THE DOPAMINERGIC NEURO-IMMUNE CONNECTION

Abstract of the Research Project

DOPAMINERGIC MODULATION OF CD4+ T LYMPHOCYTES: RELEVANCE FOR NEURODEGENERATION AND NEUROPROTECTION IN PARKINSON’S DISEASE - THE DOPAMINERGIC NEURO-IMMUNE CONNECTION

PI: Marco Cosentino, MD PhD
Team: Center for Research in Medical Pharmacology, University of Insubria, Via Ottorino Rossi n. 9, 21100 Varese VA – Italy. Phone (direct): +39 0332 217410/397410, Phone (exchange): +39 0332 217401/397401, Fax: +39 0332 217409/397409, E-mail: marco.cosentino@uninsubria.it, Skype: mark_065, URLs:
@University (EN) - http://www.uninsubria.eu/research/clinmed/cv_Cosentino.htm
@BioMedExperts - http://www.biomedexperts.com/Profile.bme/1740686/Marco_Cosentino
@ResearcherID - http://www.researcherid.com/rid/A-3848-2010
Associated partner: Interdepartmental Research Center for Parkinson’s disease, IRCCS Neurological Institute ”C. Mondino”, Pavia – Italy (PI: Fabio Blandini, MD PhD)

Parkinson’s disease (PD) stems mainly from a massive loss of dopaminergic innervation in the striatum, and dopaminergic drugs are the most important therapeutic agents currently available. Over the last few years however increasing attention has been dedicated to the occurrence in PD patients of several changes in cellular and humoral immune responses in the peripheral immune system, and recently it has been shown that CD4+ T lymphocytes infiltrate postmortem human PD specimens and mediate dopaminergic toxicity in murine models of PD, in line with the notion that the peripheral immune system actively patrols the CNS and contributes to the maintenance of functional CNS integrity.

In human peripheral blood, CD4+ T cells include effector as well as regulatory T lymphocytes (Treg), the latter being a specialized subset of T cells which are crucial for the control of immune homeostasis. Treg seem to be key neuroprotective immunomodulators in acute experimental stroke as well as in animal models of PD possibly through modulation of microglial oxidative stress and inflammation, and preliminary evidence in patients with neurodegenerative disease indicates the occurrence of specific functional alterations affecting the Treg subset.

Besides being apparent key players in neurodegeneration and neuroprotection, human Treg exhibit a peculiar sensitivity to the effects of DA: indeed among CD4+ T cells, only Treg constitutively express dopaminergic receptors and contain high amounts of endogenous DA which subserves an autocrine/paracrine regulatory loop, and dopaminergic modulation of Treg function has been reported to profoundly affect neurodegenerative processes in animal models of neuronal injury. Dopaminergic receptors regulating human Treg function are of the D1-like D5 subtype, while those regulating the proliferation of effector T cells seem to be of the D2-like D4 subtype, setting the basis for selective exploitment of dopaminergic receptor pathways for immunomodulating purposes.

Available evidence thus strongly supports thorough investigation of dopaminergic mechanisms modulating CD4+ T cells and in particular the Treg subset as potential targets for novel and selective neuroprotective strategies in neurodegeneration and in particular in PD.

The present research project aims at the comprehensive evaluation of the relevance of the dopaminergic modulation of CD4+ T cells and in particular of the Treg subset in PD. To this end, the research program will be developed along three distinct and complementary directions:
(1) CD4+ T lymphocytes will be characterized in the peripheral blood of PD patients with particular regard to the Treg subset and the intrinsic dopaminergic pathways. Studies will address: frequency of cell subsets, their functional profile, the expression of dopaminergic receptors and related pathways and their functional role and responsiveness. Assays will be performed in both naive and drug-treated subjects and correlations will be sought with disease conditons as well as with the type of (and responsiveness to) drug treatments;
(2) In vitro experiments will be devised to investigate the effects of dopaminergic agents (levodopa, DA agonists) currently used in the pharmacotherapy of PD on the functional responses of CD4+ T lymphocyte subsets. The specific responses will be investigated in relation to functional conditions and to the expression and functional responsiveness of intrinsic dopaminergic pathways; specific experiments will address the role of DA in the lymphocytes-glial cells interactions;
(3) The 6-OHDA lesion murine model of PD will be exploited to investigate peripheral immunity with particular regard to intrinsic dopaminergic pathways and their role and regulation in CD4+ T cell subsets; the presence of CD4+ T cells will be confirmed in lesioned areas of the brain, their relationship with neuronal and glial cells will be examined and the effect of drugs targeting CD4+ T cells and in particular the Treg subset will be investigated. The possibile immune effects of dopaminergic agents will be also studied in this model.

Results will show whether CD4+ T cells play a relevant role in PD and in particular whether intrinsic dopaminergic pathways in these cells may represent a target for pharmacotherapeutic intervention. Novel information will contribute to clarify whether a direct effect on peripheral immunity contributes to the overall therapeutic activity of current dopaminergic treatments: if this would be the case, then their therapeutic potential could be better exploited and optimized. In addition, in depth understanding of the role of CD4+ T cells could provide unanticipated opportunities for the experimental use of specific immunomodulating approaches targeting these cells as novel neuroprotective strategies in PD.