Origins of bone marrow transplant (BMT)
The first nuclear event which also triggered interest for the first time in bone marrow transplant, was the detonation in 1945 in New Mexico, of nuclear energy and the effects of the atomic bomb on the populations of Hiroshima and Nagasaki.
While he was studying the effects of lethal irradiation in mice in 1949, Jacobson found the protective effect of the spleen, a spleen containing hematopoietic tissue. A year later, Lorenz showed that protection could also be given by intravenous transfusion of bone marrow.
In the beginning, it was thought that protection against radiations was due to humoral components from the bone marrow transplant of the donor mouse. Five years later, in 1955, many researchers not only demonstrated that protection was due to cellular components, but also showed that the donor cells, once transfused, were able to repopulate the irradiated marrow. In 1958, an irradiation accident occurred at Vinca (Yugoslavia), and 5 doctors developed irradiation induced aplasia. In 1959, J. Mathé described the success of an allogenic bone marrow transfusion in the five doctors and showed the transitional transplant studying red cell antigens of the recipient.
The First Attempt to Graft
In the early 1960s, several studies showed the failure of the transplant to treat patients with leukemia.
In 1959, E. Donall Thomas (USA) described the success of a transplant. Concepts are beginning to be issued: lethal irradiation does not eliminate the possibility of marrow's functional recovery , the marrow transfusion is accompanied in some cases, by the graft-against-host disease.
Problems Encountered With BMT
The first problem that arised after a bone marrow transplantation was the rejection. Preventing rejection was considered by the use of immuno-suppressive drugs such as methotrexate.
The second problem was the graft-against-host disease, with symptoms such as diarrhea, weight loss, skin lesions and liver necrosis. The severity of these clinical signs is proportional to the amount of lymphoid cells transfused.
In 1966, 417 cases of familial allogenic bone marrow transplant were published, but only three of them were associated with prolonged survival of the patient.
A critical point in the history of bone marrow transplantation and the improvement of its results, was the discovery of histocompatibility or HLA.
The first transplant with an HLA compatible donor was performed in 1968 in a patient with an immune deficiency. Other HLA-compatible transplants were performed in 1970 in patients with leukemia or aplasia.
Cases of ABO blood group incompatibility were treated by plasmapheresis. Treatments of the graft versus host disease, using corticosteroids, improved survival, along with the introduction in 1980 of cyclosporine.
During the 1970s, the development of patient conditioning, thus reducing toxicity, limited the rate of relapse occurring several months after treatment. Because of the lower rate of relapse observed when patients were transplanted in the remission phase of their illness, this procedure has also become the standard procedure.
Recent Progresses in the Development of Bone Marrow Transplants
The development of bone marrow transplantation has increased in the whole world since the 1980s, not only from family related donors, but also from unrelated donors.
In the last 10 years, progresses in this field were made in 4 directions:
* Indications such as non-malignant diseases (thalassemia, drepanocytosis also called sickle cell disease, and metabolic diseases),
* research in the field of gene therapy, i.e., insertion of a healthy gene to replace a deficient one,
* transplanting cord blood stem cells that might be transfused with a degree of HLA incompatibility, without developing a severe disease against the host,
* Improvement in the lower toxicity of the graft, due to:
o A best selection of the donor's HLA,
o The development of a new generation of antibiotics, antifungal and antiviral agents,
o Growth factors to accelerate the maturation of stem cells,
o The use of monoclonal antibodies to select the CD34 + cells.
The anti-leukemic effect of bone marrow transplant has been confirmed by various studies. Controlling the balance between the deleterious effect "graft-against-host" and the beneficial "anti-leukemic" effect to the graft will be a decisive step in the progress of this therapy. The use of cytokines, such as IL.2 (interleukin-2) or the transfusion of donor leukocytes (or donor leukocyte infusion) can control this reactivity.