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D V Cramer

Publications and source records attributed to D V Cramer.

At least 109 records · Page 6Linked to original sources
PubMed1990

Toxicity of intravesical recombinant human tumor necrosis factor in cynomolgus monkeys.

Six groups of two cynomolgus monkeys were treated with escalating intravesicular doses of recombinant human tumor necrosis factor (rHuTNF) for a 6 week interval. The doses of rHuTNF ranged from 10 ng to 1 mg and were instilled weekly. Two monkeys had instillation of saline only and served as controls. The monkeys were weighed and temperatures determined before, immediately after, and 2 days following each treatment. Cystoscopic examination was performed 2 days after each treatment and blood samples were obtained. At the conclusion of the study, animals were killed and necropsy was performed. There was no observable toxicity from treatment with rHuTNF. There was no difference between treated and control monkeys with respect to temperature, weight, or blood measurements. No drug-induced alteration in bladder morphology was found by either cystoscopic or microscopic pathologic examination.

Administration, Intravesical↗
PubMed1990

Immunologic mechanisms of cardiac transplant rejection.

The successful application of cardiac transplantation as a useful therapeutic procedure has been the result of improved surgical techniques and the effective immunosuppression of cardiac rejection. Despite the improvements that have led to the successful application of cardiac transplantation, there are important limitations in our understanding and ability to manipulate the immune-mediated rejection of the donor heart by the host. Methods that allow for improved preservation of the donor heart are necessary to provide the opportunity to match more carefully the donor and recipient for histocompatibility antigens that stimulate rejection of the graft. Clinical data in humans and experimental studies in animals demonstrate that the rejection of the heart is stimulated by a wide variety of histocompatibility antigens, many of which may be neutralized by donor-recipient matching. The immunologic mechanisms that influence the survival of the graft include (1) hyperacute rejection of the graft by recipient antibody directed against foreign antigens of the donor heart, (2) T lymphocyte-mediated acute cellular rejection of the graft, and (3) chronic rejection of the graft associated with the emergence of cardiac graft arteriosclerosis in otherwise successful long-term graft recipients. An increased understanding of these processes will provide opportunities to improve cardiac transplant outcome.

Graft Rejection↗
PubMed1989

Cardiac transplantation in the rat. I. The effect of histocompatibility differences on graft arteriosclerosis.

The development of arteriosclerosis is the most serious and common complication in long-term survivors of cardiac transplantation. We have used a variety of inbred rat strains with selected histocompatibility differences to examine the influence of prolonged, mild rejection reactions on the development of pathological changes in long-term cardiac allografts. Heterotopic cardiac allografts were exchanged between rat strains that differed for MHC class I (RT1.A and/or RT1.E) antigens or groups of minor, non-MHC antigens in MHC-compatible congenic combinations. Our results demonstrate that in strain combinations in which the allograft reaction is mild and prolonged, the donor hearts exhibit pathological changes that include a diffuse, interstitial myocardial fibrosis, perivascular fibrosis, and intimal proliferation in arteries of the graft myocardium. The lesions were less prominent in animals with more active rejection and infrequent in strains that differ for class I histocompatibility antigens or syngeneic controls. These results suggest that the comparable pathological changes seen in long-term human cardiac survivors may reflect low-level, persistent allograft reactions rather than factors associated with graft anoxia or effects of immunotherapy to prevent graft rejection.

Animals↗
PubMed1989

Immunomagnetic T-lymphocyte depletion (ITLD) of rat bone marrow using OX-19 monoclonal antibody.

Graft versus host disease (GVHD) may be abrogated and host survival prolonged by in vitro depletion of T lymphocytes from bone marrow (BM) prior to allotransplantation. Using a mouse anti-rat pan T-lymphocyte monoclonal antibody (OX19) bound to monosized, magnetic, polymer beads, T lymphocytes were removed in vitro from normal bone marrow. The removal of the T lymphocytes was confirmed by flow cytometry. Injection of the T-lymphocyte-depleted bone marrow into fully allogeneic rats prevents the induction of GVHD and prolongs host survival.

Animals↗
PubMed1989

Induction of stable chimerism and elimination of graft-versus-host disease by depletion of T lymphocytes from bone marrow using immunomagnetic beads.

The goal of transplantation is the induction of immunologic tolerance. At present, nonspecific immunosuppression is used to prevent graft rejection and, commonly, graft-versus-host disease (GVHD). Nevertheless, nonspecific immunosuppressive therapy is frequently complicated by infection, malignant tumors, and drug toxicity. In order to examine whether hematopoietic chimerism can be used to induce specific allograft tolerance, we have reconstituted lethally irradiated Lewis rats with ACI bone marrow that has been depleted of T cells with use of immunomagnetic beads. This technique consists of binding OX-19, a mouse anti-rat pan-T lymphocyte monoclonal antibody, to magnetic polymer beads. Mixing of bone marrow or splenocytes with the bead/OX-19 complexes, followed by magnetic separation, results in significant depletion of T cells with minimal nonspecific cell loss. Immunomagnetic T-cell depletion of bone marrow, followed by reconstitution of a lethally irradiated host, allows for the development of stable, mixed hematopoietic chimerae without evidence of GVHD. These hosts are immunocompetent by clinical criteria. Recipients of untreated donor bone marrow that did or did not receive nonspecific immunosuppression demonstrated varying degrees of GVHD and reduced survival. The ability to rapidly and simply deplete T lymphocytes from bone marrow and produce stable, immunocompetent hematopoietic chimerae without GVHD may be an important method for tolerance induction to vascularized allografts.

Animals↗
PubMed1988

Lymphokine-activated killer cells in rats: analysis of progenitor and effector cell phenotype and relationship to natural killer cells.

The progenitor and effector cell phenotype of lymphokine-activated killer (LAK) cells generated in F344 rats by recombinant human interleukin 2 (IL-2) (rIL-2) were analyzed. Highly purified populations of peripheral blood large granular lymphocytes (LGL) exhaustively depleted of T-cells were fully capable of generating high levels of LAK activity by 3 to 5 days in culture while purified populations of resting T-cells devoid of LGL could not generate LAK activity. This pure population of LGL expressed surface markers characteristic of rat natural killer (NK) cells [i.e., OX8+, asialomonoganglioside (asialo-GM1+), laminin+, OX19-, R1-3B3-, W3/25-, Ia-, surface immunoglobulin negative (SIg-)]. Further evidence that NK cells were the progenitors of cells with LAK activity was obtained by treatment of spleen or peripheral blood lymphocytes with anti-laminin or anti-asialo-GM1 antibodies plus complement or with the lysosomotropic agent L-leucine methyl ester. These treatments effectively depleted LGL/NK cell activity and the subsequent generation of rIL-2-induced LAK activity. Analysis of the LAK effector phenotype by cell sorting demonstrated that the majority of cells with LAK activity were OX8+, asialo-GM1+, laminin+, OX6+, OX19-, R1-3B3-, W3/25-, and SIg-. Furthermore, treatment of LAK cells with L-leucine methyl ester also significantly reduced their cytolytic activity. Thus, the LAK effector cells were also LGL and expressed surface marker characteristic of activated NK cells and not those of mature T- or B-cells. The proliferative response of rat spleen or blood lymphocytes to rIL-2 appeared to be primarily associated with LGL/NK cells since depletion of NK cells by anti-asialo-GM1 or anti-laminin antibody plus complement or by L-leucine methyl ester significantly (P less than 0.001) reduced the incorporation of [3H]thymidine into DNA. In contrast, depletion of T-cells (by anti-T-cell antibody plus complement) did not significantly affect rIL-2-induced proliferation. Similarly, T-cell-depleted, highly purified populations of LGL gave substantial proliferative responses to rIL-2. These studies clearly indicate that in the rat, the major cell population activated by rIL-2 is the LGL/NK cell and these cells appear to represent the major population of cells in blood or spleen which generate broad antitumor (LAK) cytotoxicity.

Animals↗
PubMed1988

Lymphokine-activated killer cell purging of leukemia cells from bone marrow prior to syngeneic transplantation.

We have studied the effect of using lymphokine-activated killer (LAK) cells as an in vitro means for eliminating leukemic cells from normal bone marrow prior to transplantation of experimental animals. Rat LAK cells exhibit broad cytolytic activity against a variety of hematopoietic neoplasms, but do not kill normal bone marrow cells or lectin-stimulated blasts. Bone marrow was harvested from normal Fischer 344 rats, combined with increasing numbers of CRNK-16 tumor cells, and then incubated with LAK cells. The BM/tumor/LAK mixture was then administered to untreated Fischer rats, and the ability of the LAK cells to purge the bone marrow of neoplastic cells and prevent the transmission of the leukemia to recipient animals monitored. Our results demonstrate that LAK cells are capable of efficiently purging the bone marrow of neoplastic cells. Treatment of the BM/tumor mixtures with LAK cells is associated with significant prolongation of survival in the higher tumor doses (10(5) tumor cells/recipient) and complete elimination of the tumor in a high percentage of recipients at lower tumor levels (10(3)-10(4) tumor cells/recipient). At levels of BM transfer comparable to that used in humans, there was no evidence of a failure of LAK-treated bone marrow to reconstitute lethally conditioned recipient animals. However, with lower numbers of BM cells, there was an increased mortality in animals receiving LAK-treated BM, suggesting a minimal inhibition of pluripotent hematopoietic stem cell function when suboptimal numbers of BM cells are used for reconstitution. These experiments demonstrate that LAk cells are capable of eliminating neoplastic cells in bone marrow without significant destruction of immature syngeneic stem cells. LAK cells display a broad range of cytolytic activity against hematopoietic and solid tissue tumors, and are therefore capable of eliminating small numbers of tumor cells from a wide variety of neoplastic diseases of the marrow. The ability to detect and eliminate malignant cells, without interfering with reconstitution with donor marrow, suggests that immune therapy with LAK cells can be a relatively simple and efficient method to purge bone marrow prior to autologous transplantation in patients following high-dose chemotherapy for neoplastic diseases.

Animals↗
PubMed1987

Characterization of the Ia antigens involved in suppressor T cell generation in the rat.

The WRC rat, an intra-class II recombinant strain (RT1.B beta nB alpha aD alpha, beta a), was used to study the relative roles of the two class II loci in mixed lymphocyte reaction (MLR) proliferation and suppressor T cell (Ts) generation. Both MLR proliferation and Ts generation were noted in cultures of WRC with DA (RT1a) stimulator cells. In contrast, cultures of WRC with BN (RT1n) stimulator cells proliferate but do not generate significant amounts of Ts. The data suggest that RT1.B beta incompatibility is important in the generation of Ts in the WRC rat. Suppressor cells generated in cultures of WF (RT1u) with WRC stimulator cells potently suppressed a WF + WRCx test MLR, with less suppression when tested against either the WF + DAx or WF + BNx MLRs. The latter experiments suggest that Ts clones may be produced to either class II subregion, and therefore that MLR proliferation and Ts induction are not necessarily linked, but vary with particular genotypes. The current lack of other rat intra-class II recombinant strains precludes assignment of suppressor induction/activation to a single locus.

Animals↗
PubMed1987

A 90-day inhalation toxicity study of raw shale oil in Fischer 344 rats.

The potential health effects of a raw shale oil were evaluated in a 90-day inhalation study in Fischer 344 rats. Groups of 15 male and 15 female rats were exposed 6 hr/day, 5 days/week for 13 weeks to aerosol concentrations of 0, 56, 120, or 492 mg/m3. In the high-dose group, 10 males and 7 females died prior to the termination of the study, most within the first 5 weeks of the experiment. A dose-dependent suppression in weight gain was seen in all of the shale oil-exposed groups. The failure to gain weight was associated with a variety of clinicopathologic abnormalities, including a dose-related decrease in red and white blood cells, with lowered plasma protein levels and increased serum alkaline phosphatase, and with total bilirubin levels in males. The exposure of the test animals to aerosolized raw shale oil was also associated with inflammatory and hyperplastic lesions in the lungs and upper respiratory tract, atrophy of the thymus and thymic-dependent portions of the peripheral lymphoid system, and bone marrow. These changes demonstrate that inhalation of raw shale oil aerosol can produce major organ toxicity similar to that found after exposure to other unrefined oil products.

Administration, Inhalation↗
PubMed1987

Subacute study of rats fed ground beef treated with aqueous chlorine: hematologic and clinical pathology.

Aqueous chlorine is effective in reducing surface spoilage bacterial counts on carcasses of slaughter animals and is presently being used for washing beef, pork, lamb, and poultry in some plants under an interim authorization. At present, at least three GRAS affirmation petitions have been submitted by industry groups for the continued use of chlorinated water on carcasses of slaughter animals. A dearth of information exists describing the hematological and clinical pathology associated with the consumption of such treated meat by mammals. Our research evaluated the response of rats to diets containing ground beef which had been treated with aqueous chlorine. Results of the hematologic evaluations demonstrated almost no effects associated with the feeding of rats with chlorine-treated meat for 92 d. There was a slight prolongation of the prothrombin time in all male groups fed the chlorine-treated meat. This prolongation was most pronounced in the 600 ppm group and was significant (p less than 0.05) when compared with the control males. In the absence of any other hematologic evidence, it is not possible to attribute the prolonged prothrombin time to the administration of the test compound. Prothrombin times of females did not differ significantly. The clinical chemistry and urine analysis yielded results wherein the values for the control and test rats are consistent with reported values for rats under standard laboratory conditions. On the basis of these hematologic and clinical data, there were no adverse effects on male or female rats fed ground beef treated with up to 600 ppm aqueous chlorine.

Animals↗
PubMed1987

Cardiac transplantation: immune mechanisms and alloantigens involved in graft rejection.

Recent advances in surgical and chemotherapeutic approaches to cardiac transplantation have resulted in substantial improvements in patient survival. Rejection of the cardiac allograft by the recipient's immune system and complications associated with immunosuppressive therapy remain, however, important clinical problems. The rejection of the transplanted heart is a complex set of immunological reactions. Previous experimental work has indicated that a variety of mechanisms may be involved in the pathogenesis of heart rejection; these include alloantibodies, specifically sensitized cytotoxic T-lymphocytes, lymphokine-dependent T-lymphocyte delayed-type hypersensitivity reactions, and natural killer cells. The current knowledge of the role that genetic incompatibilities play in stimulating the cardiac allograft reaction and the effector mechanisms implicated in the pathogenesis of the rejection process will be discussed.

Animals↗
PubMed1986

Biochemical markers in rats: linkage relationships of aconitase (Acon-1), aldehyde dehydrogenases (Ahd-2 and Ahd-c), alkaline phosphatase (Akp-1), and hydroxyacid oxidase (Hao-1).

We have examined the linkage relationships between five biochemical markers, Acon-1, Ahd-2, Ahd-c, Akp-1, and Hao-1, and 19 other genetic loci in five breeding combinations. The genetic locus that codes for a recently described aldehyde dehydrogenase in the liver (Ahd-c) has been assigned to linkage group X (LG X). Hydroxyacid oxidase is coded for by a locus (Hao-1) that is linked to genes that encode agouti coat color and seminal vesicle proteins in linkage group IV. Alkaline phosphatase (Akp-1) was linked to the locus that encodes the C6 component of complement and this association provisionally defines a new linkage group (LG XI) in the rat. The locus Acon-1 could not be positively assigned to a specific linkage group but the results from one breeding combination suggest that this locus may be included in linkage group II. No linkage relationship could be detected for the aldehyde dehydrogenase coded for by Ahd-2.

Aconitate Hydratase↗
PubMed1986

Genetics of the antibody response to an endothelial transplantation antigen in the rat.

Immunization of MAXX (RT1n) rats with pooled spleen and lymph node cells from the BN (RT1n) strain results in the formation of alloantibodies against a nonmajor histocompatibility complex (MHC) encoded transplantation antigen on peritubular capillary and venous endothelium of the kidney. Since ACI (RT1a) strain animals did not respond to the antigen, the genetics of the in vivo humoral immune response to repeated immunization were investigated in 43 animals of the second filial generation from the responder MAXX and the nonresponder ACI strain, as well as in 13 animals produced by backcrossing (MAXX X ACI)F1 and ACI. Because 38/40 RT1n-positive animals responded, while 16/16 RT1a/a recipients did not, it was shown that the RT1n haplotype was required for responsiveness. Using the intra-MHC recombinant strains DA.1I (RT1.AnBaDaEu) and WRC (RT1.AnBnDa), the immune response was mapped within the class II region of the MHC-complex. Effects of MHC-(in)compatibility between donor and recipient on the response were ruled out, since MAXX rats formed endothelial antibodies upon immunization with the MHC-incompatible BN.1L (RT1(1), BN.1A (RT1a), and WKY (RT1k) cells, whereas ACI animals failed to produce endothelial antibodies after immunization with BN.1A cells. Furthermore, the response appears to be thymus dependent because congenitally athymic WAG/rnu (RT1u) rats failed to produce endothelial antibodies, in contrast to the euthymic WAG/Rij (RT1u) strain.

Alleles↗