Z Gastroenterol 2018; 56(05): e23
DOI: 10.1055/s-0038-1648609
Kategorie: Poster „Grundlagen-orientierte Forschung“
Georg Thieme Verlag KG Stuttgart · New York

Targeting Ulcerative Colitis with Ritonavir

H Jodeleit
1   Department of General- Visceral-, Vascular- and Transplantation Surgery, Hospital of the LMU, Munich
,
O Al-amodi
1   Department of General- Visceral-, Vascular- and Transplantation Surgery, Hospital of the LMU, Munich
,
J Caesar
1   Department of General- Visceral-, Vascular- and Transplantation Surgery, Hospital of the LMU, Munich
,
G Schütze
2   Institute of Laboratory Medicine, Ludwig-Maximilians-University Munich
,
L Holdt
2   Institute of Laboratory Medicine, Ludwig-Maximilians-University Munich
,
M Siebeck
1   Department of General- Visceral-, Vascular- and Transplantation Surgery, Hospital of the LMU, Munich
,
R Gropp
1   Department of General- Visceral-, Vascular- and Transplantation Surgery, Hospital of the LMU, Munich
,
F Beigel
3   Department of Medicine II-Grosshadern, Hospital of the LMU Munich
› Author Affiliations
Further Information

Publication History

Publication Date:
03 May 2018 (online)

 

Background:

The energy supply of inflammatory cells relies on three sources: Glucose, lipids and amino acids (AS). In homeostasis, when the major task of inflammatory cells is the maintenance of tolerance, lipids are the preferred source as lipid oxidation is the most efficient albeit slowest pathway to generate ATP. The response to an assault, however, requires the immediate activation, proliferation, differentiation of inflammatory cells, their migration to sites of inflammation and expression of cytokines, growth factors and chemokines. These processes demand prompt energy supply which is met by a metabolic switch from lipid oxidation to glycolysis which ensures swift ATP generation and the synthesis of biosynthetic intermediates albeit at the expense of efficiency. Therefore, the dependence on glycolysis might offer an 'Achilles heel' of inflammatory cells. The uptake of glucose into the cell is ensured by a family of glucose transporters (GLUT) which are differentially expressed in various tissues. The development of GLUT inhibitors has been stimulated by the observation that ritonavir which has originally been developed as an inhibitor of HIV protease coincidentally inhibits GLUT1 and 4. In this study ritonavir was tested as a potential therapeutic for the treatment of ulcerative colitis.

Methods:

Ritonavir was tested in a mouse model of UC which is based on immune compromised NOD/ScidIL-2Rγnull mice reconstituted with peripheral blood mononuclear cells (PBMC) derived from UC patients (NSG-UC). Read out was the clinical- and histological score, frequencies of human leukocytes isolated from spleen and colon and levels of amino acids in sera of mice. To further examine the impact of ritonavir on the activation of T cells PBMC were challenged in vitro with anti CD3 and anti CD28 antibodies in the presence and absence of ritonavir and subjected to flow cytometric analysis.

Results:

Mice benefited from treatment with ritonavir as indicated by significantly decreased clinical (p = 0.05) and histological (p = 7e-0.5) scores, frequencies of M2 monocytes CD14+ CD163+ CD206+ (p = 0.01) and glutamate levels (p = 0.02). Principal component analysis revealed no discrimination between the control group and the ritonavir treated groups. In vitro, ritonavir inhibited the activation of CD4+ T cells and effected frequencies of M1 (CD14+ CD64+, CD14+ CCR2+) and M2 CD14+ monocytes. As expected, ritonavir had no impact on pAKT.

Conclusion:

The FDA approved ritonavir might be a promising drug to support conventional treatment of UC patients in times of relapses.