HLA transgenic mice as humanized mouse models of disease and immunity.

Abstract

The application of molecular genetics to human disease in the past decade has been helpful in elucidating the genetic influences involved in the induction and pathogenesis of various autoimmune diseases. Among the numerous genes studied for their role in disease development, polymorphisms within HLA class I and class II loci play a significant role in predisposition to disease. HLA molecules are encoded by genes on the short arm of chromosome 6. Crystal structures of MHC molecules show a peptide binding cleft which contains the variable region of MHC molecules. Genetic polymorphism at the MHC determines the specificity and affinity of peptide binding and T cell recognition. HLA molecules play a pivotal role in T cell repertoire selection in the thymus and antigen presentation in the periphery. Analysis of T cell responses in humans has involved the use of T cell lines or clones in vitro from naturally primed individuals. On the other hand, MHC restriction, mapping of epitope recognition, and T cell function in murine systems have been determined by in vivo studies. Various experimental animal models of autoimmune diseases have been studied, contributing greatly to our basic understanding of the disease. For example, type II collagen‐induced arthritis (CIA) 1 in mice and rats has been used as an experimental model for RA. Even though the model differs in the manner polyarthritis is induced, disease expression is broadly similar to RA, with the occurrence of symmetrical peripheral polyarthritis and systemic inflammation. Although growing knowledge of the functions of T and B cells in the immune response has shed light on their role in disease induction, the pathogenic mechanisms of most autoimmune diseases remain unresolved. There are many unanswered questions as to how tolerance to self is usually maintained, because autoreactive T cells can be found in normal as well as diseased individuals. How is tolerance broken in autoimmunity? Do specific autoantigens trigger the immune system to mount tissue-destructive responses? These questions need to be solved for most of the autoimmune diseases. Although the strongest MHC association with an autoimmune disease is between HLA class I B27 and spondyloarthropathies, class II alleles are implicated in most other cases. For example, RA is strongly associated with alleles of the DRB1 locus, whereas diabetes shows a stronger association with DQB1 alleles. HLA-DR and -DQ alleles are inherited en bloc and are known to occur in linkage disequilibrium. To better understand the role of HLA molecules in autoimmune diseases, transgenic animals expressing human HLA genes associated with disease have been developed. The generation of transgenic mice expressing functional HLA molecules has been an important step toward the creation of an in vivo model for enhancing our understanding of the function of human molecules in disease induction and predisposition. The potential value of HLA transgenic animals as a “humanized” disease model was first illustrated in the HLA-B27