Allogeneic bone marrow transplantation: relation between chimaerism and immunity

Abstract

Bone marrow transplantation has been performed for almost 30 years in the Department of Paediatrics of the Leiden University Hospital. Major research efforts focussed on the accurate determination of the chimaerism and the immunological recovery of the graft recipient, and on the immunological interactions between donor and host cells. The results of our investigations and those of other groups in the field of bone marrow transplantation provided a lot of information on these topics, offering possibilities for improving the outcome of the patients by changing transplant procedures and developing novel preventive and therapeutic interventions. As was formerly shown in animal experiments, the conditioning of the graft recipient had to be tailored for the purposes of the bone marrow transplantation. It had to be either immunosuppressive, or space creating, or tumor eradicating, or a combination of these, in accordance with the original disease of the patient. It also became evident that the numbers of functional T lymphocytes remaining in the host and present in the graft had reciprocal effects on graft rejection (host-versus-graft) and graft-versus-host disease. Modification of the composition of the graft, e.g. by T-cell depletion, resulted in an increased rejection rate unless extra-immunosuppression was administered to the host. Vice versa, the occurrence and severity of graft-versus-host disease was very much dependent on HLA-matching between donor and recipient and on numbers of T cells in the graft. With regard to immune recovery after bone marrow transplantation, it was shown that the pretreatment of the host had to be adjusted to obtain engraftment of those cell lineages which were relevant for an adequate and complete immune competence of the host after bone marrow transplantation. This could nicely be illustrated by the relationship between B-cell engraftment and recovery of humoral immunity after HLA-haplo-identical bone marrow transplantation of young children, suffering from severe combined immunodeficiency disease. In later experiments our group showed that is was feasible to transfer specific immunological "memory" to vaccine antigens from donor to host by mature T cells in the graft and following priming of donor and host with the antigen prior to transplantation. Reversely, when T cells were taken out of the graft, reactivations of DNA-viruses such as CMV and EBV could be observed, frequently resulting in lethal infections. Also there was an increase of the frequency of leukaemia relapse after T-cell depleted bone marrow transplantation for leukaemia. In order to prevent these severe complications donor T-cell infusions have been tried with success, although also with an increase in occurrence and severity of graft-versus-host disease. Recent developments on the production ex vivo of virus-specific cytotoxic T cells and the transfer of these cells to the host, early after bone marrow transplantation, resulted in remarkable clinical effects. These observations open the way for further research, development and trials of adoptive immunotherapy for the prevention of leukaemia relapse after bone marrow transplantation of leukaemia patients. Also recently attention has been paid to the induction of microchimaerism with donor haemopoietic cells, following a relatively non-toxic one-day conditioning of the host, in order to attain a state of tolerance against a solid organ transplant. This possibly promising application of the presence of a blood cell chimaerism is at present under study in animal models.