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Graft-versus-host disease (GVHD) continues to be the leading cause of non-relapse mortality following allogeneic stem cell transplantation (AHCT). Unfortunately, what determines who will develop GVHD after major histocompatibility complex (MHC)-matched AHCT, even from an HLA-identical sibling, is unpredictable. Although GVHD only develops if there are some mismatches in histocompatibility antigens between the donor and host, it does not inevitably develop. Until now, scientists have mainly investigated whether differences between AHCT recipients might explain this observation.

In this study, the researchers have examined the donors to see whether differences in their immune responses might make some donors stronger "responders" than others and consequently more likely to cause GVHD. They measured the gene-expression profiles of CD4 and CD8 T cells from 50 AHCT donors with micro arrays. They report that pre-AHCT gene-expression profiling segregates donors whose recipient suffered from GVHD. Using quantitative PCR, established statistical tests, and analysis of multiple independent training-test datasets, they found that for chronic GVHD the "dangerous donor" trait (occurrence of GVHD in the recipient) is under polygenic control and is shaped by the activity of genes that regulate transforming growth factor-beta signaling and cell proliferation. These findings strongly suggest that the donor gene-expression profile has a dominant influence on the occurrence of GVHD in the recipient.

In micro array experiments, the donor-gene profile defined on day 0 showed exceedingly strong correlation with that of recipient CD4 and CD8 T cells harvested on day 365. For most genes tested by quantitative RT-PCR, differential gene expression between patients with chronic GVHD and those without was confirmed to be robust, on the basis of statistical tests and computational analysis of independent training-test datasets. From a pathway perspective, differential expression of TGF-beta-related transcripts was entirely consistent with increased TGF-beta signaling in T cells.

Can identification of strong versus weak responders be used to select AHCT donors? The predictive value of the best genes was about 80 percent. However, predictive models can be fine tuned for clinical decision-making to either optimize sensitivity or specificity. An increase in sensitivity usually comes at the expense of a decrease in specificity, and vice versa. Given that the avoidance of GVHD is usually paramount, one would expect that a bias toward the best achievable sensitivity, allowing for the most reliable selection of donors, would be clinically desirable. Other results in the article (as in others) also suggest that higher-order combinatorial searches beyond two genes could improve significantly the predictive performance of gene-expression profiling. However, higher-order predictive variable combinations do require the support of many more samples to prevent over-fitting of the model.

However, when considering the negative impact of such "dangerous donor" cells, it is critical to keep in mind that GVHD likely participates to a great extent in the generation of potent anti-tumor immune responses and that their elimination may also reduce the graft-versus-tumor effect associated with AHCT.

Competing Interests

Dr. Socié indicated no relevant conflicts of interest.