A COMPARISON OF GENE EXPRESSION IN MURINE CARDIAC ALLOGRAFTS AND ISOGRAFTS BY MEANS DNA MICROARRAY ANALYSIS1

Abstract

Acute rejection of allografts remains a significant problem in clinical transplantation, and the fundamental mechanism underlying this rejection are as yet only poorly elucidated. Recently, DNA microarrays have come into use for the study of gene expression profiles, and we have taken advantage of this new technology to investigate acute rejection. We compared mRNA profiles in murine cardiac allografts with isografts using DNA microarrays with probe sets corresponding to more than 11,000 mice genes. We screened for gene expression changes in murine cardiac allografts between fully incompatible mice strains (BALB/c H2d to C3H/He H2k) using a DNA microarray. The heart was heterotopically transplanted. Allografts (BALB/c to C3H/He) were removed on days 1, 3, and 5. As a control, isografts (C3H/He to C3H/He) harvested on days 1, 3, and 5 and native hearts of both strain mice (C3H/He and BALB/c) were obtained. On day 5, interferon-γ (IFN-γ) and many IFN-γ-inducible genes were profoundly induced in the allograft relative to isograft. Monokine induced by IFN-γ was most profoundly induced followed by inducibly expressed GTPase and Lmp-2. IFN-γ was also profoundly induced. The induction was detectable from day 3. In contrast, genes regulated by other cytokines exhibited only modest changes. IFN-γ-inducible genes are specifically up-regulated in murine cardiac allografts, suggesting that signaling mediated by IFN-γ may play an important role in the late phase of acute rejection in vivo.