Bone marrow transplantation. Part II--autologous.

Autologous bone marrow transplantation provides an effective form of "rescue" following high-dose therapy used for treating certain malignant diseases. The high doses of radiotherapy or chemotherapy, or both, should allow for greater tumor cell kill if dose-response to therapy exists for that tumor. The use of autologous bone marrow obviates the need for an HLA-identical donor, and the need for pretransplant immunosuppression; no graft-versus-host disease would ensue. We review in part II the history and background, methods of obtaining autologous stem cells, and details of the results achievable with this type of therapy. We discuss potential difficulties with autologous transplantation, as well as possible future areas of research.     

Bone marrow transplantation. Part I--Allogeneic.

Major progress in experimental and clinical research has made allogeneic bone marrow transplantation a highly effective therapy for a variety of malignant and nonmalignant diseases. Allogeneic bone marrow transplantation from histocompatible donors is now the therapy of choice for some of these disorders. We review in part I the history, technical approach, complications, and the results achievable with this therapeutic approach. Further experimentation and future goals are also discussed.     

Neutrophil marrow release. A system analysis.

Neutrophil marrow egress is governed by several processes. The most important are cell maturation, functional behavior of marrow sinusoids and humoral or neuro-vascular factors. Neutrophil release cannot be observed directly but is reflected in the size, cellular composition and kinetics of the nonproliferating pool of granulocytopoiesis in bone marrow and of blood neutrophil pool. These experimentally determined parameters were used as the basis of a mathematical model study. The model describes two catenated compartments, the nonproliferating pool of granulocytopoiesis in marrow and the total blood granulocyte pool. Cell transit from one pool to the other was assumed to be age-dependent. It was expressed by a positive sloping sigmoidal function that defines the egress potential fo the cells that increases with cell maturation. During maturation granulocytopoietic cells develop intense motility which determines the morphology of the cells on smears. Relationship between cell motility and its morphology was defined by functions determining the age-dependent probabilities of cell fixation as metamyelocytes, band- and segmented forms, respectively. The parameters of this model could be so adjusted that all experimental data were matched within experimental errors. Thus, qualitative and quantitative information on neutrophil marrow egress was obtained for normal and pathological states of granulocytopoiesis.     

Bone marrow transplantation in Canada.

Bone marrow transplantation is an established form of therapy for aplastic anemia and severe combined immunodeficiency. It is also a therapeutic option for acute leukemia in remission. Unfortunately, compatible donors are not available for most patients who could benefit from it. Further refinement of the techniques involved may make it suitable for more patients. Graft rejection, recurrent leukemia, graft-versus-host disease and interstitial pneumonia continue to be the main unsolved complications of bone marrow transplantation, but recent advances have decreased their frequency and severity. Most of the complications of allogeneic bone marrow transplantation may be eliminated with the use of autologous stem cells. For further refinement bone marrow transplantation should continue to be performed in large centres that combine treatment with research.     

Bone marrow T cells. II. Thymic dependency

Mouse bone marrow contains cells capable of responding in vitro to the T cell mitogens PHA and Con A. These cellular responses are not demonstrable in the marrow of athymic nude mice (when compared with heterozygous littermates) and are depressed 47% in the marrow of neonatally thymectomized LAF₁ mice (when compared with sham-operated littermates). Therefore, the population of “bone marrow T cells” is thymus dependent.     

In utero bone marrow transplantation of fetal baboons with mismatched adult baboon marrow.

In utero bone marrow transplantation to fetuses offers the potential advantage of ameliorating the effects of genetic disorders by transplanting allogeneic hematopoietic stem cells into recipients who are immunoincompetent and require no preparative regimen. Therefore, we undertook studies to examine the feasibility of in utero bone marrow transplantation of unrelated allogeneic adult bone marrow into fetal baboons. Thirty-one baboon fetuses were transplanted between the ages of 60 and 160 days gestation (normal gestation, 182 days) with unrelated allogeneic adult bone marrow containing a different isozyme of glucose-phosphate isomerase (GPI). Approximately one third of the 80-day fetuses demonstrated engraftment 1 month after transplantation. Three of three of the initial chimeras died in utero 45 to 80 days after transplantation and the remaining chimeras lost their graft. Furthermore, 80-day fetal baboons were able to recognize donor cells, maternal cells, and other adult baboon peripheral blood cells in a mixed lymphocyte culture (MLC) reaction but still could engraft with allogeneic bone marrow. In contrast all nonchimeric animals survived to term. These data suggest that fetal transplantation of primates is feasible using techniques employed in these studies and that transplantation of younger fetuses who are immunocompetent should be attempted.