Promising Outcomes of Original Grant:
In a previous study funded by The Michael J. Fox Foundation, we have provided compelling evidence that brain infiltration of peripheral immune cells (in particular, T lymphocytes) make a significant contribution to neurodegeneration in parkinsonism (Brochard et al., J. Clin. Invest., 2009). This raises the tantalizing possibility that preventing peripheral immune cells to enter the injured brain may provide protective benefits by decreasing inflammatory culprits. Because these cells migrate into the brain in the absence of major blood-brain barrier disruption, we believe that they are doing so through a tightly regulated mechanism that needs to be unraveled.
Objectives for Supplemental Investigation:
Since little is known about the expression and regulation of factors involved in brain extravasation of immune cells under injury conditions relevant to Parkinson disease, we propose to characterize such mechanism. Our study will be guided by two specific aims: (1) Analyze in the MPTP pre-clinical model of Parkinson disease changes in gene expression of factors known to be crucial for the passage of immune cells across the blood-brain barrier (e.g. adhesion and chemotactic molecules). (2) Confront the results obtained in our experimental model with the real pathology using postmortem tissue specimens from patients with Parkinson disease.
Importance of This Research for the Development of a New PD Therapy:
Results from this project should provide the basis for a targeted functional analysis of the most promising candidates for their importance in brain recruitment of lymphocytes and, thus, for therapeutic intervention. The identification of specific factors expressed for instance in the brain blood vessels of the affected brain regions would have the major advantage of allowing a peripheral drug administration. Such developments may solve some major limitations associated with current neuroprotective drug strategies for Parkinson disease: i) difficulties to develop drugs that cross the blood-brain-barrier, ii) drugs that act on receptors expressed constitutively in an ubiquitous manner.
The observation that brain infiltration of CD4+ T lymphocytes makes a significant contribution to neurodegeneration in parkinsonism has raised the tantalizing possibility that preventing these cells to enter the injured brain may provide protective benefits. Yet, little is known about the expression and regulation of factors involved in brain extravasation of immune cells under injury conditions relevant to Parkinson disease (PD). Therefore, we studied changes in gene expression of factors known to be crucial for the passage of immune cells across the blood?brain barrier both in the MPTP pre-clinical model of PD and in the real pathology using human postmortem tissue specimens. Our data obtained in the pre-clinical model revealed dynamic expression changes of chemotactic and adhesion factors within the injured substantia nigra. A similar differential expression of some of these factors was observed in the brain of PD patients. Overall, our study should provide the basis for a targeted functional analysis of the most promising candidates for their importance in T-cell brain infiltration and, thus, for therapeutic intervention.
Publication Based on MJFF Funding:
Bekaert A J?M, Brochard V, Lobsiger C, Hirsch EC, Combadière C, Hunot S. Molecular mechanisms of T cell trafficking into the brain in a mouse model of Parkinson's disease. 10th International Congress of Neuroimmunology. 26?30 October 2010, Barcelona, Spain.