The Effect of the Amount of Isologous Bone Marrow Injected on the Recovery of Hematopoietic Organs, Survival and Body Weight after Lethal Irradiation Injury in Mice

Abstract

The relation between the amount of isologous bone marrow injected into a lethally irradiated mouse and its 30 day survival, its bone marrow response, the histology of the bone marrow in its left femur, its peripheral blood leukocyte count, the weight of its thymus, spleen, and body, and its appearance showed that quicker recovery of these end points occurred with increasing amounts of bone marrow administered. The bone marrow parameter was the quickest to respond to the varying amounts of bone marrow injected. In addition, no optimum dose of bone marrow was found in these experiments for this end point. This indicates that the bone marrow of an irradiated mouse could be made to show even quicker return to normal by injection of greater amounts of cells. The peripheral blood leukocyte count and the spleen weight also showed very quick recovery with the massive doses of bone marrow injected. For both end points, however, an optimum response was reached, which in the leukocytes, was 64.4 x 106 -237.9 x 106 cells injected, and in the spleen weight, 12.8 x 106 -237.9 x 106. An optimum response for thymus weight was also found with bone marrow doses of 64.4 x 106 - 237.9 x 106 cells. The cell dose for the optimum response in recovery of body weight was 12.8 x 106 - 237.9 x 106. Optimum 30 day survival was reached with injection of 64.4 x 106 bone marrow cells in these experiments. However, doses from 12.8 x 106 to 64.4 x 106 cells were not tested. The dose of bone marrow cells that was calculated to give 50 per cent 30-day survival was 0.42 x 106 (0.17 x 106, 1.92 x 106) cells for the males and 1.06 x 106 (0.42 x 106, 2.51 x 106) cells for the females. The calculated dose of bone marrow cells that would give 1 per cent 30-day survival of the males was 0.008 x 106 (0.0008 x 106, 0.0284 x 106) and for the females 0.0102 x 106 (0.001 x 106, 0.040 x 106) cells. These point estimates seem to be unreliable in view of the extremely large 95% confidence intervals. However, in experiments done by other workers at the National Cancer Institute similar to those reported in this paper, M. Schneiderman determined a threshold dose ranging from 0.0026 to 0.0320 x 106 cells by a somewhat different analysis of the data.7 Jacobson et al. cite a figure of 3-5 x 106 bone marrow cells from young donor mice as causing 53% 28-day survival in CF No. 1 mice exposed to 900 r.2 In using bone marrow from older mice, they found that 5-9.9 x 106 cells caused 54.9% 28-day survival. They also estimate that 50,000 cells are necessary to produce significant recovery of mice after an LD99 exposure. This figure is similar to that determined from the results of the present experiments. The results obtained from mice injected intravenously with a massive dose of bone marrow 3 days after irradiation indicated that the number of cells in the bone marrow of the right femur can be elevated within a few hours after injection. However, this could be observed only in an irradiated animal where the number of cells in the right femoral bone marrow was already low. A similar observation was made by Graevsky.8 This finding gives further support to the hypothesis that intravenously injected bone marrow transplants to bone marrow sites in the irradiated host.9

Improvement in rejection, engraftment rate and survival without increase in graft‐versus‐host disease by high marrow cell dose in patients transplanted for aplastic anaemia

“…Also, it was unbiased by postgrafting immunosuppression, since all but 12 patients were given methotrexate. A correlation between marrow cell dose and speed of engraftment has been described in a number of animal models (Urso & Congdon, 1957;Thomas et al, 1962;Appelbaum et al, 1978;Bodenberger et a), 1980). Previous clinical studies have given conflicting results with one study reporting a correlation (Niederwieser et al, 1983) and two studies failing to observe correlations between marrow cell dose and speed of engraftment (Thomas et al 19 77;Atkinson et al, 1985).…”

Influence of donor lymphocytes on the incidence of primary graft failure after allogeneic bone marrow transplatition in a murine model

“…Beside host immunosuppression and histocompatibility, the number of marrow cells transferred must be regarded as one of the most critical factors with respect to successful long-term engraftment. Although early experimental data (Vos, 1964;Urso & Congdon, 1957) stressed the role of the size of the marrow inoculum, its significance has not been commonly accepted in the clinical setting. Usually, marrow cell harvesting leads to cell doses in the range of 1-4 x 10' cells/kg body weight.…”

“…the relative impact of donor lymphocytes, compared with other factors influencing marrow engraftment, has not been definitively established (Martin, 1992). Besides host immunosuppression and GvHR, the total number of haemopoietic cells transplanted was considered to be critical for successful allografting (Urso & Congdon, 1957: Lapidot et al 1988Uharek et al, 1992). To evaluate the relative role of donor lymphocytes and marrow cell dose, lethally irradiated mice received increasing numbers of allogeneic bone marrow cells that had been depleted of different lymphocyte subsets.…”

Unexpected roles for bone marrow stromal cells (or MSCs): a real promise for cellular, but not replacement, therapy

“…This led to the application of BM transplants in certain diseases and radiation accidents in the early 1950s in Europe. As stem cells could not be isolated at that time, all of the cells in BM aspirates were administered to patients simultaneously (Thomas et al, 1957;Urso and Congdon, 1957). In his first report of six cases, Thomas described the results of giving marrow cells from unrelated donors.…”