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Biomedical subjects

L D Shultz

Publications and source records attributed to L D Shultz.

At least 199 records · Page 11Linked to original sources
PubMed1984

"Viable motheaten," a new allele at the motheaten locus. I. Pathology.

A new spontaneous autosomal recessive mutation has recently occurred at the motheaten (me) locus on Chromosome 6 in strain C57BL/6J mice. Homozygotes for the new allele, designated "viable motheaten" (mev), have a mean life span of 61 +/- 2.4 days, compared with only 22 +/- 1.3 days for C57BL/6J-me/me mice. Like the original motheaten mutation, the immediate cause of death in mev/mev mice appears to be severe pneumonitis associated with accumulations of macrophages, granulocytes, and lymphocytes in the lungs. However, because of its longer life span, progression of the disease in mev/mev mice is more amenable to investigation. Eosinophilic crystalline material in alveolar macrophages from mev/mev mice is associated with extravasation of erythrocytes into alveoli. These crystals are morphologically indistinguishable from hematoidin, which results from hemoglobin breakdown following uptake of erythrocytes by macrophages. Severe macrocytic hypochromic anemia with abnormalities in size and shape of erythrocytes develops by 7 weeks. A two-fold increase in peripheral leukocyte count and a five-fold increase in the percentage of neutrophils is seen by 10 weeks. Viable motheaten mice develop focal granulocytic skin lesions by 4 days of age, show depletion of cells from the thymus cortex by 4 weeks, and lack lymphoid follicles in the lymph nodes, spleen, and Peyer's patches. Excessive erythropoiesis and myelopoiesis in the spleen result in marked splenomegaly. Lymph nodes and spleens from mev/mev mice contain increased numbers of plasma cells by 3 weeks; and by 6 weeks, large numbers of atypical plasma cells with Russell bodies are evident. Development of glomerulonephritis by 10 weeks is characterized by granular depositis of immunoglobulin and complement within glomeruli. A twofold increase of blood urea nitrogen levels is present by 15 weeks. Sterility of male mev/mev mice is associated with Leydig cell depletion in the testes, lowered testosterone levels, and impaired spermatogenesis.

Alleles↗
PubMed1983

The effect of immunosuppression on streptozotocin-induced diabetes in C57BL/KsJ mice.

The objective of this study was to determine whether mature thymic-derived T-lymphocytes were required for streptozotocin (SZ)-induced insulitis. C57BL/KsJ male mice were immunocrippled by thymectomy at 3 wk of age followed 1 wk later by lethal irradiation (1000 R) and hematopoietic reconstitution with syngeneic bone marrow (pretreated with anti-Thy 1.2 antiserum and complement to eliminate mature T-lymphocytes). As a control for the systemic effects of lethal irradiation itself, thymus-intact males were also irradiated and reconstituted with anti-Thy-1.2-treated marrow cells. This latter treatment resulted in a reconstitution of functional T-lymphocytes. Independent of the presence or absence of functional T-lymphocytes, irradiation extensively damaged the testes and produced at least a 50% reduction in plasma testosterone levels. In such effeminized males, the hyperglycemic response following 6 daily injections of SZ (35 mg/kg) was reduced in comparison to unirradiated males. Pancreatic insulin content was reduced 50% in both thymus-intact and thymectomized groups receiving lethal irradiation and SZ treatment; this correlated with histologic findings of small, beta-cell-depleted islets. Focal leukocytic infiltrates of the exocrine pancreas were induced by the irradiation. Streptozotocin-induced insulitis was also observed regardless of the presence (in thymus-intact mice) or absence (in thymectomized mice) of phytohemagglutinin-responsive T-lymphocytes. Both groups exhibited intact B-lymphocyte function as measured by proliferative responsiveness to lipopolysaccharide. Severe immunosuppression of both T- and B-lymphocyte function was produced by subcutaneous injection of hydrocortisone into thymectomized mice 48 h prior to initiation of SZ treatments. This treatment prevented SZ-induced beta-cell necrosis and eliminated lymphocytic infiltrates in the endocrine and exocrine pancreas. We conclude that functional (mature) T-lymphocytes are not required to mediate the beta cytotoxicity of multiple low doses of SZ in inbred strains in which insulitis accompanies islet destruction. The ability of hydrocortisone to protect beta-cells from the direct cytotoxic action of SZ as well as to eliminate leukocytic infiltration in the pancreas would support the hypothesis that insulitis is a consequence of beta-cell destruction, in this model, rather than its cause. DIABETES 32:148-155, February 1983.

Animals↗
PubMed1983

Hematopoietic stem cell function in motheaten mice.

Mice homozygous for the autosomal recessive mutation "motheaten" have normal numbers of multipotential hematopoietic stem cells in the bone marrow and spleen as determined by spleen colony assay. Histologic examination shows no qualitative abnormality in morphology of stem cell colonies in recipients of bone marrow or spleen cells from motheaten mice. Despite the apparently normal ontogeny, distribution, and differentiative capacity of CFU stem cells, bone marrow and spleen cells from motheaten mice fail to save congenic +/+ lethally gamma-irradiated hosts. This impaired lifesparing capacity is not due to defective self-renewal but appears to be due in part to pulmonary hemorrhage from alveolar capillaries in the gamma-irradiated hosts. Treatment of motheaten mice with 500 R gamma-irradiation followed by reconstitution with normal bone marrow cells increases the lifespan of this mutant to 10 months of age. The early onset of pneumonitis and subsequent short lifespan of motheaten mice is determined at the level of progenitor cells in the bone marrow.

Animals↗
PubMed1982

The contribution of mast cells to the histamine content of the central nervous system: a regional analysis.

W/WV mice are severely deficient in mast cells. The absence of mast cells in skin and salivary glands was found to be paralleled by a drastic decrease of the histamine levels in these tissues when compared to non-anemic +/+ control mice. Brains of W/WV mice are also devoid of mast cells. A comparison of the histamine concentrations in several brain regions of W/WV mice and controls revealed a moderate decrease in cerebral cortex, thalamus, hypothalamus and midbrain but no change in pons, medulla and cerebellum. These findings provide strong evidence that mast cells contribute to the histamine content in forebrain regions but not in hindbrain regions. It is speculated that there may exist histaminergic neurons intrinsic to the medulla and pons.

Animals↗
PubMed1982

Immunodeficiency and reticulum cell sarcoma in mice segregating for HRS/J and SJL/J genes.

Hairless (hr/hr) mice segregating for SJL/J and HRS/J genes (SJL-HRS) were compared to their haired counterparts with respect to immune responsiveness, tumour development and ecotropic murine leukemia virus (MuLV) expression. Homozygosity at the hairless locus did not affect expression of MuLV. There was however, a significant depression of the cellular immune response of these mice as characterized by depressed reactions in phytohemagglutinin, concanavalin A and mixed leukocyte assays. Haired and hairless mice did not differ significantly in response to B-cell mitogens or in production of cytotoxic antibody. The depressed cellular immune response in hr/hr mice is associated with a distinctive histologic type of spontaneous reticulum cell sarcomas. The importance of these results in relation to previous studies of HRS/J hairless mice is discussed.

Animals↗
PubMed1981

Mutations in mice that influence natural killer (NK) cell activity.

A series of mutations in mice was tested for splenic NK-cell activity against YAC-1 target cells. Mutations at six loci that reduce NK-cell activity in the homozygous state were identified, including beige (bg), hairless (hr), motheaten (me), obese (ob), steel (Sl) and, to lesser extent, dominant spotting (W). Motheaten mice displayed the most profound NK-cell deficiency, with NK-cell activity virtually absent. Two mutations, nude (nu) and lymphoproliferation (lpr), produced elevated NK-cell-mediated lysis. The double homozygous recessive nu/nu bg/bg nude-beige mouse was viable and NK-cell-deficient, with activity slightly higher than that of +/? bg/bg beige littermate controls. Pigmentation mutants related to beige, including pale ears (ep), pearl (pe) and ruby eyes (ru2J) did not dramatically influence NK-cell levels. Unlike the obese gene, other mutations leading to obesity, diabetes (db) and yellow (Ay), did not impair NK-cell function. The possible site of gene action of these mutations in the NK-cell pathway is discussed.

Anemia↗
PubMed1979

Expression of endogenous murine leukaemia viruses in AKR/J streaker mice.

MICE of the AKR/J strain show high rates of spontaneous thymic lymphoma and are chronically infected with murine leukaemia viruses. Total thymectomy in young mice of this strain results in a marked decrease in the incidence of leukaemia. The finding of athymic mutant mice on the AKR/J background (referred to as streaker mice) is of importance in the study of genetic factors which influence virus expression and leukaemogenesis. Here we report that mice of both normal and mutant genotypes vary in the expression of a particular class of murine leukaemia virus. This lower virus expression in conjunction with the absence of a thymus leads to a lower tumour incidence in streaker mice.

Journal Article↗
PubMed1978

The mouse mutant "motheaten." II. Functional studies of the immune system.

Motheaten mice have normal levels of T lymphocytes but reduced levels of B lymphocytes. Those B cells that are present show an impaired proliferative response to B cell mitogens and no plaque-forming cell response to thymus-independent antigens. T lymphocyte function is also defective in motheaten mice, as assayed by the proliferative responses to T cell mitogens, and by the capacity to develop cytotoxic killer cells against allogeneic cells. Motheaten mice possess spleen cells capable of suppressing normal B cell responses to thymus-independent antigens. This suppressor cell is not sensitive to anti-Thy-1 antibody plus complement treatment but is partially removed by adherence on plastic. Overall, the motheaten mouse suffers a functional severe combined immunodeficiency of both B and T cells, even though these cells are present. We postulate that the inescapable lethality of the motheaten defect is due to the lack of immunocompetence during the critical developmental period before adulthood and perhaps to an autoaggressive component as well.

Animals↗
PubMed1976

Motheaten, an immunodeficient mutant of the mouse. II. Depressed immune competence and elevated serum immunoglobulins.

Mice homozygous for the recessive mutation motheaten (me) are deficient in capacity for immune response but show an elevated level of serum immunoglobulins. In comparison to spleen cells from normal sibs, spleen cells from me/me mice have a severely depressed 19S PFC response to SRBC. In the GVH assay, spleen and thymus cells from motheaten donors caused significantly weaker reactions than like cells from normal sibs. Serum electrophoretic patterns of motheaten mice showed increased levels of alpha-, beta-, and gamma-globulins and decreased levels of albumin. Increases in quantities of all major classes of immunoglobulins were found in serum of me/me mice 5 weeks of age and older. Elevation of serum IgM was evident by 3 weeks of age and had reached 25 times the levels in normal sibs by 6 weeks of age. Immunoelectrophoresis and Ouchterlony analysis showed motheaten serum to have both kappa and lambda2 light chains. Evidence of autoimmunity was found in motheaten mice in the granular deposition of IgM and IgG in kidney glomeruli. Motheaten mice, thus, appear to have a severe immune deficiency, but the basic nature of the deficiency is not yet known.

Alpha-Globulins↗
PubMed1973

Fate of listeria monocytogenes in normal rabbit serum.

Viability of Listeria monocytogenes suspended in either normal rabbit serum or listericidal factor is significantly reduced before cell lysis. In normal serum Listeria populations are initially reduced by clumping of viable bacteria, and the cells within these clumps are morphologically altered and killed by the listericidal factor in serum. This clumping is complement independent and does not occur after suspension in purified listericidal factor. In electron micrographs, densely stained amorphous material was seen surrounding clumped cells suspended in serum. Initial damage to Listeria suspended in either serum or listericidal factor appears to be confined to plasma and mesosomal membranes. The mesosomes are rapidly disorganized, and the plasma membrane becomes crenated and separates from the cell wall. Subsequently, the fibrillar organization of the nuclear region disrupts, and the cytoplasm increases in granularity. Studies utilizing Listeria protoplasts provided evidence in support of the plasma membrane as the site of listericidal action. Cell death may be related to loss in enzyme function after crenation of the plasma membrane and mesosomal dissolution.

Animals↗
PubMed1971

Cytotoxicity of rabbit blood for Listeria monocytogenes.

Our studies reveal that normal rabbit blood contains a potent bactericidin active against Listeria monocytogenes. The factor is present in greatest amounts in fresh undiluted serum but is absent in platelet extracts. A correlation was observed between the virulence of Listeria strains and their relative ability to survive in serum. The bactericidal titers obtained for plasma and plasma serum indicate that clotting must occur for optimum expression of antilisterial activity. The lethal action is not elevated after immunization with viable Listeria nor does it appear to depend on heat-labile components of complement. The active factor was removed from serum by filtration through a cellulose asbestos filter pad and further purified by carboxymethyl cellulose chromatography. Iron significantly diminishes serum lethality and completely abolishes the action of the purified component. The listericidal factor resembles beta-lysin but may be a distinct part of a multiple system of similar bactericidins.

Animals↗
PubMedDate not supplied

Gamma-interferon is one of several direct B cell-maturing lymphokines.

Two classes of molecules often released after the interaction of T lymphocytes, macrophages and antigen are B-cell maturation factors (BMF)1-3 and immune (gamma) interferon (IFN-gamma)4-7. BMFs directly induce the maturation of resting B lymphocytes to the state of active immunoglobulin secretion, while IFN-gamma is defined by the reduction of viral infectivity in vitro. However, interferons have been shown to have a variety of effects and they have also been reported both to increase and decrease B-cell differentiation in intact animals and complex cellular mixtures in vitro. Here we show that murine IFN-gamma produced by recombinant DNA technology shows similar biological effects to BMFs from two other sources. All three preparations induce immunoglobulin secretion by both normal resting murine splenic B cells and the comparable B-cell tumour line WEHI-279.1 (refs 1, 3). IFN-gamma and the other two BMFs are not identical, however, as anti-IFN-gamma antibodies block the effects on B cells of IFN-gamma, but not those of the other two lymphokines. IFN-gamma may be one of several molecules with a direct role in driving the maturation of resting B cells to active immunoglobulin secretion.

Animals↗
PubMedDate not supplied

Maintenance of CD5+ B cells at an early developmental stage by interleukin-5: evidence from immunoglobulin gene usage in interleukin-5 transgenic mice.

We have characterized the development and expansion of CD5+ B cells in interleukin-5 (IL-5) transgenic mice in terms of autoantibody production and immunoglobulin gene usage. CD5+IL-5R alpha+ B cells maintained in the presence of IL-5 secreted fewer autoantibodies and had fewer N nucleotides at the 3' end of the D elements compared with CD5- B cells. The reduction in nucleotides, along with the finding that CD5+IL-5R alpha+ B cells in IL-5 transgenic mice use Q52 families more frequently than age-matched control B cells, also suggests that these cells have the characteristics of fetus-type B cells and represent an early stage of B-cell development. All of the VH11 families were expressed with JH1 and the Q52 families were frequently expressed with JH1. Furthermore, JH proximal DQ52 was frequently used in IL-5 transgenic mice. All of these characteristics in terms of immunoglobulin gene usage have been described for CD5+ B cells. These results suggest that IL-5 maintains CD5+ B cells that have a fetus-type of immunoglobulin gene usage. This cytokine could be responsible for prolonging the life span of immature CD5+ B cells, which subsequently mature to CD5- B cells that secrete polyreactive natural antibodies.

Animals↗
PubMedDate not supplied

Motheaten, an immunodeficient mutant of the mouse. I. Genetics and pathology.

A new recessive mutation, motheaten (me), is on chromosome 6, 21.9 +/- 4.3 recombination units distal to white (Miwh). Mice homozygous for the new mutation have neutrophilic lesions of the skin beginning as early as day 1, and pneumonitis with many macrophages in the alveoli as early as day 3. They suffer high mortality from birth onward and none has survived longer than 8 weeks. The lymph nodes may be enlarged, but the thymus, Reyer's patches, and lymphatic tissue of the spleen are much reduced in size. Lymph nodes, spleen, and Peyer's patches lack lymphatic nodules. The lymph nodes and spleen contain many plasma cells. There are increased numbers of neutrophils and monocytes in the peripheral blood, and increased numbers of neutrophils in bone marrow at the expense of red cell precursors. Hematopoietic tissue in the spleen is increased and appears more active than normal. Motheaten mice appear to have an immune deficiency beginning very shortly after birth.

Animals↗
PubMedDate not supplied

Blockade of CD40-CD154 interferes with human T cell engraftment in scid mice.

Antibodies to the ligand for CD40 (CD154) have been shown to exert profound effects on the development of cell-mediated immune responses in mice. The present study shows that an antibody to human CD154 (hCD40L) inhibits in vivo Tetanus toxoid (TT) specific secondary antibody responses in hu-PBL-scid mice, as well as the expansion of xenoreactive human T cells in the scid mice. A possible cause for the reduced expansion of xenoreactive, human T cells, was the decreased expression of murine B7.1 and B7.2 caused by the administration of anti-hCD40L. Therefore, it may be that defective maturation of murine antigen-presenting cells impeded the priming and expansion of human xenoreactive T cells.

Adult↗