Successful Allogenic Bone Marrow Transplantation in Man: Chimerism, Induced Specific Tolerance and Possible Anti-Leukemic Effects

Abstract

A patient suffering from acute lymphoblastic leukemia in the third progressive phase, refractory to the majority of available treatments, was given total-body irradiation of 800 r. dosage, after administration of methyl-nitro-imidazolyl-mercaptopurine (300 mg. daily for 4 days). One week after irradiation, he received an infusion of a mixture of equal parts of bone marrow from six donors (mother, sister, father and three brothers), a total of 5.8 x 1010 nucleated cells. Myeloid restoration began 2 weeks after the infusion and continued to progress rapidly. The reality of the graft was demonstrated by study of the erythrocytic antigens. Nearly all the erythrocytes found in the blood after 6 months belonged to the phenotype of one of the male donors. Studies of chromosomes and leukocyte sex chromatin suggested that a small proportion of leukocytes were being produced by the cells of one of the female donors. The patient was found to produce beta 2A, beta 2M and gamma globulins of the Inv type of the donors, suggesting that lymphoid cells may also have been successfully grafted. A skin graft from the male donor whose marrow graft had apparently been accepted was still perfectly intact 7 months after grafting, whereas the grafts from other donors were rejected, indicating a specific tolerance to tissues from this donor. Previous studies of compatibility between the recipient and the various donors by a histocompatibility test described by us, or by means of similarities in leukocyte antigens, indicated that the accepted donor had been antigenically more nearly compatible than the others. What appeared to be a secondary syndrome became manifest 1 week after marrow transfusion; it consisted of weight loss, digestive disorders (anorexia, nausea, vomiting, diarrhea), hepatic disturbances (hepatomegaly, increased serum concentrations of various enzymes), transient polyadenopathy (histologically composed of histiocytic proliferation and lymphocytic aplasia), desquamative erythrodermia, eosinophilia exceeding 50 per cent, and superinfection (including a probable miliary tuberculosis). The syndrome was controlled by careful symptomatic treatment; its intensity gradually abated. Reactivation of the secondary syndrome was accomplished by reinjection of leukocytes from the donor whose graft had been tolerated. This was controlled by Δ-1-cortisone and symptomatic treatment. The patient was still alive and in apparently complete hematologic remission from the leukemia 12 months after the treatment described above. Particular reasons for this success possibly include the absence of previous blood transfusions and the use of multiple marrow donors.

Visual outcome and cataract development after allogeneic stem‐cell transplantation in children

“…Allogeneic stem‐cell transplantation (SCT), first described in the mid‐1960s (Mathe et al. 1965), is now an established treatment of haematological malignancies offering a chance of cure in children who do not respond to conventional treatment and in children with other severe haematological and inborn diseases, such as haemoglobinopathies and severe combined immunodeficiencies.…”

Hematopoietic stem cell transplantation and cellular therapy

“…The beneficial effect of allogeneic bone marrow on leukemia after TBI was reported by Barnes and Loutit in 1957. 50 In man the antileukemic effect of allogeneic bone marrow was first described by Mathe´et al, 51 the term adoptive immunotherapy was proposed by Mathé. Patients with acute leukemia and GVHD had less relapses, but only those with chronic GVHD surviving more than 150 days had an improved survival.…”

Can graft-versus-leukemia reactivity be dissociated from graft-versus-host disease?

“…In 1956 Barnes et al (1), exploring X-ray irradiation plus BMT as a therapeutic regimen for transplantable leukemia in mice, first demonstrated superiority of alloBMT to syngeneic BMT in achieving successful eradication of leukemia. In 1965, Mathé et al (2) described the first case of an irradiated leukemia patient exhibiting successful engraftment of allogeneic bone marrow (alloBM) with prolonged leukemia-free survival, suggesting that the allogeneic transplant exerted an antileukemic effect superimposed on that of radiotherapy. At that time it had become clear that immune reactivity of the donor graft against host tissues generates GvHD (3).…”