Inflammation in Parkinson’s Disease and Experimental Neural Transplantation. Role of Cellular Responses, Cytokines and Immunosuppression in Graft Rejection.

Abstract: Parkinson’s disease (PD) is a common neurodegenerative disorder. There is no proven protection, but many treatments can partially improve symptoms. The disease is caused by monogenetic mechanisms in very few cases, but for the majority of patients the etiology is unknown. Epidemiological studies have identified a potential role for inflammation. The thesis investigates inflammation and immune responses in the context of PD from two aspects, the pathological process in human brains, and the reactions to experimental neural tissue transplantation. Transplantation may be used to repair the brain in advanced disease, and immunosuppressive treatment and anti-inflammatory strategies may retard the disease. In the human brain study, activated microglia were found in the substantia nigra, whereas no inflammatory responses could be detected in the putamen, another region affected by the disease. In the neural tissue transplantation studies, inflammatory and cellular host responses were compared for different graft combinations, syngeneic (same rat-to-rat strain), allogeneic (different rat-to-rat strains), concordant (mouse-to-rat) and discordant xenografts (porcine-to-rats and mice), and the effects of immunosuppression. Syngeneic and allogeneic grafts survive, and induce transient immune responses, with only minor microglia activation, limited lymphocytic infiltration and cytokine production. Concordant and discordant xenografts are rejected in most cases and combinations of immunosuppressive drugs are needed. The cytokine profiles include high levels of TNF (tumor necrosis factor) and IFN (interferon). Immunosuppressive treatment reduced most cytokines, except for TNF that remained high in brain tissue. Lymphocytes, glia and microglia cells were idnetified as cellular sources for cytokine production. It is concluded, that inflammatory reactions play a role in PD pathology. Experimental transplantation can be used as a model for focal inflammation/immunology in the central nervous system. Determination of cytokine profiles can be used to rationally assess effects of immunosuppressive drugs on immune and inflammatory reactions. Neural tissue xenografting can result into surviving grafts, provided a limited tissue reponse is achieved by a combination of immunosuppressive drugs. In discordant settings, grafts are rejected by innate immune responses, and delayed type of hypersensitivity reactions that are difficult to suppress, with drug treatment. Anti-inflammatory drugs may be effective in protecting neurons and to improve graft survival