In 1949, Leon Orris Jacobson and Egon Lorenz showed to the United States that intravenous injection of bone marrow extracts from a donor (D) mouse line, into a recipient (R) mouse line subjected to lethal irradiation, activated in the latter the restoration of bone marrow thus rescuing them from death. They believed they had discovered a humoral factor from within the donor mice, which potentiated the multiplication of hematopoietic precursors in the bone marrow of the recipient mice. Yet, John Loutit and Dirk Van Bekkum demonstrated that this “repairing factor” could be replaced by bone marrow cells. Instead of a hypothetical factor stimulating the proliferation of some stem cells spared by the irradiation, they showed that it was the injected stem cell graft, which multiplied and differentiated to restore the once destroyed bone marrow. Moreover, this graft was obtained with the transfusion of cells that were autologous (from the same animal), isogeneic (from another of the same inbred strain), allogeneic (from another strain), or even xenogeneic (for example cells of rats transfused into mice). All cases led to the rapidly progressive repair of bone marrow function and, simultaneously, its repopulation.
However, the graft of allogeneic cells provoked in the recipient an immune reaction of the donor lymphocytes against the recipient cells and tissues. This would develop into a serious disease of varying intensity but generally fatal, named the graft-versus-host disease (GvHD) characterized by a complex syndrome associating digestive, skin, cardiac, respiratory, hematological and immunological signs. What remained unclear was whether this reaction also concerned the tumor cells, known at the time to be destroyed by non-specific yet strong immunological shock. In other words, it remained unclear as to whether the GvH reaction accompanied reactions of the graft against leukemia (GvL) or tumor (GvT) cells.
In the late 50s, Georges Mathé thus committed himself to researching the potential use of bone marrow transplants in the treatment of leukemia. In a patient with leukemia already treated by chemotherapy, what remained to be determined were the methods of choosing the best donor, the correct dose of irradiation to precede the transplant, and the intensity of the GvH and GvL reactions.
Mathé started by comparing the conditions of application in humans to the results acquired in animals, in particular the dosimetries in mouse and human and the role of blood transfusions prior to the bone marrow transplantation. The prior introduction of mature allogeneic bone marrow-derived cells into the organism permitted the later transplanted graft to induce reactions conserved in the organism’s memory and thus to activate unexpectedly intense and poorly controllable responses.