There are many diseases nowadays which can only be treated or cured by transplanting functional organs from life or deceased donors. The operational techniques underlying transplantation have been developed during the past decades to reach a high standard and efficacy and matching of human leukocyte antigens (HLA, mediators of immunological recognition as foreign) led to a feasible amount of successful transplantation applications. But still, these are unthinkable without the help of immunosuppressive medication, necessary to detain the immune system from rejecting the foreign organ. Transplantation tolerance, a status defined as acceptance of the grafted organ without immunosuppressive medication and functional impairment is therefore the “holy grail” in clinical organ transplantation. [PubMed Review]
Many therapeutic rationales developed in experimental animal models of organ engraftment have failed a translation into the clinical application to human patients, most probably due to the lifelong history of multiple encounters with a most variable amount of pathogens. This is the great difference to inbred animal models, living in sterile conditions and therefore harbouring more or less unaffected immune systems. So far, the liver is the only organ setting in which a reasonable amount of patients (approximately 20%) of patients can reach a state of “operational tolerance”, but the mediating mechanisms are still under investigation. To evolve the current knowledge into a therapeutical application would be the defined goal.
In January of 2008 there has been a series of three publications in the New England Journal of Medicine, concerning this issue in human patients, all working with different methods to induce tolerance, two with renal and one with liver transplantation.
In the first approach, five patients with end-stage renal disease received bone marrow transplantation additionally to a kidney from related living donors (T. Kawai et al. 2008 NEJM) [PubMed].
These grafts were to some extend HLA-mismatched, but in four out of five patients, the transplanted donor derived bone marrow cells mediated unresponsiveness towards the foreign organ. The immunosuppression could be withdrawn and renal function was normal for up to 5.3 years after transplantation.
The second paper describes the case of a patient who has been treated before transplantation to ablate his immune cells, followed by combined transplantation of blood forming cells and the renal graft (J.D. Scandling et al. 2008;NEJM) [PubMed]. The patient tolerated the HLA-matched organ and function was maintained for 28 months after withdrawal of immunosuppressive medication.
In the third report, a 9 year old girl received a liver from a deceased 12 year old boy (S.I. Alexander et al. 2008; NEJM) [PubMed]. She developed a full blood cell chimerism, meaning that her complete immune system was ablated and shifted to a male status (positive for x- and y-chromosomes), derived from the organ donor. She developed tolerance with no signs of rejection of the received organ for 17 months.
This chimerism, described for the girl, usually appears for some time and is associated with the induction of tolerance but gets lost after some months. But still, the appearance of a small amount of donor derived immune cells, could often be associated to transplantation tolerance, mediating acceptance or unresponsiveness.
Altogether these case reports show that many possible treatments can result in tolerance but all are depending on factors which are so far not completely predictable. Or, as in the case of the girl receiving the liver transplantation, the onset of tolerance and the cause was a coincidence. At least, almost in all cases, the results are unequal and no clear rationale can be seen. Further investigation in this field is needed and maybe one day the combined results can result in a broad therapeutical application.
Kawai, .T. (2008). HLA-mismatched renal transplantation without maintenance immunosuppression.. New England Journal of Medicine, 358(4), 353-361.
Scandling, J.D. (2008). Tolerance and Chimerism after Renal and Hematopoietic-Cell Transplantation. New England Journal of Medicine, 358(4), 362-368.
Alexander, J.I. (2008). Chimerism and tolerance in a recipient of a deceased-donor liver transplant.. New England Journal of Medicine, 358(4), 369-374.
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