Functional genomics of immune responses

Abstract

Compilation of a draft of the sequence of the human genome [1,2] and concurrent technologic advances have made the simultaneous analysis of thousands of genes experimentally feasible. The study of the expression and function of many genes is called functional genomics. Technologies such as DNA microarrays, which quantitate the expression of all mRNAs (called the transcriptome), are becoming readily available. The expression of the complete transcriptome in the yeast Saccharomyces cerevisiae during biologic responses has been analyzed [3]. Although these experimental approaches are being applied to many different biologic responses and diseases, this article focuses on the analysis of the complex immune networks following transplantation. Similar approaches have been initiated to investigate the numerous genes that are presumed to comprise the alloimmune response following transplantation. The development of DNA microarray technology enables investigation of the complete transcriptome of expressed genes during allograft rejection. The goal of the global analysis of gene expression is to determine the molecular mechanisms of immunity and to discover new biologic targets for pharmaceutical agents and diagnostics. Paradigms of transplantation in lung and other solid organs indicate that the rejection response involves hundreds of genes that are controlled by complex regulatory networks. Models of transplantation in genedeficient (knockout) mice support this concept. More than 100 strains of genedeficient mice have been identified in which allograft survival is prolonged. With few exceptions, these strains eventually reject allografts, with delays observed in kinetics. These results indicate that the deleted genes are important, but not necessary, for allograft rejection. These observations indicate that the functions of many of these genes can be compensated for by alternative mechanisms that are, at least in part, functionally redundant. It is evident that allograft rejection in animal models involves the functions of numerous genes in concert. Studies of