Renal

Laboratory of Molecular Immunology

Transplantation is an important therapeutic option for end-stage renal disease. Despite improved immunosuppressive agents, rejection remains a major source of morbidity and mortality. Acute rejection is the strongest predictor of chronic rejection, which is the major cause of graft failure. Despite intensive study, the molecular basis of rejection remains incompletely understood. Our laboratory is currently performing clinical studies and investigating animal models of graft rejection.

Our objective is to develop molecular models based on gene expression profiles that will predict and diagnose clinical categories classified as acute "rejection", "stable," and "infection". In addition, the models will be used to investigate "high-risk" patients with a documented episode of rejection to select gene expression profiles that will predict rejection before the development of clinical criteria of rejection. Also, the models will be used to select expression profiles that identify genes common to all rejection episodes, regardless of the time point following transplantation. The models will be constructed from >10,000 genes, validated bybootstrap methods, and optimized by minimizing the predictive error. To investigate different biological components of rejection, we will construct three models: an antigen independent, antigen dependent, and global model. Patients will be monitored with a timed surveillance protocol to collect graft biopsies and peripheral blood mononuclear cell samples. Gene expression will be analyzed by DNA microarrays, and the expression profiles tested with the models. The graft samples, due to proximity to the rejection process, are more likely to show strong correlations between clinical diagnoses and molecular profiles. The peripheral blood mononuclear cells, although more anatomically distant, would provide a powerful noninvasive tool to monitor rejection if significant correlations can be detected.

See http://perkinslab.bwh.harvard.edu

1. Finn PW, Stone JR, Boothby MR, Perkins DL. Inhibition of NF-kappaB-dependent T cell activation abrogates acute allograft rejection. J. Immunol, 2001. 167(10):5994-6001.
   
   
2. McKee C, Stone J, and Perkins DL. Prolonged allograft survival in TNF receptor 1 deficient recipients is due to immunoregulatory effects, not to inhibition of direct anti-graft cytotoxicity. J Immunol 2002; 168(1):483-489.
   
   
3. He H, Stone JR, and Perkins DL. Analysis of Robust Innate Immune Response after Transplantation in the Absence of Adaptive Immunity. Transplantation 2002, Feb. 15, No. 3 Vol. 3.
   
   
4. Christopher K, Mueller T, Perkins DL, Analysis of the Innate and Adaptive phases of Allograft Rejection by Cluster McKee C, Stone J, and Perkins DL. Prolonged allograft survival in TNF receptor 1 deficient recipients is due to immunoregulatory effects, not to inhibition of direct anti-graft cytotoxicity. J Immunol 2002; 168(1):483-489. Analysis of Transcriptional Profiles. J. Immunol. 2002. in press.
   
   
5. He H, Stone JR, and Perkins DL. Analysis of Differential Immune Responses Induced by Innate and Adaptive Immunity Following Transplantation. Immunology. 2002. In press.