Leire Ruiz Cerdá (1), Itziar Irurzun-Arana(1), Ignacio Gonzalez-Garcia(1) (2), Chuanpu Hu(3), Honghui Zhou(3), An Vermeulen(4), Iñaki F. Trocóniz(1), José David Gómez-Mantilla(1)
(1)Pharmacometrics & Systems Pharmacology, Department of Pharmacy and Pharmaceutical Technology, University of Navarra, Pamplona 31080, Spain (2) Pharmacy and Pharmaceutical Technology Department. University of Valencia. Valencia, Spain (3) Janssen Research and Development, LLC, Spring House, PA 19477, USA (4)Janssen Research and Development, a division of Janssen Pharmaceutics NV, Beerse B-2340, Belgium
Objectives: To mechanistically characterize the co-stimulation process within immune responses with emphasis on alterations occurring in Systemic Lupus Erythematosus (SLE) using a Systems Pharmacology approach.
Methods: The co-stimulation process involves antigen presentation to T cells [1]. The network was built based on a rigorous bibliographic review, focused on the components of the immune responses that have been reported to be altered in SLE. Boolean expressions [2] and scripts to simulate the evolution of the entire network, were written in the R environment. We simulated a continuous autoantigen exposure and evaluated the differences in the network dynamics by perturbation of different nodes. The network was validated through simulations (10,000) to obtain relative expression profiles for each component of the network.
Results: The network consisted of 50 nodes, 16 of which have been reported to be altered in SLE, and 140 relationships. From the 50 nodes, 17 corresponded to cytokines, 9 to Antigen-presenting cell (APC) surface molecules, 17 to T cell surface and intracellular molecules, 5 to differentiated T cell subpopulations and the remaining nodes corresponded to the autoantigen and T cell activation signals. The established network was considered validated based on the good agreement obtained when comparing expression profiles reported in literature for selected nodes and the corresponding relative expression simulated profiles. In addition, performing virtual knockout of nodes reported to be altered in SLE led to expression profiles similar to those presented in real SLE patients.
Conclusions: A systems pharmacology model for co-stimulation, a fundamental step in the mechanism triggering immune response, has been developed and validated. In its actual status, the model can be challenged by testing the effect of blocking or activating different pathways to help in target identification. Current ongoing developments involve (i) applying reduction methods towards a mechanistic model that can be handled in PKPD analyses, and (ii) expanding the network including T cell differentiation mechanisms and antigen presentation to B cells.
References:
[1] Rahman, Anisur, and David A Isenberg. 2008. “Systemic Lupus Erythematosus.” The New England Journal of Medicine 358 (9): 929–39.
[2] Thakar J, Pilione M, Kirimanjeswara G, Harvill ET, Albert R (2007) Modeling systems-level regulation of host immune responses. PLoS Comput Biol 3: e109.
Reference: PAGE 24 () Abstr 3376 [www.page-meeting.org/?abstract=3376]
Poster: Drug/Disease modeling - Other topics