Bone marrow transplantation.

The goals in bone marrow transplantation are its application to the treatment of diseases arising in the blood-forming tissues of man. Techniques for procuring and grafting marrow are of the needle-and-syringe type and are based on the normal physiological processes in which stem cells circulate through blood and other fluids of the mammalian organism. Destruction of bone marrow by irradiation, chemicals, or unknown agencies provides the immediate experimental system for demonstrating the therapeutic value of marrow transplants. Genetic diseases characterized by abnormal marrow function are also modifiable by grafts of blood-forming tissues. Studies with identical twins are critical experiments for showing the clinical value of grafts, even though the transplanted cells cannot be identified by the usual marker techniques. Among the best results seen with marrow grafting is the presumed cure of certain rare hereditary immune-deficiency disorders of children. A major problem in bone marrow transplantation-one that delays its wider clinical application-is the immune reaction from cells growing out of the foreign transplant which attack the host (the graft-versus-host reaction). Attempts to use a graft-versus-host response to eliminate tumor cells is a part of the marrow research program. The history of the processes that led to some of the achieved goals in marrow grafting shows the usual multicentric origin of an idea. Certain individuals play critical roles in developing the idea. Finally, a body of knowledge is accumulated that opens up or limits prospects for the future. In bone marrow transplantati on, future achievements will depend in part on the progress that is made in the areas of cell separation, bone marrow banking, and tissue culture.

Adenocarcinoma of the gallbladder in guinea pigs.

Adenocarcinoma of the gallbladder developed in 17 of 68 untreated and in 26 of 83 irradiated guinea pigs of inbred strains 2 and 13. The carcinomas spread widely by direct extension and through lymphatic and blood vessels to lymph nodes, mesenteries, omenta, abdominal wall, liver, lungs, bones, and spleen. Whole-body exposure to gamma or X-radiation increased both the number of tumors and metastases in male inbred guinea pigs but not in females. Significantly fewer (9 of 98) noninbred than inbred guinea pigs developed gallbladder carcinomas after irradiation. In 9 untreated noninbred guinea pigs gallbladder carcinomas were not found. Inasmuch as the effect of irradiation was not dose-dependent, an indirect systemic effect of irradiation was postulated. This is the first report on the occurrence of spontaneous gallbladder adenocarcinomas in guinea pigs.

Secondary disease mortality in rat-mouse radiation chimeras.

Two statistical experimental designs were used to investigate factors involved in 90-day mortality from secondary disease in lethally irradiated mice treated with rat bone marrow. Secondary disease is a graft-versus-host syndrome that has a mortality of about 65-95% in this transplant situation. When the factors--age-of-donor-cells, day-of-cell-injection, dose-of-marrow-cells, sex, and environment--were examined for their main effects and interactions, some combinations of these factors were found to give about 25% 90-day mortality. The experiments indicate that the lowest mortality can be achieved with an injection of 40 million or more cells 1 day after irradiation and an ultraclean environment of unlimited filter-top caging.

Effects of spaceflight on the number of rat peripheral blood leukocytes and lymphocyte subsets.

Experiments were carried out on peripheral blood leukocytes and spleen lymphocytes from 29 male rats that were flown during the Spacelab Life Sciences 1 (SLS-1) nine-day mission on the shuttle Columbia in June 1991 and on appropriate ground controls. On the day of landing, there was a significant decrease in the total white blood cell counts (P < 0.0001) of flight animals in comparison to controls. There was also a significant decrease in the absolute number of lymphocytes (P < 0.0001) and monocytes (P < 0.0001) in the flight animals. A slight decrease in the absolute number of eosinophils and a slight increase in the number of neutrophils were observed at landing, compared with preflight values. Immunophenotyping of the peripheral blood and spleen lymphocytes of flight and control animals indicated that, on the day of landing, there was a decrease in the absolute number of CD4 and CD8 positive cells and B lymphocytes. However, relative percentages of peripheral blood CD4+, CD8+, and B cells were not found to be depressed. No differences were discerned in the percent reactivity of spleen lymphocytes of flight animals compared with controls. The observed decrease in the number of leukocytes and lymphocytes at the immediate postflight period was transient and all values returned to the control levels by nine days postflight.

The first official meeting of the International Society for Experimental Hematology.

In 1972, 85 scientists from 10 countries came to Milwaukee to participate in the first official meeting of the International Society for Experimental Hematology. We summarize here some of the events leading up to the meeting, fondly recollect the enthusiastic spirit of the meeting and reprint the program, which is not all that different in content from the program of the 21st meeting.

Lymphatic tissue changes in rats flown on Spacelab Life Sciences-2.

Thymus, spleen, inguinal lymph node, and bone marrow specimens from rats flown on the 14-day Spacelab Life Sciences-2 mission were examined after staining of tissue sections. The primary observation was a transient retrogressive change in lymphatic tissues in the rats within a few hours after landing. There was a diffuse increase in tingible body-containing macrophages in the cortex of the thymus, thymus-dependent areas of the splenic white pulp, and inguinal lymph node. This was not observed 9 days after recovery. The in situ labeling of fragmented DNA strands catalyzed by exogenous terminal deoxynucleotidyltransferase (TdT) with ApopTag reagents (Oncor, Gaithersburg, MD) inside the tingible body-containing macrophages indicated that the process was one of apoptosis. No increase in tingible body macrophage activity was noted in thymus and spleen tissue obtained from rats in flight on flight day 13. The reaction to gravitational stress from readaptation to 1 G is the most likely explanation of the transient retrogressive change in lymphatic tissues.

Hymenolepis nana: intestinal tissue phase in actively immunized mice.

We investigated the fate of the intestinal cestode Hymenolepis nana in immunized mice. Immunity was induced by infection with the parasite eggs. These immunized animals and unimmunized controls were then challenged with 50,000 H. nana eggs. The mice were killed 4 to 90 hr after challenge, and H. nana in the intestinal tissue were counted. At 4 hr after challenge the unimmunized and immunized animals had approximately equal numbers of oncospheres. By 12 hr there were fewer parasites in the immunized than in the unimmunized animals. At 90 hr, no H. nana were seen in the immunized mice, whereas in the unimmunized animals the median number of cysticercoids was more than 1,000. It appears, therefore, that in mice well immunized to H. nana by infection, challenge oncospheres can burrow into the intestinal tissue before they are killed. The reduced number of oncospheres in the immunized mice 12 hr after challenge, and the accumulation of eosinophils near individual oncospheres still present, indicate that an immune response to the parasite was taking place. Absence of a lymphocyte infiltration near any of the oncospheres suggests that the mechanism of immunity was not lymphocyte mediated; thus, the histopathology of the reaction is consistent with that of humoral immunity.

A review of certain low-level ionizing radiation studies in mice and guinea pigs.

Starting in the early 1940s, Egon Lorenz and collaborators at the National Cancer Institute began an extended study of chronic low-level ionizing radiation effects in what was then the tolerance range for man. Observations on life span, body weight and radiation carcinogenesis, among others, were made in mice, guinea pigs and rabbits. At the then-permissible exposure level, 0.1 R** per 8-h day until natural death, experimental mice and guinea pigs had a slightly greater mean life span compared to control animals. In addition, there was marked weight gain during the growth phase in both species. Increased tumor incidence was also observed at the 0.1-R level in mice. The primary hypothesis for increased median life span has been rebound regenerative hyperplasia during the early part of the exposure; in the presence of continuing injury, there is physiological enhancement of defense mechanisms against intercurrent infection. The body weight gain has not been explained.

Growth of mycobacterium bovis (BCG) in T lymphocyte-depleted mice.

BCG Montreal (10-6 viable bacilli) injected intravenously into adult thymectomized, irradiated, and bone marrow-reconstituted (THXB) C57Bl times C3H F1 hybrid mice induced a progressive systemic infection which killed 95% of the animals within 60 days. Control mice infected with this dose of BCG did not die. The infected THXB mice failed to develop detectable levels of tuberculin hypersensitivity although they did show considerable Arthus (3 h) reactivity. The BCG-infected THXB mice lost weight progressively, and the root spleen and root lung indices increased substantially as the infection proceeded. None of the THXB mice developed an antibacterial immune response to the systemic BCG infection, and this was reflected by the continued persistence of macroscopic lung granuloma in these animals. The BCG-infected control mice developed as many surface tubercles as did the THXB animals, but the granulomas rapidly regressed in size and numbers in the normal mice. The lung changes correlated with the amount of tritiated thymidine incorporated by the lung cells in the later stages of the BCG infection. T cell depletion depressed the early splenic peak normally seen in BCG-infected controls, but, on the other hand, there was a progressive increase in lung counts in the THXB mice as the infection progressed and this late peak was not seen in the control animals. The significance of these findings is discussed in relation to the development of antituberculous immunity by BCG-infected mice.