Analysis of costimulation by 4-1BBL, CD40L, and B7 in graft rejection by gene expression profiles.
Recent studies affirm costimulatory blockade as a beneficial means of preventing allograft rejection. The precise molecular effects of these pathways, however, are not entirely understood. A striking example is in the costimulatory pathways, 4-1BB/4-1BBL, CD40/CD40L, and B7/CD28. Blocking any one of these prolongs graft survival, yet each operates via distinct immunomodulatory signals. To examine the mechanistic relationships among these signals, our approach was a comprehensive investigation of their molecular constituents. Using a model of heterotopic heart transplantation in mice with a costimulatory pathway deficiency, we analyzed the expression profiles of a large panel of immune and inflammatory genes using ribonuclease protection assays coupled with algorithms. We found that while graft survival was prolonged in all groups, each pathway modulates a unique profile of expressed genes. There were 19 genes, for example, with significant changes in expression compared to the control, yet none of these were similarly modulated in all three groups. Our study reveals that despite similar delays of allograft rejection, the molecular basis for this effect is distinct in all three costimulatory pathways. Furthermore, we underscore the existence of numerous molecular mechanisms affecting graft survival. This, in turn, provides crucial implications for clinical treatment post-transplant where inhibitors would be designed to target multiple mechanisms.
DeFina
Rachel
R
Laboratory of Molecular Immunology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, PBB-170, Boston, MA 02115, USA.
Christopher
Kenneth
K
He
Hongzhen
H
Mandelbrot
Didier
D
Gu
Yongping
Y
Finn
Patricia
P
Perkins
David L
DL
D053330:4-1BB Ligand; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D051940:B7-2 Antigen; D018106:CD28 Antigens / Q000378:metabolism; D019013:CD40 Antigens / Q000378:metabolism; D023201:CD40 Ligand / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D020869:Gene Expression Profiling; D016654:Genes, RAG-1 / Q000235:genetics / Q000502:physiology; D006084:Graft Rejection / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D006085:Graft Survival / Q000276:immunology*; D016027:Heart Transplantation / Q000276:immunology*; D007124:Immunoenzyme Techniques; D007371:Interferon-gamma / Q000378:metabolism; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017475:Receptors, Nerve Growth Factor / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D012259:Ribonuclease, Pancreatic / Q000378:metabolism; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D053330:4-1BB Ligand; D015703:Antigens, CD; D051940:B7-2 Antigen; D018106:CD28 Antigens; D019013:CD40 Antigens; C497965:Cd86 protein, mouse; D008562:Membrane Glycoproteins; D017475:Receptors, Nerve Growth Factor; D018124:Receptors, Tumor Necrosis Factor; C505715:Tnfrsf9 protein, mouse; C505975:Tnfsf9 protein, mouse; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D014409:Tumor Necrosis Factor-alpha; D023201:CD40 Ligand; D007371:Interferon-gamma; D012259:Ribonuclease, Pancreatic