI-IMS) is a technology which analyses proteins and peptides in tissue, preserves their spatial localization, and generates molecular maps within the tissue section. In a pilot study we employed MALDI imaging mass spectrometry to profile and identify peptides and proteins expressed in normal-appearing white matter, grey matter and multiple sclerosis brain lesions with different extents of remyelination. The unsupervised clustering analysis of the mass spectra generated images which reflected the tissue section morphology in luxol fast blue stain and in myelin basic protein immunohistochemistry. Lesions with low remyelination extent were defined by compounds with molecular weight smaller than 5300Da, while more completely remyelinated lesions showed compounds with molecular weights greater than 15,200Da. An in-depth analysis of the mass spectra enabled the detection of cortical lesions which were not seen by routine luxol fast blue histology. An ion mass, mainly distributed at the rim of multiple sclerosis lesions, was identified by liquid chromatography and tandem mass spectrometry as thymosin beta-4, a protein known to be involved in cell migration and in restorative processes. The ion mass of thymosin beta-4 was profiled by MALDI imaging mass spectrometry in brain slides of 12 multiple sclerosis patients and validated by immunohistochemical analysis. In summary, our results demonstrate the ability of the MALDI-IMS technology to map proteins within the brain parenchyma and multiple sclerosis lesions and to identify potential markers involved in multiple sclerosis pathogenesis and/or remyelination.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers; Brain; Female; Humans; Male; Middle Aged; Multiple Sclerosis; Nerve Fibers, Myelinated; Pilot Projects; Proteins; Proteomics; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Thymosin

Chromosome 7q21-22 and, in particular, the region surrounding D7S554 emerged from the recent American genome screen in multiple sclerosis (MS) as the most promising region genome-wide for harboring a disease susceptibility gene. We tested association between D7S554 and MS in 217 Sardinian trio MS families by the transmission disequilibrium test (TDT), and in a Northern Irish case-control study comprising 542 individuals. In both populations, we found evidence for significant allelic association (P(c)=0.04 and P(c)=0.0002, respectively). In a second stage, we analysed five microsatellite markers in a 4 megabase interval on chromosome 7q21-22 in the same set of Sardinian families. Parental transmission of a single allele of one of these markers, i.e. D7S3126, was significantly distorted (P(c)=0.008). D7S554 and D7S3126 are located at distances of, respectively, 40 and 81 kb 5' from the startcodon of the protachykinin-1 gene (TAC1), and occur in strong linkage disequilibrium (P<10(-7)). Our study indicates that the previous finding of linkage with D7S554 refers possibly to the presence of an MS susceptibility effect in vicinity to TAC1. In addition, a second independent association was uncovered between a microsatellite polymorphism in the plasminogen activator inhibitor-1 gene, i.e. D7S477, and MS. Overall, the analysis presented here may contribute to the increasingly refined genomic map of MS and underscores the requirement for a further high-resolution screening of chromosome 7q21-22.

Topics: Adult; Case-Control Studies; Chromosomes, Human, Pair 7; Family Health; Female; Gene Deletion; Genetic Predisposition to Disease; HLA-DR Antigens; HLA-DRB1 Chains; Humans; Ireland; Italy; Linkage Disequilibrium; Male; Microsatellite Repeats; Multiple Sclerosis; Plasminogen Activator Inhibitor 1; Polymorphism, Genetic; Protein Precursors; Substance P; Tachykinins; Thymosin; Ubiquitins

Monocytes from patients with multiple sclerosis (MS) express decreased numbers of class II major histocompatibility complex (MHC) antigens in peripheral blood and are poor stimulators in the autologous mixed lymphocyte reaction (autoMLR). We assessed the effect of prothymosin-alpha (ProT alpha) on the expression of MHC class II antigens by monocytes. Immediately after isolation, monocytes were analyzed for MHC class II antigen expression using a radiolabelled monoclonal antibody specific for a monomorphic determinant on HLA-DR antigens. After incubation with ProT alpha we observed significant increases in HLA-DR antigens on MS monocytes (1.5- to 4-fold increase compared to freshly isolated monocytes). Kinetic analysis revealed that enhancement peaked after 2 days of incubation with ProT alpha. The increase in HLA-DR antigen on MS monocytes resulted in the restoration of the deficient autoMLR in MS patients. This is the first demonstration suggesting a link between HLA-DR antigen expression and cellular immune defects in MS. The significance of low autoMLR responses for T suppressor levels in MS patients is discussed.

Topics: Adult; Female; HLA-DR Antigens; Humans; Lymphocyte Culture Test, Mixed; Male; Monocytes; Multiple Sclerosis; Protein Precursors; T-Lymphocytes; Thymosin

We have recently demonstrated that peripheral blood monocytes from patients with multiple sclerosis (MS) have a defect in stimulating autologous and allogeneic T lymphocytes. This defect was found to correlate with disease activity. In this report we demonstrate that prothymosin alpha (ProT alpha), a rat thymus fraction 5 polypeptide, restores the MS monocyte stimulatory defect. The concentrations of ProT alpha which induced optimal enhancement of the mixed lymphocyte responses (MLR) were significantly higher when monocytes from patients with active disease were used as stimulators than when monocytes from patients with inactive disease were used. T4+ cells tested with autologous stimulatory monocytes harvested from an inactive stage of MS exhibited considerably higher proliferative responses than when stimulated with autologous monocytes obtained from an acute relapse. The decreased autologous proliferation of T4+ cells in MS patients was restored to normal levels after preincubation with ProT alpha in the environment of autologous monocytes. Our results demonstrate that ProT alpha is capable of fully restoring the deficient stimulatory function of MS monocytes and monocyte-associated functional defects of MS-derived T4+ cells.

Topics: Humans; Lymphocyte Culture Test, Mixed; Monocytes; Multiple Sclerosis; Protein Precursors; T-Lymphocytes; Thymosin

Experimental allergic encephalomyelitis (EAE) was induced in strain 13 guinea pigs by sensitization with 10 micrograms of myelin basic protein (BP) in complete Freund's adjuvant (CFA). These animals were treated with saline or with thymosin factor V in 3 different doses in 3 separate experiments. Thymosin had no suppressive effect on the incidence and severity of EAE.

Topics: Animals; Autoimmune Diseases; Encephalomyelitis, Autoimmune, Experimental; Freund's Adjuvant; Guinea Pigs; Humans; Mice; Multiple Sclerosis; Myelin Basic Protein; Thymosin

Nonspecific stimulation either with unfractionated thymus factor (TF) or fractions IV and VIII of TF was carried out in 13 patients with clinically definite multiple sclerosis (MS). Thymus hormones were given in a daily dose of 10 mg from 1 to 14 months. Three patients became non-tolerant to TF and were undergoing the treatment with TF IV or TF VIII. After immunostimulation 8 remained unchanged, 2 slowly improved (by one degree in Kurtzke's scale), 2 markedly worsened and 1 died. Five patients suffered 8 relapses, 3 showed slow progression and 2 developed either acute nephropyelitis or periodontitis. During this brief therapy, no convincing conclusion may be drawn regarding the effect upon the clinical course, although there is suggestion that thymus factor does not abolish the relapses in multiple sclerosis.

Topics: Adult; Female; gamma-Globulins; Humans; Male; Middle Aged; Multiple Sclerosis; Thymosin; Thymus Extracts; Thymus Hormones