Systems biology approach to transplant immune tolerance

Abstract

Solid organ transplantation has achieved increased success during the past decade, largely related to advances in immunosuppression and control of acute rejection [ [1] Lodhi S.A. Lamb K.E. Meier-Kriesche H.U. Solid organ allograft survival improvement in the United States: The long-term does not mirror the dramatic short-term success. Am J Transplant. 2011; 11: 1226 Crossref PubMed Scopus (268) Google Scholar ]. However, long-term graft survival has not changed as the result of multiple factors, including irreversible chronic rejection and patient death caused by the side effects of standard immunosuppressive drugs [ [1] Lodhi S.A. Lamb K.E. Meier-Kriesche H.U. Solid organ allograft survival improvement in the United States: The long-term does not mirror the dramatic short-term success. Am J Transplant. 2011; 11: 1226 Crossref PubMed Scopus (268) Google Scholar ]. Tolerance induction thus remains a goal in the field of transplantation. It has been demonstrated that mixed chimerism, a state in which bone marrow cells of different genetic background coexist, is associated with donor-specific transplantation tolerance. Mixed chimerism through nonmyeloablative bone marrow transplantation has been shown to induce tolerance to kidney allografts in humans [ 2 Kawai T. Cosimi A.B. Spitzer T.R. et al. HLA-mismatched renal transplantation without maintenance immunosuppression. N Engl J Med. 2008; 358: 353 Crossref PubMed Scopus (834) Google Scholar , 3 Scandling JD, Busque S, Dejbakhsh-Jones S, et al. Tolerance and withdrawal of immunosuppressive drugs in patients given kidney and hematopoietic cell transplants. Am J Transplant. 2012, March 8. [Epub]. Google Scholar , 4 Leventhal J. Abecassis M. Miller J. et al. Chimerism and tolerance without GVHD or engraftment syndrome in HLA-mismatched combined kidney and hematopoietic stem cell transplantation. Sci Transl Med. 2012; 4: 124ra28 Crossref PubMed Scopus (309) Google Scholar ]. Systems Biology Approach to Transplant Tolerance: Proof of Concept Experiments Using RNA Interference (RNAi) to Knock Down Hub Genes in Jurkat and HeLa Cells In VitroJournal of Surgical ResearchVol. 176Issue 1PreviewSystems biology is gaining importance in studying complex systems such as the functional interconnections of human genes [1]. To investigate the molecular interactions involved in T cell immune responses, we used databases of physical gene-gene interactions to constructed molecular interaction networks (interconnections) with R language algorithms. This helped to identify highly interconnected “hub” genes AT(1)P5C1, IL6ST, PRKCZ, MYC, FOS, JUN, and MAPK1. We hypothesized that suppression of these hub genes in the gene network would result in significant phenotypic effects on T cells and examined this in vitro. Full-Text PDF