PubMed Health⌕ Search

Biomedical subjects

L D Shultz

Publications and source records attributed to L D Shultz.

At least 181 records · Page 10Linked to original sources
PubMed1988

The immunological mouse mutants nude (nu) and rhino (hrrh) generate cytotoxic effector cells following adoptive immunotherapy but fail to reject a transplanted tumor.

Adoptive immunotherapy, consisting of cyclophosphamide injection and the i.v. transfer of tumor-sensitized T cells, resulted in rejection of the immunogenic fibrosarcoma, MCA/76-9, by syngeneic C57BL/6J (B6) mice. The same treatment of tumor-bearing congenic immunodeficient mice, homozygous for the deleterious mutations nude (nu) and rhino (hrrh), did not result in tumor rejection. Paradoxically, the intratumor and intrasplenic changes taking place in each of the three strains after therapy were indistinguishable. There was an increase in Thy-1+, Ly-2+, or L3T4+ cells at the tumor site 8 days after adoptive immunotherapy and a similar increase in Thy-1+ cells in the spleen. Moreover, the T cells isolated from the tumors or spleens from each genotype were shown to be specifically cytotoxic in vitro as well as in an in vivo Winn assay. Further evidence that immune amplification had occurred in the immunological mutant mice was provided by experiments showing (a) the ability of spleen cells from tumor-bearers and those tested after therapy to produce IL-2 in response to Con A stimulation and (b) an increase in class II-MHC antigen expression by tumor-associated macrophages. The data suggest that, although amplification of antitumor immune responses occurred in the immunological mutants, the absence of a critical host factor limited the potency of the antitumor response.

Animals↗
PubMed1988

NOD marrow stem cells adoptively transfer diabetes to resistant (NOD x NON)F1 mice.

Autoimmune beta-cell destruction occurred in otherwise diabetes-resistant F1 mice from an outcross between the nonobese diabetic (NOD) and nonobese normal (NON) inbred strains after adoptive transfer of hematopoietic stem cells from NOD donors. F1 mice were lethally irradiated and reconstituted with either NOD, NON, or F1 bone marrow. Only F1 mice reconstituted with NOD bone marrow developed hyperglycemia. The long (greater than or equal to 16-wk) prodromal period required for expression of overt diabetes contrasted with the rapidity (4-6 days) with which kidney-grafted F1 or NON islets (but not anterior pituitary) were eliminated from diabetic F1 mice. Thus, development of beta-cell-specific immunologic effectors was a chronic process, but once sufficient levels of autoimmunity were achieved, implanted beta-cells could be eliminated in an acute fashion. Thus, expression of NOD diabetogenic alleles in hematopoietic progenitor cells is sufficient for development of anti-beta-cell immunity. The elimination of grafted NON islets shows the effectors are capable of eliminating beta-cells from mice without the diabetogenic genotype.

Animals↗
PubMed1987

Adenosine deaminase activity in recipients of bone marrow from immunodeficient mice homozygous for the wasted mutation.

Mice homozygous for the mutation wasted (wst/wst) have been postulated to be a model for the form of human severe combined immunodeficiency disease (SCID) that is secondary to a genetic deficiency of adenosine deaminase (ADA). To test this hypothesis more critically, we transplanted marrow from wst/wst and littermate control mice into lethally irradiated normal recipients. The Vmax and Km values for ADA in recipient's hematologic and non-hematologic tissues did not differ significantly. These results indicate that the wasted mouse is not a model for ADA deficiency and SCID.

Adenosine Deaminase↗
PubMed1987

Effect of immunodeficiency on diabetogenesis in genetically diabetic (db/db) mice.

The pathogenesis of diabetes in C57BL/KsJ-db/db mice has been proposed to entail autoimmune mechanisms. We have combined immunodeficiency genes with the db mutation to determine whether beta cell necrosis and establishment of severe diabetes would occur in the absence of normal T and/or B lymphocyte functions. Inbred mice carrying the recessive mutations, severe combined immunodeficiency (scid), X-linked immunodeficiency (xid), nude (nu), and the Y-linked autoimmune accelerator (Yaa), were crossed with strains congenic for the db mutation. The diabetes syndrome was studied in double homozygotes produced in the F2 generation. In another experiment, C57BL/KsJ-db/db males were made T cell function deficient by adolescent thymectomy followed by lethal irradiation and bone marrow reconstitution. None of these manipulations served to prevent the induction of a severe diabetes syndrome in any of the model systems analyzed. Thus, diabetogenesis characterized by massive necrosis of the pancreatic beta cells and atrophy of the pancreatic islets was observed in both the absence of normal T cell function (as assessed by absence of T cell mitogen response) and humoral autoimmunity against beta cell antigens (insulin, retroviral p73). In conclusion, our data indicate that anti-beta cell autoimmunity is not a primary event in the etiopathogenesis of diabetes in the db/db mouse.

Animals↗
PubMed1987

Genetically determined murine models of immunodeficiency.

We have discussed more than 30 mutant genes known to cause abnormalities in the development and regulation of the immune system. The loci defined by these deleterious alleles have been assigned to 13 different autosomal chromosomes in addition to X and Y. It is important to note that these single genes do not act alone but function in concert with the background genome. Studies of these mutations on different inbred strain backgrounds are contributing important information on the influence of background modifying genes. The development of stocks of mice carrying multiple mutations on an inbred strain background enables the use of a well-characterized mutation to explore a less-well-understood genetic model. Investigators are urged to assure proper conditions for studies with immunological mutants by using the appropriate methods of animal husbandry. A detailed guide for maintaining immunologically compromised rodents has been prepared. These experiments performed by nature provide a valuable resource for investigating the immune system in normal and pathologic states. As the gene products of the loci defined by these mutations become known, the information obtained will provide additional insight into mechanisms underlying normal immune function as well as immunologic disease processes in man.

Animals↗
PubMed1987

Development of plasmacytoid cells with Russell bodies in autoimmune "viable motheaten" mice.

Mice homozygous for the autosomal recessive mutation "viable motheaten" (mev) are severely immunodeficient, show polyclonal B-cell activation, and express multiple autoantibodies over a maximum life span of 25 weeks. Lymphoid tissues from these mice contain large numbers of atypical plasma cells in which discrete glycoprotein inclusions are found within the endoplasmic reticulum. Such plasma cells are termed "Mott cells," and the inclusions are called "Russell bodies." Dense accumulations of Mott cells are present in the marginal zones of the spleen and in the lymph nodes of mev/mev mice. Russell bodies in Mott cells from mev/mev mice contain immunoglobulin (Ig) as shown by immunofluorescence microscopy at the light-microscopic level and by indirect protein A-immunogold localization at the electron-microscopic level. Ultrastructural analyses reveal the presence of amorphous, lamellar, and crystalline Russell bodies. These Ig crystals have a periodicity of 150-190 A. Lymph node cell preparations which were enriched in Mott cells by velocity sedimentation failed to secrete Ig in a polyclonal reverse plaque assay. An obligate role of the thymus in Mott cell development is evidenced by the absence of Mott cells in neonatally thymectomized mev/mev mice and in mice doubly homozygous for the nude (nu) and mev mutations. These data suggest that Mott cells in mev/mev mice are thymic-dependent plasmacytoid cells resulting from chronic B-cell activation accompanied by impaired Ig secretion.

Age Factors↗
PubMed1986

Production of immunoglobulin isotypes by Ly-1+ B cells in viable motheaten and normal mice.

Almost all B cells in autoimmune mice with the viable motheaten (mev) mutation express the Ly-1 cell surface antigen, which marks a minor population of B cells constituting a separate lineage in normal mice. Immunoglobulins primarily of the M and G3 classes, which in both normal and mev mice contain high levels of lambda light chain, are produced in excess in mev mice. These and other observations suggest that the development of B cells that express Ly-1 is regulated independently from the development of B cells that do not express Ly-1. B cells bearing the Ly-1 surface antigen may play specialized roles in the normal immune system and in autoimmunity by regulating other B cells via lymphokines, by producing antibodies to self and certain foreign antigens, and by preferentially secreting immunoglobulin M and immunoglobulin G3.

Animals↗
PubMed1986

Non-germ-line elements (NGE) are present in the T cell receptor beta-chain genes isolated from the mutant mouse, motheaten (me/me).

Extra nucleotides (which we call NGE, for non-germ-line elements) are inserted at the junctions of rearranged V, D, and J segments in the immunoglobulin heavy and T cell receptor beta-chain V region genes. NGE addition helps diversity HV3 regions of these genes. It is believed that NGE are added enzymatically and without template during the joining process. Terminal deoxynucleotidyl transferase (TdT) is thought to be the cause of NGE formation. TdT is normally detected in murine thymus and bone marrow cells, but its presence in the immunodeficient mutant mouse, Motheaten (me/me), is extremely reduced in these tissues. To determine whether this TdT deficiency could affect NGE formation during the V-D-J joining of antigen receptor genes, we cloned several rearranged T cell receptor beta-chain genes from thymocytes of me/me mice. Our sequence analysis revealed that Motheaten thymus beta-chain genes have approximately 4 base pair NGE, which are comparable in size to the NGE of wild-type genes. These results do not support the idea that TdT is the NGE-forming enzyme, although it is still possible that a low but residual level of TdT is capable of NGE formation in Motheaten. Alternatively, our data may suggest that the TdT activity in Motheaten T cells is normal; however, the number of TdT+ cells is greatly reduced in the Motheaten thymus, due to a severe defect in T cell development.

Animals↗
PubMed1986

Evaluation of the mouse mutant "wasted" as an animal model for ataxia telangiectasia. I. Age-dependent and tissue-specific effects.

The wasted mouse, an animal model proposed for the genetically transmitted human disease ataxia telangiectasia (AT), was examined for its biological, cytogenetic and biochemical properties. In affected homozygotes, a marked age-dependent decrease in the ratio of spleen and thymus to body weight, and a slight but significant decrease in the liver to body weight ratio were observed while no such change was found in the kidney. An age-dependent increase was observed in the frequency of both spontaneous and gamma-ray-induced chromosomal aberrations in bone marrow cells of wasted mice. In littermate control mice, neither of these alterations was observed in an age-dependent manner. The activity of a primer activating enzyme, which has been reported to be deficient in AT cells, also decreased with age in spleen cells, but not in liver cells of affected mice. However, alterations in apurinic DNA endonuclease activity were not detected in the developmental stages examined. These data indicate that this mouse mutant may serve as a useful animal model for studying the relationships between DNA repair and lymphoid tissue differentiation.

Aging↗
PubMed1986

Effect of DNA-damaging agents on isolated spleen cells and lung fibroblasts from the mouse mutant "wasted," a putative animal model for ataxia-telangiectasia.

Spleen cells from control and wasted (wst) mice, a putative animal model for the human genetic disease ataxia-telangiectasia, were tested for inhibition of replicative (semiconservative) DNA synthesis after treatments with bleomycin, gamma-irradiation, 4-nitroquinoline 1-oxide, and ultraviolet irradiation. The wasted cells were found to be more resistant than control cells to the first three treatments, but equally sensitive to ultraviolet light. Bleomycin-stimulated repair synthesis in spleen cells was also studied by the CsCl/bromodeoxyuridine method and found to be similar in cells from wasted and control animals. Similarly, no differences in sensitivity to killing by gamma-rays, as manifested by relative cloning efficiencies, were demonstrated between primary lung fibroblasts from mutant and control mice. We concluded that observed defects in DNA repair in wasted cells are not identical to those reported in human cells from ataxia-telangiectasia patients.

4-Nitroquinoline-1-oxide↗
PubMed1985

Attenuation of exogenous murine mammary tumor virus virulence in the C3H/HeJ mouse substrain bearing the Lps mutation.

A major change in mammary tumor incidence (MTI) and latency has occurred in the C3H/HeJ mouse substrain maintained at The Jackson Laboratory. The average time required for 50% of the C3H/HeJ mice to develop a mammary tumor changed from 40 weeks of age to the current 61 weeks of age. This 61-week median MTI in the C3H/HeJ substrain is significantly different from the less than 40-week median MTI seen in other C3H substrains infected with an exogenous milk-transmitted murine mammary tumor virus (MuMTV). The median MTI of over 80 weeks in MuMTV-negative C3H substrains also is significantly longer than that seen in C3H/HeJ mice. Although the median MTI for the C3H/HeJ substrain has changed significantly, the continued presence of an exogenous MuMTV in C3H/HeJ mice was confirmed by the presence of high levels of gp52 antigen in the milk of lactating females. Presence of an exogenous MuMTV in C3H/HeJ female mice also was confirmed by their ability to pass their exogenous MuMTV(HeJ) via their milk to exogenous MuMTV-negative BALB/cByJ, C3H, or C3H hybrid mice. These foster-nursed mice exhibited the reduced tumor frequency and the increased median MTI seen in their C3H/HeJ foster mothers. The change in tumor incidence and latency in the C3H/HeJ substrain is not due to the loss of the exogenous MuMTV but to the occurrence of an attenuated MuMTV. Selection of this attenuated MuMTV may be related to the presence of the Lps mutation that occurred during the same time period that the MTI changed in the C3H/HeJ substrain.

Animals↗
PubMed1984

Evaluations of wasted mouse fibroblasts and SV-40 transformed human fibroblasts as models of ataxia telangiectasia in vitro.

Fibroblast cultures from wasted mice have been derived and the responses of these cultures to bleomycin treatment or gamma-irradiation have been examined. No differences were observed between wasted fibroblasts and littermate controls in the post-treatment inhibition of DNA replication. In contrast, a human SV-40 transformed ataxia telangiectasia fibroblast line mimicked the abnormal response of primary ataxia telangiectasia fibroblasts to gamma-rays or bleomycin and thus appears to be a useful in vitro model of ataxia telangiectasia.

Animals↗
PubMed1984

Novel B-cell maturation factor from spontaneously autoimmune viable motheaten mice.

Both in vivo and in vitro, mice homozygous for the viable motheaten mutation show severe immunodeficiency, polyclonal B-cell activation and Ig secretion, and spontaneous production of a lymphokine [B-cell maturation factor (BMF)] that directly drives the maturation of normal or tumor B cells to the state of active Ig secretion. BMF from motheaten mice is distinct from previously identified forms in its cells of origin (B cells) and biochemical characteristics (apparent Mr 15,000 by gel filtration and NaDodSO4/PAGE; pI 4.3 by chromatofocusing). Among the known murine single-gene models of autoimmunity, only motheaten mice show high levels of spontaneous BMF production, which therefore may be an important component in the development of this form of autoimmunity/immunodeficiency disease. The coincidence of spontaneous BMF production and uncontrolled Ig secretion within the same mutant mouse constitutes the strongest evidence to date for a significant physiological (in vivo) role for BMFs.

Animals↗