To study the effect of immunologic stimuli on renal expression of Ia antigens (the class II products of the major histocompatibility complex), we induced acute graft-vs-host disease (GVHD) in mice and assessed Ia expression in the host kidney. Serologic absorption analyses showed that the amount of host Ia antigen increased up to tenfold in kidney, and immunofluorescence demonstrated that this increase occurred predominantly in renal tubule epithelial cells. To determine whether these alterations reflected changes in Ia gene transcription, we hybridized DNA probes for mRNAs encoding either Ia E alpha or A beta chains to total RNA extracted from the kidneys of normal mice and mice with acute GVHD. Northern hybridization blots revealed that the level of Ia mRNA expression in GVHD kidney is enhanced about sevenfold when compared with that found in normal kidney. Using the E alpha probe, this result was shown to reflect increased expression of C3H host Ek alpha mRNA, since the Eb alpha gene is not transcribed by the C57BL/6 donor strain used. We conclude that the increase in expression of Ia in renal tubule epithelium during GVHD probably reflects increased I-region gene transcription in host kidney cells. These findings may have implications for the pathogenesis of renal allograft rejection and immunologic renal disease.