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Biomedical subjects

S S Boggs

Publications and source records attributed to S S Boggs.

At least 19 recordsLinked to original sources
PubMed1992

Enhancement of cell production in long-term bone marrow culture.

In an effort to increase the long-term production of hematopoietic cells in vitro, Origen hybridoma cloning factor (HCF) was added at the initiation of Dexter type cultures, in which whole bone marrow (BM) was seeded into tissue culture flasks and formed an adherent stromal layer that supported the proliferation and differentiation of primitive cells. After about six weeks, all the cultures were fully established, and continuous production of nonadherent cells was maintained for at least 27 weeks. In the groups with 20% HCF, there was a significant (three- to fourfold) increase in the steady-state cell production of 106 +/- 17 x 10(4) cells/ml compared to 26 +/- 10 x 10(4) in controls. In some cases the ability of HCF to increase productivity was limited by the nutrients and metabolic products in the culture medium. Cell number varied inversely with glucose and pH. HCF increased the concentration and absolute number of myeloid progenitors (granulocyte-macrophage colony forming units and spleen colony forming units) in the nonadherent layer and shifted the differentiation of granulocyte-macrophage colony forming units toward the production of cells of the monocyte/macrophage lineage. Spleen colonies produced from 10(5) cells from cultures with HCF were more numerous (8 +/- 2 versus 4 +/- 2) and larger than those from control cultures (2.6 versus 0.2 mg/colony), but they contained the usual cell lineages (erythrocytic, granulocytic and megakaryocytic).

Animals↗
PubMed1992

Mixed xenogeneic chimeras (rat + mouse to mouse). Evidence of rat stem cell engraftment, strain-specific transplantation tolerance, and skin-specific antigens.

We report the induction of stable and reliably detectable mixed xenogeneic chimerism through the coadministration of a mixture of untreated rat bone marrow plus T cell-depleted mouse bone marrow into B10 recipients conditioned with total body irradiation (TCD B10 mouse + untreated F344 rat----B10 mouse). Recipients repopulated as true mixed lymphopoietic chimeras, with from 1-21.6% rat-derived lymphoid cells in peripheral blood and splenic lymphoid tissue. Production of rat platelets was also demonstrated. Rat platelet and lymphoid chimerism was reliably detectable in chimeras from 1 to 7 months following reconstitution, suggesting engraftment of the rat bone marrow stem cell. Production of each stem cell-derived lineage appeared to be under independent regulation since a significantly greater proportion of platelets were rat-derived (24-81%) than were lymphocytes (1-21.6% rat), while erythrocytes were preferentially syngeneic (less than 2% rat). The tolerance induced by this model was highly donor strain-specific: donor-specific rat and mouse skin grafts were accepted while MHC-disparate third-party mouse (C3H; H-2k) and rat (Wistar Furth; Rt1Au) skin grafts were promptly rejected. Although specifically prolonged xenogeneic donor rat skin grafts underwent a slow chronic rejection, and some totally disappeared. In spite of this, chimeras retained their lymphoid chimerism, suggesting the presence of skin-specific antigens. This model for mixed xenogeneic chimerism with reliably detectable rat lymphoid cells may provide a model to study the existence of tissue-specific antigens across a species barrier, as well as mechanisms responsible for the induction and maintenance of this strain-specific transplantation tolerance.

Animals↗
PubMed1991

Cross-species bone marrow transplantation: evidence for tolerance induction, stem cell engraftment, and maturation of T lymphocytes in a xenogeneic stromal environment (rat----mouse).

Transplantation of untreated F344 rat bone marrow into irradiated B10 mouse recipients (non-TCD F344----B10) to produce fully xenogeneic chimeras resulted in stable xenogeneic lymphoid chimerism, ranging from 82% to 97% rat. Survival of animals was excellent, without evidence for GVH disease. The specificity of tolerance which resulted was highly donor-specific; MHC disparate third party mouse and rat skin grafts were promptly rejected while donor-specific F344 grafts were significantly prolonged (MST greater than 130 days). Multi-lineage rat stem cell-derived progeny including lymphoid cells (T- and B-lymphocytes), myeloid cells, erythrocytes, platelets, and natural killer (NK) cells were present in the fully xenogenic chimeras up to 7 months after bone marrow transplantation. Immature rat T-lymphocytes matured and acquired the alpha/beta T-cell receptor in the thymus of chimeras in a pattern similar to normal rat controls, suggesting that immature T-lymphocytes of rat origin could interact with the murine xenogeneic thymic stroma to undergo normal maturation and differentiation. This model may be useful to study the mechanisms responsible for the induction and maintenance of donor-specific transplantation tolerance across a species barrier.

Animals↗
PubMed1991

Time of death of CNS tumor-bearing rats can be reliably predicted by body weight-loss patterns.

A request by the Institutional Animal Care and Use Committee for an alternative to death as an end point in a cancer research project using a rat brain 9L tumor cell model led to a search for reliable criteria for predicting time of death in this type of experiment. These experiments evaluated the therapeutic effectiveness of radiation alone, continuous intracerebral infusions of 5-iodo-2-deoxyuridine (IUDR) alone, and a combination of both therapies. We found that a characteristic pattern of body weight changes occurs after injection of 9L tumor cells into the brain ventricles or parenchyma. The initial phase was characterized by a loss of body weight which appeared to be related to surgery and, in the irradiated groups, to the subsequent doses of radiation under anesthesia on days 4, 6, and 7. After this initial phase (phase 1), a second period of weight change (phase 2) which was characterized by an overall gain of body weight interrupted temporarily in 76 out of the 149 rats by reversible episodes of weight loss of 1 to 5 days duration. The length of this phase 2 weight gain period was significantly extended by XRT-IUDR treatment in the rats with intraparenchymal tumors. The third and final phase consisted of a period of irreversible weight loss which may be related to cachexia. The third phase was similar in duration for control, XRT, IUDR and XRT-IUDR groups of rats and had a mean length of 9.8 +/- 0.27 days.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Latent deficiency of the hematopoietic microenvironment of aged mice as revealed in W/Wv mice given +/+ cells.

The macrocytic anemia of W/Wv mice can be cured by injection of +/+ bone marrow cells (BMC) from WBB6F1 mice. However, it has been observed that some W/Wv recipients appear to "lose" their cure with time, an effect that does not appear to be related to the age of the BMC donor. The present study was undertaken to determine the effect of recipient age on W/Wv responses to BMC injection. The effect of aging on erythroid parameters was similar in untreated W/Wv mice and +/+ controls. In both genotypes, hematocrit (HCT) and red blood cell count (RBC) decreased, and the modal red blood cell size (peak) increased between 13 and 150 weeks of age. As anticipated, mean HCT and RBC values were lower and peak values higher in W/Wv mice compared to +/+ controls at every age. However, the rate of decrease in HCT and RBC with age was the same for both genotypes, suggesting that the age effect and W gene effect were independent. Peak values increased slightly more with age for W/Wv than for +/+ controls. When female W/Wv mice in three age groups (23.5, 70, and 91.5 weeks old) were injected with 5 x 10(5) BMC from 20-week-old +/+ female donors and HCT, RBC, and peak were determined monthly, improvement was seen in most W/Wv recipients. However, in the older mice this improvement was slower and often was not sustained; 100% of the youngest recipients, 80% of the middle-aged, and only 30% of the older groups were cured after 3 months. Taken together, these data suggest a latent deficiency of the aging hematopoietic microenvironment that is revealed in W/Wv mice by the stress of continuing erythroid demand on the limited number of normal donor BMC.

Aging↗
PubMed1990

The generation of natural killer (NK) cells from NK precursor cells in rat long-term bone marrow cultures.

In this report, we describe a novel long-term bone marrow culture (LTBMC) system to study the origin and generation of natural killer (NK) cells from NK precursors. Rat bone marrow was cultured for 4 wk in RPMI 1640 with 5% fetal calf serum and 2-mercaptoethanol to allow the formation of an adherent stromal cell layer containing NK precursor cells. After addition of interleukin 2 (IL-2), the LTBMC generated high numbers (up to 100-fold expansion in 7 d) of pure 3.2.3+ large granular lymphocytes with lytic activity against NK-sensitive and -resistant tumor targets, as well as antibody-dependent cellular cytotoxicity. NK activity in LTBMC could be detected 3 d after addition of as little as 1 U/ml rIL-2, whereas lymphokine-activated killer activity was found 5 d after addition of at least 10 U/ml rIL-2. In vivo depletion and in vitro complement lysis studies showed that the NK precursor cells in LTBMC did not express the NK-associated surface markers asialo GM1 or 3.2.3. We also found that LTBMC cells did not exhibit colony growth in granulocyte/macrophage or spleen colony-forming unit assays. The generation of NK cells from NK precursors required, in addition to IL-2, a second growth/maturation factor(s), which was present in the conditioned medium of the LTBMC. This LTBMC system provides a unique in vitro model to study the development of NK cells from precursor cells, the role of the bone marrow stromal microenvironment in this development, and the lineage relationship of NK cells to other hematopoietic cells.

Animals↗
PubMed1990

Targeted gene modification for gene therapy of stem cells.

Ideally, gene therapy would correct the specific gene defect without adding potentially harmful extraneous DNA sequences. Such correction can be obtained with homologous recombination between input DNA sequences and identical (homologous) sequences in the genomic target gene. The development of techniques for obtaining virtually pure populations of hematopoietic stem cells should permit the use of the highly efficient nuclear microinjection methods for transfer of DNA. These techniques combined with new highly sensitive methods for detecting cells with the specified genetic modification of nonexpressed genes would make homologous recombination-mediated gene therapy feasible for hematopoietic stem cells. These advances are reviewed with particular emphasis on approaches to targeted gene modification of hematopoietic stem cells and speculation on directions for future research.

Animals↗
PubMed1990

A new rat brain tumor model: glioma disseminated via the cerebral spinal fluid pathways.

A rat brain tumor model has been developed with the clinical and pathological features of dissemination via the cerebral spinal fluid (CSF) pathways. A precise number of 9L gliosarcoma cells (5 x 10(2) to 5 x 10(5)) is stereotactically injected into the CSF of the lateral ventricle. The interval until the onset of neurological symptoms and then death is reproducible and dependent upon the number of cells injected. The median survival of three groups of rats receiving 5 x 10(5) cells in three different experiments was 17, 18 and 19 days respectively. For three groups receiving 5 x 10(4) cells, the median survival was 23, 24 and 25.5 days respectively and for two groups receiving 5 x 10(3) cells the median survival was 28 and 30 days respectively. The animals developed multiple tumor implants along the CSF pathways usually resulting in hydrocephalus. This tumor model was developed to simulate dissemination via CSF pathways as seen with medulloblastoma and other primitive neuroectodermal tumors of the central nervous system. It will be used to evaluate the therapeutic efficacy of intraventricularly administered anti-neoplastic drugs against small implants and malignant cells in the CSF pathways.

Animals↗
PubMed1990

Intra-cerebral ventricular infusion of 5-iodo-2-deoxyuridine (IUDR) as a radiosensitizer in the treatment of a rat glioma.

The efficacy of 5-iodo-2-deoxyuridine (IUDR) as a radiosensitizer when administered by continuous infusion into the cerebral spinal fluid (CSF) of the lateral cerebral ventricle was evaluated in a 9L gliosarcoma rat brain tumor model. Stereotactic implantation of a 5 x 10(4) tumor cell suspension into the left caudate nucleus was carried out in four groups of 10 rats each. Control animals had a median survival of 16.9 days (range 16-21 days). IUDR, 8.4 mg over 7 days administered by continuous infusion into the left lateral ventricle produced a slight survival advantage (median survival 21.5 days, range 12-56). Irradiation of the entire brain, 8 Gy on days 4, 6 and 7 after tumor cell implantation also produced a slight improvement in survival (median 19.5 days, range 17-34). The combination of radiation and IUDR infusion into the CSF produced a marked survival advantage (median 30.5, range 22-54) compared to the control and single modality treatment groups. This is the first demonstration of the effectiveness of IUDR as a radiosensitizer when administered into the lateral cerebral ventricle in the treatment of an intraparenchymal brain tumor.

Animals↗
PubMed1990

16,16-Dimethyl prostaglandin E2 and/or syngeneic bone marrow transplantation increase mouse survival after supra-lethal total body irradiation.

We evaluated the effects of 16,16-dimethyl prostaglandin E2 (dm-PGE2), with and without syngeneic bone marrow transplantation (BMT) on the survival and hematopoietic recovery of mice given 14-20 Gy total body irradiation (TBI). Survival of mice given combined dm-PGE2 and BMT was improved significantly over that of mice given either treatment alone. The 30-day survival after 14, 15, 16 or 18 Gy TBI for combined treatment was 97, 90, 20 or 10 percent, respectively. The corresponding 30-day survival rates for mice given BMT alone were 69, 60, 7 or 0 percent, respectively. For dm-PGE2 alone, 30-day survival was 63, 20, 10 or 0 percent, respectively. Deaths in both dm-PGE2 treated groups generally occurred after day 10 whereas deaths in the BMT group occurred before day 10. All irradiated controls were dead on or before day 10; after larger doses, deaths clustered around day 5. After 20 Gy TBI, all mice in all groups were dead by day 7. Studies of white blood cell recovery 1-9 days after 14 Gy TBI showed improvement with BMT, whereas dm-PGE2 did not enhance recovery. Nucleated cells per humerus, spleen weight, and spleen iron uptake (erythropoiesis) were also improved by BMT but not dm-PGE2.

16,16-Dimethylprostaglandin E2↗
PubMed1989

5-Iodo-2-deoxyuridine administered into the lateral cerebral ventricle as a radiosensitizer in the treatment of disseminated glioma.

A rat brain tumor model (Fischer 344 rats) with the clinical and pathological features of dissemination via the cerebrospinal fluid (CSF) pathways was used to demonstrate the efficacy of 5-iodo-2-deoxyuridine (IUDR) as a radiosensitizer when it is administered directly into the CSF. Stereotaxic implantation of 9L gliosarcoma cells (5 X 10(5) into the CSF of the lateral cerebral ventricle resulted in widespread dissemination and median survival of 18.5 and 20 days (range, 10-22) in two experiments. A continuous 7-day infusion of IUDR into the CSF starting on the day of tumor implantation did not provide any beneficial effect. Irradiation of the cranial spinal axis with 800 rad on days 4, 6, and 7 after implantation achieved an increase in survival time that was modest but statistically significant. However, the combination of IUDR infusion and radiotherapy resulted in marked improvement in survival time and a 10% cure rate (two of 20 rats). This is the first demonstration in vivo that IUDR administered into the CSF can be a potent radiosensitizer.

Animals↗
PubMed1989

The effect of syngeneic marrow injection upon recovery in sub- and near-lethally irradiated mice.

Mice were given sub-lethal (200-600 cGy) or near-lethal (800 cGy) whole body irradiation and the effect of injecting syngeneic marrow on subsequent hematopoietic recovery was studied. Marrow cell injection enhanced erythropoietic recovery after sub-lethal irradiation as reflected in hematocrit values and rate of appearance of 59Fe-labeled red cells in blood. However, this enhanced erythropoiesis was only seen in the spleen, and 59Fe uptake in marrow was reduced. When the irradiation dose was kept constant and the marrow dose increased from 10(5) to 10(6) to 10(7) cells, there was a somewhat erratic increase in spleen 59Fe and a decrease in marrow 59Fe uptake. When marrow cell number was kept constant and the dose of irradiation was increased from 200 to 400 to 600 to 800 cGy, there was an exponential increase in spleen 59Fe uptake but the marrow 59Fe uptake changed from depressed after lower doses to increased after 800 cGy. Cell injection after sub-lethal irradiation did not increase or decrease granulocytopoiesis. Injection of irradiated marrow cells also reduced marrow erythropoiesis and this was evident after both sub- and near-lethal irradiation. However, injection of irradiated cells did not increase splenic erythropoiesis. Following splenectomy, the depressed marrow erythropoiesis attending injection of viable cells was virtually eliminated but no increase was seen. These data suggest that the injection of autologous or syngeneic marrow may not be effective as a means of accelerating hematopoietic recovery after irradiation unless near-lethal or lethal dose have been received.

Animals↗
PubMed1986

Efficient transformation and frequent single-site, single-copy insertion of DNA can be obtained in mouse erythroleukemia cells transformed by electroporation.

Electroporation has recently been shown to have advantages over the commonly used method of calcium phosphate precipitation for obtaining DNA-mediated transformation of certain types of cells. Although mouse erythroleukemia cells and other cells of hematopoietic origin are not transformed at useful frequencies by calcium phosphate-DNA precipitation methods, we obtained high frequencies of transformation (approximately 10(-5)) of these cells with electroporation. Even higher transformation frequencies (approximately 10(-3)) were obtained with human fibroblasts. Another advantage of electroporation was found when analysis of Southern blots of DNA from 243 transformed erythroleukemia cell colonies indicated that, under appropriate conditions, about 79% of the transformed cells had the exogenous DNA integrated in single copies at single sites. Under conditions of higher DNA and lower cell concentrations using fibroblasts, cotransformation was obtained with two plasmids that confer HAT or G418 resistance when integrated into cellular DNA. About 23% of the transformed cells developed both types of resistance. We describe a simple, inexpensive apparatus for carrying out electroporation.

Animals↗
PubMed1985

Effect of rabbit antimouse brain serum on marrow cells capable of curing W/Wv mice.

The W/Wv mouse has a recessively inherited defect in hematopoietic stem cells (HSC) but can be cured of its hematopoietic abnormalities by infusion of marrow from a co-isogeneic, +/+ mouse. The "curative" cell for the W/Wv is thought to be a subcompartment of the HSC that is capable of forming hematopoietic spleen colonies (CFU-S) in irradiated mice. The curative HSC must have a very high proliferative potential and it is known that HSC with variable degrees of proliferative potential are found within the CFU-S compartment. Rabbit antimouse brain serum (RAMBS) was used to treat +/+ marrow and its effect upon CFU-S and upon curative cells was compared with the effect of normal rabbit serum (NRS) or of sham treatment. CFU-S were reduced to 70%-79% of control by NRS and to 8%-9% by RAMBS. Curative cells for the W/Wv were not detectably reduced by NRS; they were reduced by RAMBS, but to only approximately 20%-30% of control. Thus, it appeared to a certain degree that RAMBS spared HSC with a high proliferative potential when compared with its effect on the entire CFU-S compartment.

Animals↗
PubMed1984

Aging and hematopoiesis. II. The ability of bone marrow cells from young and aged mice to cure and maintain cure in W/Wv.

The proliferative ability of hematopoietic stem cells (HSC) was compared in young and aged mice. Infusion of coisogeneic marrow cures the hematopoietic defect of the W/Wv, a mouse with a recessively inherited defect in stem cells, including HSC. W/Wv were cured with equal frequency by relatively small doses of marrow (5 X 10(4) nucleated cells, an average of 2-3 "curative" HSC per aliquot) from 3-month-old or 27-month-old +/+ donors. After functioning in the originally cured W/Wv for 26 months, the marrow was used to cure other W/Wv. After functioning in secondary recipients for 16 months, it was, in turn, used to cure still other W/Wv. There was no difference between "old" and "young" bone marrow with respect to the frequency of cure in W/Wv, the duration of cure--or, in regard to marrow from cured W/Wv, the number of nucleated and peroxidase-positive cells per humerus and the number of cells capable of producing spleen colonies in irradiated recipients. Thus, these studies fail to disclose any evidence for a proliferative limitation for old as compared to young HSC.

Aging↗