Analysis of the major histocompatibility complex in graft rejection revisited by gene expression profiles

The precise role of major histocompatibility complex (MHC) molecules in graft rejection remains incompletely understood. The important role of foreign peptides in the alloimmune response was recently recognized.

We performed a comparative study of the functions of minor antigens Class I, Class II, and CD1 in murine cardiac allograft rejection by investigating the expression of a large panel of immune and inflammatory genes. To investigate the role of MHC Class II and I, our protocol analyzed allograft recipients deficient in MHC Class II and b2 microglobulin (b2-M), a critical component of the Class I heterodimer. We also included CD1 deficient recipients to differentiate effects in the beta2-M deficient strain due to CD1 deficiency versus the combined inactivation of CD1 and Class I. The serum cytokines tumor necrosis factor (TNF)-alpha interleukin (IL)-6, interferon (IFN)-gamma and IL-1beta were evaluated posttransplant by ELISA. The intragraft expression of 55 chemokines, chemokine receptors, and CD markers were measured by ribonuclease protection assay. The data were analyzed through hierarchical clustering dendrograms and self-organizing maps.

The analysis indicates that each gene deficiency induces both the upregulation and the downregulation of distinct subsets of genes and that similar kinetics of rejection can be attributed to different molecular mechanisms.

The study provides novel insights into the role of classical and non-classical MHC molecules in graft rejection.