PhD ceremony Ms. A. Mattos Pinto: Redirecting Interleukin-10 in the fibrotic liver: effects on the pathogenesis
|When:||Fr 28-06-2013 at 09:00|
PhD ceremony: Ms. A. Mattos Pinto, 9.00 uur, Academiegebouw, Broerstraat 5, Groningen
Dissertation: Redirecting Interleukin-10 in the fibrotic liver: effects on the pathogenesis
Promotor(s): prof. K. Poelstra
Faculty: Mathematics and Natural Sciences
The most important results of the research of Adriana Mattos Pinto were: 1) PEGylation of Interleukin-10 improved its pharmacokinetics and decreased inflammation and fibrosis in a model of mice with hepatic injury. 2) Specific targeting of Interleukin-10 to the hepatic stellate cells (HSCs) in the fibrotic liver led to an exacerbation of fibrosis via an effect on macrophages.
Her thesis describes the effects of the delivery of Interleukin-10 to the fibrotic liver. Interleukin-10 plays an important role in the communication between cells and participates in a variety of processes: it inhibits inflammatory responses and attenuates activities in fibroblast-like cells, such as hepatic stellate cells (HSC) in the liver. After chronic hepatic damage HSCs become activated and start the overproduction and deposition of scar tissue, which affects normal liver functions. The treatment of the disease without disturbing other important processes is very difficult. Interleukin-10 is known to inhibit HSCs activation, but it also affects immunological responses which lead to unwanted effects in patients. Our aim was therefore to specifically target interleukin-10 directly to the hepatic stellate cells. Our strategy yielded surprising results: the fibrotic process was stimulated and not inhibited. Additional studies showed that other cell types (M2c macrophages) were activated after delivery of interleukin-10 to HSCs and this then stimulated the fibrotic process. Our studies thus provide new insights into regulatory processes that govern liver fibrosis. The role of interleukin-10 is different than expected and M2c macrophages seem to play a significant role during the development of the disease. These new insights can be used to set up a therapy for liver fibrosis which affects millions of people worldwide because to date there is no effective treatment for this serious disease. Our studies also show that the control of the fibrotic process through the delivery of targeted cytokines is possible, yet the effect in certain cell types can be rather surprising.