Chimerism After Solid Organ Transplantation: Not Only Numbers Count

Abstract

To the Editor: We thank Mengel and colleagues for their interest in our paper. Their letter encounters several issues we would like to comment on. Mengel et al. report that by using a short tandem repeat (STR)-PCR method they were not able to observe more than two genotypes in transplanted organs, which would contradict the presence of pre-transplant, or 'background' chimerism. In the papers they refer to, recipient-derived parenchymal cells in transplanted organs were detected in donor organs by using a STR-PCR that analyzed one highly polymorphic STR marker. With this technique, only two different genotypes were consistently found. However, this does not rule out the presence of background chimerism. As they point out in their letter, their STR-PCR technique has a threshold of 3–5%. The nested PCR we used is much more sensitive, detecting one male cell in up to 200 000 female cells. Therefore, it is likely that the background chimerism as we described it, was not detected in their assay because their threshold was too high. We investigated the presence of chimeric cells in liver, kidneys and hearts that theoretically could have been used for transplantation. Our main conclusion is that chimerism occurs as a background phenomenon in normal organs. Apart from two kidneys that showed extensive chimerism, the number of chimeric cells in all normal organs from our study was lower than the number of chimeric cells found in allografts in most transplantation studies (1, 2). Therefore, our data do not challenge the occurrence of recipient-derived chimerism, they just provide evidence of an additional source for the presence of chimeric cells in organ allografts. The question remains whether chimerism influences graft survival. Both our group and the group of Mengel have not been able to demonstrate this in previous studies (3, 4). In their letter, Mengel et al. emphasize that the future challenge lies in the elucidation of mechanisms involved in the migration, homing and transdifferentiation of progenitor cells into damaged organs. It is likely that many different factors influence these mechanisms. We recently demonstrated that the sex difference between donors and recipients is such a factor (4). However, because graft outcome itself is influenced by many different factors too, studying the precise role of chimerism in this multifactorial process is a challenge by itself. Mengel et al. state that the effect of chimerism is most likely related to the amount of chimeric cells present. If this is the case, the influence of background chimerism can only be very low, because it consists of a relatively small number of cells. However, we think that the phenotype of chimeric cells may be of greater importance than their presence in numbers. This was previously demonstrated in experimental models in which a very low number of chimeric T cells (namely, 2–3% of circulating T cells) led to a Graft versus Host reaction (5). It is possible that also in human solid organ transplantation, small numbers of chimeric cells with a particular phenotype may greatly influence graft outcome, and therefore, background chimerism may play an important role in graft survival.