The impact of immune-activating processes following transplantation on chronic allograft nephropathy

Abstract

Background. The long-term success of organ transplantation is influenced by numerous alloantigen-dependent and -independent risk factors. However, only very little information is presently available on the influence of systemic immune-activating processes following organ engraftment. Methods. To simulate the clinical situation of sequential organ transplantation, rat renal allograft recipients received additional immune activating stimuli (secondary donor-specific and third-party skin grafts) after transplantation at serial time intervals (4 and 8 weeks). The overall observation period was 16 weeks. Results. All control animals survived the observation period. In contrast, recipients receiving additional third-party or donor-specific skin grafts were beginning to die 12 weeks after organ engraftment with only few animals surviving 16 weeks. Systemic immune activation by additional third-party and in particular by additional donor-specific skin grafts resulted in significant temporary and long-term functional deterioration. Morphologic changes progressed significantly, particularly after a secondary challenge with donor-specific skin grafts. ED1+ monocytes/macrophages, T-cell infiltrates, and intragraft mRNA expression for CD25 were significantly elevated by 16 weeks, following an additional immune challenge. Analysis of early intragraft events showed strong up-regulation of CD25 transcripts, suggesting fast stimulation of intragraft immune processes. Conclusion. Both alloantigen-specific and -unspecific systemic immune activation processes, following experimental organ transplantation, contribute to chronic graft deterioration. Those results seem relevant for long-term immunosuppressive protocols and clinical situations of sequential organ transplantation.