Chimerism After Solid Organ Transplantation

Abstract

To the Editor: In a recent volume of the American Journal of Transplantation, Koopmans and colleagues (1Koopmans M Hovinga ICLK Baelde HJ et al.Chimerism in kidneys, livers and hearts of normal women: Implications for transplantation studies.Am J Transplant. 2005; 5: 1495-1502Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar) describe a phenomenon coined “background chimerism” in organs from females who had born sons or received blood transfusions. The presented data further confirmed the hypothesis that besides the setting of organ transplantation in situ chimerism can be found in different solid organs. The authors carefully employed a well‐established technique of Y‐chromosome in situ hybridization to detect male‐derived cells in female organs and confirmed their findings by a Y‐specific qualitative PCR. In the majority of the analyzed specimens, only few Y‐chromosome‐positive cells were detected, comprising probably less than one cell in thousand. Only two women had up to 10% of Y‐chromosome‐positive cells in their kidneys. Whereas all studies applying Y‐chromosome in situ hybridization to demonstrate chimerism of transplanted organs are challenged, by this study we have applied a different approach. Using a highly sensitive and specific short tandem PCR (DNA fingerprinting), more than 100 transplant specimens have been investigated. Up to now, not more than two different genotypes were observed in transplanted organs with this technique (2Mengel M Jonigk D Marwedel M et al.Tubular chimerism occurs regularly in renal allografts and is not correlated to outcome.J Am Soc Nephrol. 2004; 15: 978-986Crossref PubMed Scopus (39) Google Scholar, 3Kleeberger W Rothamel T Glockner S Flemming P Lehmann U Kreipe H High frequency of epithelial chimerism in liver transplants demonstrated by microdissection and STR‐analysis.Hepatology. 2002; 35: 110-116Crossref PubMed Scopus (110) Google Scholar, 4Kleeberger W Versmold A Rothamel T et al.Increased chimerism of bronchial and alveolar epithelium in human lung allografts undergoing chronic injury.Am J Pathol. 2003; 162: 1487-1494Abstract Full Text Full Text PDF PubMed Scopus (165) Google Scholar, 5Mengel M Jonigk D Wilkens L et al.Chimerism of metanephric adenoma but not of carcinoma in kidney transplants.Am J Pathol. 2004; 165: 2079-2085Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar). If background chimerism is quantitatively playing a significant role, at least three different DNA fingerprints (donor, recipient and background) should be detectable. Furthermore, chimeric, i.e. recipient‐derived, cells were found in tumors which developed in an allograft definitely after the organ was transplanted. This shows that chimerism beyond any doubt occurs de novo in the setting of organ transplantation (5Mengel M Jonigk D Wilkens L et al.Chimerism of metanephric adenoma but not of carcinoma in kidney transplants.Am J Pathol. 2004; 165: 2079-2085Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar). Dilution experiments to determine the sensitivity and specificity of the STR‐PCR method demonstrated that a minimum of five cells of one individual (e.g. recipient) can be specifically detected against a background of >100 cells of another individual (e.g. donor). Hence, the STR approach is limited by a threshold of 3–5% what might explain why background chimerism has escaped from detection in this assay. Consequently, when background chimerism is suggested as a possible explanation for the phenomenon of intra‐organ mixed chimerism, it is mandatory to consider quantitative aspects. In this regard, it is evident that background chimerism in most instances is not sufficient to cause an admixture of nondonor alleles exceeding 5% and more. Furthermore, in all chimeric cases that were detected by STR analysis after solid organ transplantation, a recipient derivation of nondonor cells could be proved by allele‐specific identification. The evidence for background chimerism presented by Koopmanns and coworkers does not rule out that a significant incorporation of possibly adult stem‐cell‐derived parenchymal cells of recipient origin takes place in most instances being causative for chimerism of transplanted organs. However, obviously the amount of chimeric cells, independently of its source (recipient‐derived or background chimerism), is low and in transplanted kidneys it is too small to provide a significant source for tubular epithelial cell regeneration (2Mengel M Jonigk D Marwedel M et al.Tubular chimerism occurs regularly in renal allografts and is not correlated to outcome.J Am Soc Nephrol. 2004; 15: 978-986Crossref PubMed Scopus (39) Google Scholar). Therefore, the future challenge will lie in the elucidation of the molecular mechanisms involved in the migration, homing and transdifferentiation of circulating progenitor cells into a damaged organ. This will be the prerequisite to evolve any therapeutical potential of chimerism, independent of its source.