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Can regulatory T cells be used for cellular therapy in Neuromyelitis optica patients?

Subject Area Molecular and Cellular Neurology and Neuropathology
Molecular Biology and Physiology of Neurons and Glial Cells
Term since 2020
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 441072869
 
Neuromyelitis optica (NMO) is a devastating inflammatory disease of the central nervous system (CNS) with yet unknown pathogenesis. Major hallmarks of NMO include lesions located especially in the optic nerve as well as extensive longitudinal spinal cord lesions and the production of anti-AQP4-antibodies in the majority of NMO patients. Aquaporin 4 (AQP4) is a water channel that is abundantly present in the CNS of humans and rodents where it is located mostly on the endfeet of astrocytes at the blood brain barrier (BBB) and glia limitans. Although it has been shown that anti-AQP4 antibodies are pathogenic we and others could demonstrate in mouse/rat-NMO-models that this is only the case when anti-AQP4 antibodies bind their target under inflammatory conditions that can be induced with CNS antigen specific T cells. Additionally it has been shown that general T cell activity is elevated in NMO patients and furthermore that AQP4 specific T cells in NMO patients can be activated through cross-reactivity to bacterial adenosine triphosphate-binding cassette (ABC) transporter permease. In a physiological state humoral and cellular immune components are important players in host defence against non-self-antigens that can turn against self through mechanisms of cross reactivity when dysregulation occurs in the immune system. Therefore powerful counter-mechanisms, i.e. tolerance, that should prevent autoimmunity are present in the healthy immune system. On the one hand, there is deletion of autoreactive T and B cells in thymus or bone marrow, a process known as central tolerance. On the other hand, there are mechanisms that take care of cells that escape central tolerance induction and suppress them in the periphery, therefore called peripheral tolerance. The main mediators of peripheral tolerance are regulatory T cells (Treg cells). Unfortunately no studies concerning Treg cell impairment and their involvement in possible treatment options in NMO exist to date. Therefore the main focus of this project is to determine the potential benefit of Treg cell based immune therapy for patients with NMO:(i) We will investigate whether Treg cell numbers in NMO patients differ compared to HC, especially regarding the proportion of AQP4 specific Treg cells.(ii) We will establish a stable and sufficiently expandable human Treg cell culture applicable in cell transfer therapy. (iii) We will analyse whether Treg cells, especially AQP4 specific Treg cells, have an impaired function in NMO patients.Ultimately, this project will pave the way to establish an efficient, current Good Manufacturing Practice (cGMP)-compatible protocol that enables us to produce an antigen specific and stable human Treg cell culture that is expandable in sufficient numbers to ensure a safe and effective treatment with low risk of side effects for patients with NMO.
DFG Programme Research Grants
 
 

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