Tryptophan degradation in autoimmune diseases Opitz, C A; Wick, W; Steinman, L ...
Cellular and molecular life sciences : CMLS,
10/2007, Letnik:
64, Številka:
19-20
Journal Article
Recenzirano
Recent evidence points to tryptophan (Trp) degradation as a potent immunosuppressive mechanism involved in the maintenance of immunological tolerance. Both Trp depletion and downstream Trp ...catabolites (TCs) appear to synergistically confer protection against excessive inflammation. In this review, we give an overview of the immunosuppressive properties of Trp degradation with special focus on TCs. Constitutive and inducible Trp degradation in different cell types and tissues of human and murine origin is summarized. We address the influence of Trp degradation on different aspects of autoimmune disorders such as multiple sclerosis. Possible therapeutic approaches for autoimmune disorders targeting Trp degradation are presented, and key issues relevant for the development of such therapeutic strategies are discussed.
There is a significant unmet need for serum biomarkers in relapsing-remitting multiple sclerosis (RRMS) that are predictive of therapeutic response to disease-modifying therapies. Following a recent ...Stanford study which reported that pretreatment levels of serum interleukin (IL)-17F could predict poor response to interferon-β (IFNβ) therapy, we sought to validate the finding using samples from a large clinical trial.
The validation cohort included 54 good responders (GR) and 64 poor responders (PR) selected from 762 subjects with RRMS from the IM IFNβ-1a dose comparison study (Avonex study C94-805). Subjects were classified as GR and PR based on the number of relapses, Expanded Disability Status Scale score, and new and enlarging T2 lesions on MRI. Serum samples were assayed for IL-17F using a multiplexed Luminex assay and for IL-17F/F using an ELISA. Replicate aliquots from the Stanford study were also assayed to assure reproducibility of methods.
Median pretreatment and post-treatment serum IL-17F levels were not statistically significantly different between GR and PR, and serum IL-7/IL-17F ratios were also not predictive of response status. Replicate aliquots from the Stanford study showed good correlation to their original cohort (r = 0.77).
We were unable to validate the finding that serum IL-17F is a predictor of PR in a large independent cohort of subjects with RRMS. Differences in patient populations and methodology might explain the failure to validate the results from the Stanford study.
Multigenic programs controlling susceptibility to apoptosis in response to ionizing radiation have not yet been defined. Here, using DNA microarrays, we show gene expression patterns in an ...apoptosis-sensitive and apoptosis-resistant murine B cell lymphoma model system both before and after irradiation. From the 11,000 genes interrogated by the arrays, two major patterns emerged. First, before radiation exposure the radioresistant LYar cells expressed significantly greater levels of message for several genes involved in regulating intracellular redox potential. Compared with LYas cells, LYar cells express 20- to 50-fold more mRNA for the tetraspanin CD53 and for fructose-1,6-bisphosphatase. Expression of both of these genes can lead to the increase of total cellular glutathione, which is the principle intracellular antioxidant and has been shown to inhibit many forms of apoptosis. A second pattern emerged after radiation, when the apoptosis-sensitive LYas cells induced rapid expression of a unique cluster of genes characterized by their involvement in mitochondrial electron transport. Some of these genes have been previously recognized as proapoptotic; however others, such as uncoupling protein 2, were not previously known to be apoptotic regulatory proteins. From these observations we propose that a multigenic program for sensitivity to apoptosis involves induction of transcripts for genes participating in mitochondrial uncoupling and loss of membrane potential. This program triggers mitochondrial release of apoptogenic factors and induces the "caspase cascade." Conversely, cells resistant to apoptosis down-regulate these biochemical pathways, while activating pathways for establishment and maintenance of high intracellular redox potential by means of elevated glutathione.
Currently available medicines approved for use in Europe and North America reduce the relapse rate in relapsing/remitting multiple sclerosis by about 30%. These medications may be no more efficacious ...than intermittent use of corticosteroids at the time of relapse. New directions for therapy of multiple sclerosis include blockade of α4 integrin, the use of altered peptide ligands, inhibition of Th1 cytokines, and DNA vaccination.
Experimental autoimmune encephalomyelitis (EAE) has served as a prototypic model of T cell-mediated, organ-specific autoimmune disease, and as a useful model for the human disease, multiple sclerosis ...(MS). Frei et al. demonstrate that in two strains of mice with a double knockout, where both TNF- alpha and LT- alpha are inactivated, that EAE may develop. The disease in these double knockout mice progresses in an apparently typical fashion, concordant with what is observed in the usual inbred strains of mice where EAE is induced: there is clinical paralysis, and histopathology reveals intense perivascular and parenchymal infiltration with CD4+ T cells and demyelination. They conclude, and I agree, that the results are surprising, given the large body of information suggesting that TNF- alpha and LT- alpha are important in the pathogenesis of EAE and MS. However, before accepting their ultimate conclusion that, "these results indicate that TNF alpha and LT- alpha are not essential for the development of EAE," it is worthwhile to consider the limitations of the first-generation knockouts that have been employed in their study. Certain misconceptions have arisen concerning the interpretation of experiments with these contemporary knockouts. This is especially true when trying to understand the role of critical effector molecules like cytokines, in the development of complex phenotypes, like the paralysis and inflammation seen in EAE. Many of these cytokine molecules have diverse biological activities, and many of the functions of these molecules can be duplicated by other cytokines. Thus, in animals with disrupted or "knocked out" cytokine genes, one may expect many diverse changes in several physiological processes, and one might find that after all is done, that another gene and its product can replace the function of the gene that was disrupted.
: Homopolymers or peptides containing a high percentage of cationic amino acids have been shown to have a unique ability to cross the plasma membrane of cells, and consequently have been used to ...facilitate the uptake of a variety of biopolymers and small molecules. To investigate whether the polycationic character of these molecules, or some other structural feature, was the molecular basis for the effect, the ability of a variety of homopolymers to enter cells was assayed by confocal microscopy and flow cytometry. Polymers of l‐ or d‐arginine containing six or more amino acids entered cells far more effectively than polymers of equal length composed of lysine, ornithine and histidine. Peptides of fewer than six amino acids were ineffective. The length of the arginine side‐chain could be varied without significant loss of activity. These data combined with the inability of polymers of citrulline to enter cells demonstrated that the guanidine headgroup of arginine was the critical structural component responsible for the biological activity. Cellular uptake could be inhibited by pre‐incubation of the cells with sodium azide, but not by low temperature (3 °C), indicating that the process was energy dependent, but did not involve endocytosis.
Spinal cord injury results in a massive loss of neurons, and thus of function. We recently reported that passive transfer of autoimmune T cells directed against myelin-associated antigens provides ...acutely damaged spinal cords with effective neuroprotection. The therapeutic time window for the passive transfer of T cells was found to be at least 1 week. Here we show that posttraumatic T cell-based active vaccination is also neuroprotective. Immunization with myelin-associated antigens such as myelin basic protein (MBP) significantly promoted recovery after spinal cord contusion injury in the rat model. To reduce the risk of autoimmune disease while retaining the benefit of the immunization, we vaccinated the rats immediately after severe incomplete spinal cord injury with MBP-derived altered peptide ligands. Immunization with these peptides resulted in significant protection from neuronal loss and thus in a reduced extent of paralysis, assessed by an open-field behavioral test. Retrograde labeling of the rubrospinal tracts and magnetic resonance imaging supported the behavioral results. Further optimization of nonpathogenic myelin-derived peptides can be expected to lead the way to the development of an effective therapeutic vaccination protocol as a strategy for the prevention of total paralysis after incomplete spinal cord injury.
Objective: To investigate in a military setting the potential role of intrinsic biomechanical and anthropometric risk factors for, and the incidence of, exertional medial tibial pain (EMTP). Methods: ...A prospective clinical outcome study in a cohort of 122 men and 36 women at the Australian Defence Force Academy. Each cadet underwent measurements of seven intrinsic variables: hip range of motion, leg length discrepancy, lean calf girth, maximum ankle dorsiflexion range, foot type, rear foot alignment, and tibial alignment. Test–retest reliability was undertaken on each variable. A physician recorded any cadet presenting with diagnostic criteria of EMTP. Records were analysed at 12 months for EMTP presentation and for military fitness test results. Results: 23 cadets (12 men, 11 women) met the criteria for EMTP after 12 months, with a cross gender (F/M) odds ratio of 3.1. In men, both internal and external range of hip motion was greater in those with EMTP: left internal (12°, p = 0.000), right internal (8°, p = 0.014), left external (8°, p = 0.042), right external (9°, p = 0.026). Lean calf girth was lower by 4.2% for the right leg (p = 0.040) but by only 2.9% for the left leg (p = 0.141). No intrinsic risk factor was associated with EMTP in women. EMTP was the major cause for non-completion of the run component of the ADFA fitness test in both men and women. Conclusions: Greater internal and external hip range of motion and lower lean calf girth were associated with EMTP in male military cadets. Women had high rates of injury, although no intrinsic factor was identified. Reasons for this sex difference need to be identified.
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