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1.
Int Immunopharmacol ; 9(5): 599-608, 2009 May.
Article in English | MEDLINE | ID: mdl-19539557

ABSTRACT

CD4(+)CD25(+) Treg and IL-10(+) Tr1 cells play a major role in controlling autoimmunity by suppressing self-reactive T cells. Dysfunction of Tregs appears to be a critical factor in the pathogenesis of autoimmune diseases. Multiple sclerosis (MS) is an inflammatory demyelinating disorder of CNS, where CD4(+) T cells result in nervous tissue damage. The aim of this study was to investigate the protective role of Treg and Tr1 cells in a mimic model of human MS in Cynomolgus monkeys. This study indicated the suppressive capacity of Tregs from MS monkeys was impaired compared with naive controls. The population of CD4(+)CD25(+) Tregs was decreased in acute stage of MS. However, they showed a restored function and percentage in remitting monkeys. In stable phase, CD4(+)CD25(+) Tregs differentially expressed elevated level of CD62P cell adhesion molecule which contributes to the mechanism by which Treg cells inhibit CD4(+) T cell responses. On the other hand, the percentage of CD4(+)IL-10(+) Tr1 and suppressive function of Tr1 cells were found reduced in MS monkeys. IL-10 secretion was diminished almost 9-fold in active MS, and recovered in active MS. This deficit in IL-10 secretion was specific to CD3/CD46, but not to CD3/CD28 stimulation. The concentrations of IFN-gamma secreted by CD3/CD46-activated T cells were also not affected. These results demonstrate that Tregs are dysfunctional in Cynomolgus monkey with MS. Loss of regulatory function appears to be an important factor in the pathogenesis of MS. Hence, to develop new approaches for induction of Tregs in vivo may be beneficial for the clinical treatment in autoimmune diseases.


Subject(s)
Interleukin-10/metabolism , Multiple Sclerosis/immunology , T-Lymphocyte Subsets/metabolism , T-Lymphocytes, Regulatory/metabolism , Animals , CD4 Antigens , Cell Adhesion , Disease Models, Animal , Gene Expression Regulation , Humans , Interleukin-10/genetics , Interleukin-10/immunology , Interleukin-2 Receptor alpha Subunit , Macaca fascicularis , Multiple Sclerosis/metabolism , Multiple Sclerosis/pathology , P-Selectin/genetics , P-Selectin/immunology , P-Selectin/metabolism , Self Tolerance , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/pathology , T-Lymphocytes, Regulatory/immunology , T-Lymphocytes, Regulatory/pathology
2.
Biochem Biophys Res Commun ; 369(2): 641-7, 2008 May 02.
Article in English | MEDLINE | ID: mdl-18312851

ABSTRACT

Neuron differentiation is a complex process involving various cell-cell interactions, and multiple signaling pathways. We showed previously that CD40 is expressed and functional on mouse and human neurons. In neurons, ligation of CD40 protects against serum withdrawal-induced injury and plays a role in survival and differentiation. CD40 deficient mice display neuron dysfunction, aberrant neuron morphologic changes, and associated gross brain abnormalities. Previous studies by Tone and colleagues suggested that five isoforms of CD40 exist with two predominant isoforms expressed in humans: signal-transducible CD40 type I and a C-terminal truncated, non-signal-transducible CD40 type II. We hypothesized that differential expression of CD40 isoform type I and type II in neurons may modulate neuron differentiation. Results show that adult wild-type, and CD40(-/-) deficient mice predominantly express CD40 type I and II isoforms. Whereas adult wild-type mice express mostly CD40 type I in cerebral tissues at relatively high levels, in age and gender-matched CD40(-/-) mice CD40 type I expression was almost completely absent; suggesting a predominance of the non-signal-transducible CD40 type II isoform. Younger, 1 day old wild-type mice displayed less CD40 type I, and more CD40 type II, as well as, greater expression of soluble CD40 (CD40L/CD40 signal inhibitor), compared with 1 month old mice. Neuron-like N2a cells express CD40 type I and type II isoforms while in an undifferentiated state, however once induced to differentiate, CD40 type I predominates. Further, differentiated N2a cells treated with CD40 ligand express high levels of neuron specific nuclear protein (NeuN); an effect reduced by anti-CD40 type I siRNA, but not by control (non-targeting) siRNA. Altogether these data suggest that CD40 isoforms may act in a temporal fashion to modulate neuron differentiation during brain development. Thus, modulation of neuronal CD40 isoforms and CD40 signaling may represent important therapeutic modalities for neurodegenerative and neurodevelopmental disorders, as well as, for enhancement of neurogenesis.


Subject(s)
CD40 Antigens/metabolism , Neurons/cytology , Neurons/metabolism , Animals , CD40 Antigens/chemistry , Cell Differentiation/physiology , Cell Line , Mice , Mice, Knockout , Protein Isoforms/chemistry , Protein Isoforms/metabolism
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