Risk of donor lymphocyte infusions following allogeneic bone marrow transplantation.

Clinical data so far suggest that the resistance to induction of graft-vs.-host disease (GVHD) by donor lymphocyte infusions is less prominent in allogeneic bone marrow transplant patients than indicated by the limited results of experimental studies in animals published many years ago. To confirm this apparent discrepancy, graded numbers of donor type splenocytes were given at various intervals after bone marrow transplantation to mouse radiation chimeras. The results were closely similar to the previously published data, in that the chimeras developed a high degree of tolerance, equivalent to 2-3 log protection. It was also observed that this tolerance can be broken by prior treatment with a lethal dose of cyclophosphamide. It is postulated that the leukemic cells in relapsed patients reduce the suppressor cell population that is responsible for the resistance to re-induction of GVHD.

Both bone marrow- and non-bone marrow-associated factors determine susceptibility to experimental autoimmune encephalomyelitis of BUF and WAG rats.

To determine the feasibility of treatment with allogeneic bone marrow for experimental autoimmune encephalomyelitis, we investigated the susceptibility to experimental autoimmune encephalomyelitis of bone marrow chimeras using BUF, (WAG X BUF)F1 (high responder), and WAG (low responder) rats. In contrast to previous studies in which other rat strains were used, the response was largely determined by the genotype of the grafted bone marrow, but the influence of a non-bone marrow-associated factor was evident. The latter factor was identified as a low corticosterone response in BUF rats and a high corticosterone response in WAG rats. After adrenalectomy, a significant proportion of WAG rats developed clinical experimental autoimmune encephalomyelitis. The bone marrow-associated factor of resistance appeared to be the activity of cyclophosphamide-sensitive suppressor cells. The latter cells were found to interfere with the formation of inflammatory foci in the central nervous system, while corticosterone primarily prevents the clinical expression of lesions.

Treatment of experimental allergic encephalomyelitis in rats with total body irradiation and syngeneic BMT.

Experimental allergic encephalomyelitis (EAE) was induced in Buffalo rats by immunization with syngeneic spinal cord homogenate in complete adjuvant. EAE, an autoimmune disease of the central nervous system (CNS), is regarded as a model for multiple sclerosis. When severe paresis had developed, rats were treated with high-dose total body irradiation (TBI) and transplanted with syngeneic BM from healthy donors. Nine Gy TBI followed by syngeneic BMT greatly accelerated recovery of paresis compared with untreated controls. In 6-33% of the treated animals a relapse of EAE was observed shortly after treatment. Reimmunization 20 days after treatment, resulted in a relapse in 12-44% of the rats. Employing the maximally tolerated dose of TBI (10 Gy) did not significantly alter the incidence of spontaneous or induced relapses. Furthermore, it was shown that irradiation of the CNS only was not sufficient for the induction of complete regression of paresis. The origin of the cells responsible for these relapses is discussed, as is the importance of reimmunization in evaluating the effect of treatment of experimental autoimmune disease.

Remission induction of adjuvant arthritis in rats by total body irradiation and autologous bone marrow transplantation.

Following the demonstration that adjuvant arthritis in rats can be cured with total body irradiation (TBI) and allogeneic or syngeneic bone marrow, the efficacy of autologous bone marrow was investigated in the experiments reported here. Bone marrow from arthritic rats, harvested at the same time that the recipients were irradiated, and real autologous bone marrow were found to be similarly effective as bone marrow grafts from naive syngeneic donors. Sublethal TBI with lower doses was less effective, but the highest tolerated doses of 8 Gy approached the effect of 9 Gy and bone marrow rescue. In contrast, partial body irradiation of either the affected limbs, or of the whole body except the limbs, resulted in only partial and temporary regression of the arthritis.

Regression of adjuvant-induced arthritis in rats following bone marrow transplantation.

Total body irradiation followed by bone marrow transplantation was found to be an effective treatment for adjuvant arthritis induced in rats. This treatment is most effective when applied shortly after the clinical manifestation of arthritis--i.e., 4-7 weeks after administration of Mycobacterium tuberculosis. Transplantation of bone marrow at a later stage results in a limited recovery, in that the inflammatory reaction regresses but the newly formed excessive bone is not eliminated. Local irradiation of the affected joints had no effect on the disease. It could also be excluded that the recovery of arthritis following marrow transplantation is due to lack of available antigen. Transplantation of syngeneic bone marrow is as effective as that of allogeneic bone marrow from a rat strain that is not susceptible to induction of adjuvant arthritis. The beneficial effect of this treatment cannot be ascribed to the immunosuppressive effect of total body irradiation, since treatment with the highly immunosuppressive drug Cyclosporin A resulted in a regression of the joint swelling but relapse occurred shortly after discontinuation of the treatment.