Objective
A series of experiments on Iymphocytes with the newly recognized recept of the gamma/delta type will be perfomed in CNS tissue from multiple sclerosis (MS) subjects and on cells isolated from the blood and CSF. TCR gamma/delta cells have been identified in preliminary studies in chronic established MS lesions. They were present in close association with hsp-65 on reactive oligodendrocytes. These oligodendrocytes also showed strong immunoreactivity for markers suggesting their recent derivation. Thus, we present the hypothesis that TCR gamma/delta cells reacting to antigens expressed on reactive oligodendrocytes might play a role in the expansion and persistence of the MS lesion. These oligodendrocytes might be involved in remyelination and their damage might impede tissue repair. The protocol to be employed to test this hypothesis consists of three experimental strategies. For the first, polymerase chain reaction (PCR) analysis will examine expression and rearrangement of delta and gamma chains of TCR in MS lesions. Subsequently, PCR product will be subclone and sequence. These investigations should provide us with information whether any dominant pattern within the V-D-J junctional region can be detected in MS. Since this region (CDR3) of the T cell receptor is thought to be primarly involved in antigen recognition, these studies should provide us with data whether gamma/delta T Iymphocytes within MS lesion may arise as a response to a common antigen. For the second TCR gammaldelta Iymphocytes will be isolated from the blood and CSF of MS patients. These cells will also be studied with PCR for V to J rearrangements. PCR products will be clone and sequence. The sequences obtained from CNS will be compared with that obtained from blood and the CSF to find possible local specificity. In the third strategy, TCR gamma/delta cells isolated from MS patients will be expanded, cloned and studied functionally. In this specific aim, we shall ask whether TCR gamma/delta cells from MS patients demonstrated a unique antigen reactivity to myelin/oligodendrocyte antigens or to antigens expressed as a result of tissue injury, such as heat shock protein, and whether any antigen response is associated with specific usage of V and J segments of delta or gamma chains. A positive answer to this question would provide us with evidence of specific recognition and attraction of these cells into the CNS.
The implications of this proposal relate to a better understanding of the mechanisms affecting demyelination, remyelination and tissue repair in MS.
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Coordinator
50134 FIRENZE
Italy
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