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Biomedical subjects

K S Landreth

Publications and source records attributed to K S Landreth.

44 records · Page 3Linked to original sources
PubMed1981

Deficiency in cells expressing terminal transferase in autoimmune (motheaten) mice.

The extensive breakdown of immune homeostasis in the motheaten mouse (me/me) has been ascribed to a single gene defect on chromosome 6 (ref. 1). These mice develop skin lesions within the first week of life, do not thrive, and die within the first 3--8 weeks. There is severe hypergammaglobulinaemia with multiple species of circulating autoantibody and deposition of immune complexes in the thymus, skin, lungs and kidneys. A single gene defect producing such catastrophic results may provide an important model for understanding autoimmune phenomena. We report here a virtual absence of terminal deoxynucleotidyl transferase-positive (TdT+) cells in the bone marrow, thymus and spleen of motheaten mice. TdT is a DNA polymerase which has the unique capacity to polymerize nucleotides in the absence of template direction. Although no in vivo biological function of this enzyme has been established, its unique appearance in the bone marrow and thymus of adult mammals and its in vitro biochemical activity have led to a proposed role for TdT in the somatic diversification of lymphocytes. Bone marrow TdT+ cells have been shown to belong to both T and B cell populations and may also include precursor cells common to these lineages. Although the role of TdT in the acquisition of appropriate T- and B-cell specificities is not known, our results are the first to correlate the virtual absence of TdT+ cells with a severe autoimmune syndrome. We investigated the level of TdT+ cells in neonatal me/me mice and their normal littermates and the susceptibility of TdT+ cells to circulating autoantibody in motheaten mouse serum.

Animals↗
PubMed1981

Myelogenous production and maturation of B lymphocytes in the mouse.

Cells of the B lymphocyte lineage in young adult murine bone marrow were identified and resolved into compartments based on cell size and the expression of the mu heavy chain of IgM in the cytoplasm (cmu) or on the cell surface (smu). The proliferative status, renewal rate, and intercompartmental transit of cells through the defined compartments were determined using established protocols of in vivo tritiated thymidine (3H-TdR) administration, followed by radioautography of bone marrow smears. In addition, we specifically tested whether any of the defined cell compartments were derived from long-lived lymphocytes that are known to enter the marrow. Only large cells immediately incorporated the DNA precursor and both small cmu+ smu- and cmu+ smu+ cells were postmitotic lymphocytes. Large cmu+ smu- cells were found to be a rapid transit compartment in which the last mitosis of B lymphocyte differentiation takes place. All large cmu+ smu- cells divided only once, and both daughter cells entered the postmitotic small cmu+ smu- population. Large cmu+ smu- cells relied for their maintenance entirely on cell input from an Ig- progenitor compartment. Progenitors of cmu+ smu- large cells were not small lymphocytes, proliferated less rapidly than their descendants, and maintained the input of large cmu+ smu- cells for up to 40 hr. Approximately 70% of small cmu+ smu- cells were the immediate division products of large cmu+ smu- cells, whereas the remainder were derived from a precursor with no detectable mu synthesis. Small cmu+ smu+ cells were the maturation products of small cmu+ smu- cells. This conversion appeared to take place at random rather than as a function of postmitotic age. Renewal times for small cmu+ cells without or with detectable smu were calculated to be 48 and 96 hr, respectively. Only the cmu- smu+ compartment included long-lived cells. All other mu+ populations either proliferated or were replaced by newly produced cells. A conspicuous minor population of large smu+ B cells were detected, and the data relating to these were subjected to several interpretations. These observations provide insight into the origin and fate of B lineage precursors in the marrow and suggest a scheme for the terminal stages of B lymphocytes formation that is similar to the myelogenous production of other hemopoietic cells.

Animals↗
PubMed1976

Appearance, properties, and origin of altered human hemoglobin in feces.

Altered hemoglobin (Hb) has been found in the feces as a sequel to an upper gastrointestinal bleed. Active Hb antigen of increased anodic mobility was detected on immunoelectrophoresis of melena stools using a goat anti-Hb. The Hb derivative was also identified in polyacrylamide gel electrophoresis using 412 nm. absorbance. The alteration could be simulated in vitro by incubation of hemolysate with duodenal juice or purified carboxypeptidase B alone, or by a mixture of carboxypeptidases A and B. Treatment of hemolysate or purified Hb with acid, gastric juice, pepsin, pancreatic juice, bile, trypsin, or chymotrypsin failed to produce the characteristic alteration. Instead, no change, or production of alpha and beta chains, or gradual but complete elimination of the Hb antigen was seen. This latter all or none pattern is presumed to prevail in the large bowel on the basis of incubations of hemoglobin-feces mixtures. Individuals documented to be bleeding into the colon were found to have at least a portion of their Hb antigen in the unaltered form by immunoelectrophoresis. This finding may be of value in identifying the general origin of a gastrointestinal bleed.

Carboxypeptidases↗
PubMedDate not supplied

Critical windows in development of the rodent immune system.

The immune system of rodents, like that in humans, develops from a population of pluripotential hematopoietic stem cells (HSC) that are generated early in gestation from uncommitted mesenchymal stem cells in the intraembryonic splanchnoplure surrounding the heart. This early population of HSC gives rise to all circulating blood cell lineages, including cells of the innate and acquired immune system. To access the impact of chemical exposure on the developing immune system and establish developmental windows of potential vulnerability to these exposures, it is essential to first consider the anatomical development of hematopoietic and lymphopoietic tissues and the sequence of appearance of cells that give rise to the immune system. This is particularly true in embryonic development because, after they initially appear in intraembryonic mesenchyme early in gestation, HSC migrate through an orderly series of tissues before establishing residence in the bone marrow and thymus. The effect of exposure to chemical insults in utero, then, may differ depending on the specific timing of exposure and anatomical location of hematopoiesis. Mechanisms and consequences of developmental immunotoxicity in experimental animals will need to be considered in that context. This review presents an overview of developmental hematopoiesis and a working hypothesis of critical developmental windows of vulnerability of this developmental system to toxic insult by chemical exposure.

Age Factors↗
PubMedDate not supplied

Biological and clinical correlates after chemotherapy and granulocyte colony-stimulating factor administration.

STUDY OBJECTIVE: To evaluate specific biological markers to improve understanding and use of granulocyte colony-stimulating factor (G-CSF) in patients receiving chemotherapy DESIGN: Prospective, randomized study. SETTING: University-affiliated hospital and cancer center. PATIENTS: Twenty-five patients randomized to begin G-CSF either 24 hours after chemotherapy (standard arm), or on the day the absolute neutrophil count (ANC) was below 1000/mm3 after chemotherapy (delayed arm). INTERVENTIONS: To determine the effect of G-CSF on granulopoiesis, peripheral blood mononuclear cells were assayed by semisolid culture medium and flow cytometry for granulocyte progenitors and clonogenic CD34 antigen-positive cells. These biological markers were correlated with G-CSF administration schedules and the ANC. MEASUREMENTS AND MAIN RESULTS: The effect of timing of G-CSF administration on rate of neutrophil recovery, duration of neutropenia, length of G-CSF therapy, delays of chemotherapy cycles, and neutropenic fever events was evaluated. Regardless of G-CSF schedule or chemotherapy regimen, the appearance of mobilized hematopoietic progenitors begins at the neutrophil nadir and parallels granulocyte recovery. Our data also demonstrate that proper timing of G-CSF administration produces similar rates of neutrophil recovery and comparable clinical outcomes. CONCLUSION: Based on the correlation between biological markers and ANC, we propose that the postchemotherapy ANC is a surrogate marker of renewed granulopoietic activity. The relevance of this finding in relationship to the clinical application of G-CSF remains to be further defined.

Adult↗