Kurzfassung

The availability of the amino acid arginine has emerged as a key control mechanism within the mammalian immune system. Upon liberation of myeloid cell arginase (EC 3.5.3.1), arginine in the inflammatory microenvironment is metabolised to ornithine and urea. This mechanism is crucially involved in inflammation- and cancer-associated immunosuppression with profound impairment of T lymphocyte and NK cell functions. Arginine can be recycled in certain mammalian tissues from citrulline via the...The availability of the amino acid arginine has emerged as a key control mechanism within the mammalian immune system. Upon liberation of myeloid cell arginase (EC 3.5.3.1), arginine in the inflammatory microenvironment is metabolised to ornithine and urea. This mechanism is crucially involved in inflammation- and cancer-associated immunosuppression with profound impairment of T lymphocyte and NK cell functions. Arginine can be recycled in certain mammalian tissues from citrulline via the enzymes argininosuccinate synthase (ASS; EC 6.3.4.5) and argininosuccinate lyase (ASL; EC 4.3.2.1). In preliminary experiments we demonstrated that primary human T lymphocytes can use citrulline or argininosuccinate to resume proliferation and effector functions under conditions of arginine limitation, most likely via ASS and ASL expression. This proposal aims to analyse this mechanism in depth as a very promising pharmacological way to treat arginase-induced immunosuppression. As a crucial step towards potential clinical applications, this project aims to characterise the mechanism(s) of citrulline / argininosuccinate-induced immune cell re-activation in the context of arginase-mediated arginine deficiency and 1. analyse the full range of T cell and NK cell functions in the context of citrulline or argininosuccinate supplementation 2. study the regulation of expression of ASS and ASL in human primary T lymphocytes and NK cells. » weiterlesen» einklappen