[Bone marrow transplantation in panmyelopathy].
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Biomedical subjects
Publications and source records attributed to R Storb.
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Fifteen dog families were studied in mixed leukocyte culture. In eight families of seven different breeds, one-way nonstimulation in mixed leukocyte culture was observed. This could be explained by lymphocyte-defined (LD) homozygosity in most instances. In one family, an inclusion phenomenon was postulated, and in another, a deletion. LD homozygotes can serve as reference for LD typing and can also help elucidate the relative role of the LD locus for transplantation of organs.
Previous studies have shown that a single transfusion with whole blood from the intended marrow donor 10 days before 1,200 R of total body irradiation (TBI) and marrow grafting can immunize a dog and lead to rejection of the subsequent marrow graft. The present study explored the effect of time on immunization to marrow grafts by preceding blood transfusion. All receipents were given 1,200 R of TBI followed with 4 hr by a hemopoietic graft from an unrelated donor mismatched at the major canine histocompatibility complex. Two groups of recipients were studed. In group 1, 7 dogs were given a transfusion of blood from the marrow donor 24 hr before TBI, and 6 rejected the graft; in group 2, 16 dogs were given transfusion of blood from the marrow donor 3 months before TBI, and 8 rejected the graft. The frequency of rejection in both groups was significantly greater than in untransfused dogs mismatched with their donors at the canine major histocompatibility complex (11 rejections in 67 transplants). The results indicate that exposure to donor blood from 24 hr to 3 months before marrow grafting significantly increases the likelihood of graft rejection.
Nine long-term canine radiation chimeras and their canine histocompatibility locus (DL-A) compatible, mixed leukocyte culture negative littermate marrow donors were studied between 545 and 1282 days after 1,200 R total body irradiation and marrow grafting. Before the time of testing, marrow donors were immunized against their chimeras by repeated skin grafts which they rejected. Skin fibroblasts from chimeras and their donors were tested for cell inhibition (CI) in the microcytotoxicity assay be exposure to lymphocytes from chimeras, donors and normal dogs and the effects of various sera on CI were evaluated. Lymphocytes from sensitized marrow donors consistently inhibited fibroblasts from the chimeras (eight of nine dogs); CI was abrogated by chimeric serum in only three of eight cases. Only two chimeras showed consistent CI of their "own" fibroblasts; CI was blocked by chimeric serum in one of the two. The remaining seven chimeras did not show consistent CI. Sequential studies in 16 additional recipients of DL-A compatible littermate marrow were carried out from 45 to 439 days after marrow grafting. Seven of the 16 did not show CI of chimeric fibroblasts by chimeric lymphocytes at any time. Nine showed CI on one or several occasions. Serum blocking factors were seen on one occasion in each of two chimeras. In conclusion, the CI assay is able to detect immunity against "minor" histocompatibility systems in dogs. Both long- and short-term chimeras occasionally demonstrated CI of chimeric fibroblasts but serum blocking factors did not appear to be necessary for maintaining stable graft-host "tolerance."
An attempt was made to demonstrate in vivo the presence of blocking factors in the serum of canine chimeras with grafts of chimeric skin onto the marrow donor as an indicator system. Even very large amounts of chimeric serum (one-fourth of the plasma volume infused daily from day 2 before skin grafting until rejection) failed to modify first and third set skin graft rejection patterns. Thus, serum blocking factors could not be demonstrated by this in vivo approach.
Twenty-five dogs with malignant lymphoma (L) and 18 dogs with solid, nonhematologic tumors (ST) were treated with 1200 R total body irradiation (TBI). Rescue from the otherwise lethal hemopoietic toxicity by infusion of autologous marrow aspirated before TBI was attempted, and survival, response to TBI, and immune reactivity post-grafting were determined. Eight L dogs survived more than 14 days post TBI and marrow grafting, and 12 out of 19 evaluable dogs showed a decrease of 75 per cent or more in clinically detectable tumor. There was no evident relationship between clinical status or marrow status before TBI and survival of more than 14 days or tumor response to TBI. Seven of the 8 survivors ultimately developed recurrent tumor. Eight ST dogs survived more than 14 days. Only 4 of 14 evaluable ST dogs showed significant clinical response of their tumor to TBI. Humoral and cellular immune reactivity were significantly impaired during the 10-week period following TBI and marrow grafting in all dogs studied. These results indicate that therapy in addition to lethal doses of TBI is necessary to cure spontaneous L or to significantly affect ST in dogs. They also provide baseline data which are necessary to assess the immunotherapeutic effectiveness of allogeneic marrow grafts.
Pulmonary macrophages were obtained from a canine radiation chimera 221 days after irradiation. A variant of soluble glutamic oxaloacetic transaminase was utilized to demonstrate that these cells were of donor origin, providing evidence that pulmonary macrophages in the dog are of marrow origin.
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