PubMed Health⌕ Search

Biomedical subjects

L D Shultz

Publications and source records attributed to L D Shultz.

At least 145 records · Page 8Linked to original sources
PubMed1992

The nonobese diabetic scid mouse: model for spontaneous thymomagenesis associated with immunodeficiency.

Homozygosity for the severe combined immunodeficiency (scid) mutation results in a block in T- and B-lymphocyte development. An unusually high incidence of spontaneous thymic lymphoma development was observed after transfer of this mutation from the C.B-17 congenic strain background onto the diabetes-susceptible nonobese diabetic (NOD) background. Thymomagenesis in the NOD-scid/scid mouse was associated with expression of an NOD mouse-unique endogenous ecotropic murine leukemia provirus locus (Emv-30, mapped to proximal region of chromosome 11) not expressed in the standard substrain NOD/Lt thymus. All tumors exhibited insertions of ecotropic proviruses, whereas only a subset also exhibited proviral integrations of mink cell focus-forming retrovirus. Neither class of retrovirus was associated with consistent integration into genes previously associated with activation of oncogenesis. We propose that the unusual features of T-cell ontogeny characteristic of the NOD inbred strain synergize with the scid-imparted block in thymocyte development, leading to activation of the NOD-unique Emv-30 to initiate thymomagenesis.

Animals↗
PubMed1992

Animal models for immunodeficiency diseases.

Immunodeficient animals continue to provide insights into the development and function of the immune system. These animals also serve as models for the propagation of normal and malignant human cells and as hosts for infectious agents, including HIV. New developments in basic and applied research using immunodeficient animals were discussed at a recent workshop.

Acquired Immunodeficiency Syndrome↗
PubMed1992

Differentiation of epidermal Langerhans cells in macrophage colony-stimulating-factor-deficient mice homozygous for the osteopetrosis (op) mutation.

The osteopetrosis (op) mutation is within the gene for macrophage colony-stimulating factor (M-CSF). Homozygotes (op/op) lack M-CSF activity and show abnormalities in the differentiation of osteoclasts and other cells within the macrophage lineage. The effect of the op mutation on the development of Langerhans cells (LC) was determined in order to assess differentiation of such cells in vivo in the absence of M-CSF. (C57BL/6J X C3HeB/FeJ)F2-op/op and +/? Littermate control mice were raised from +/? breeders obtained from the Jackson Laboratory. The mice were killed with ether anesthesia at 4 weeks after birth and skin specimens were excised and examined by immunohistochemistry using anti-mouse pan macrophage monoclonal antibodies (MoAb), F4/80 and BM8; anti-mouse LC MoAb, NLDC-145, M1-8, and MIDC8; and anti-mouse Ia MoAb, M5/114. In epidermal sheets, numbers of LC were counted. Histochemical staining of adenosine diphosphatase (ADPase) localization was also performed as a marker of LC. Epidermal LC from op/op mice showed reactivity with all these MoAb. Numbers of LC were slightly reduced, but the reduction was not significant statistically. The presence of Birbeck granules in LC of op/op mice was confirmed by electron microscopy but the cytoplasmic projection of LC was not prominent. From these results, it appears obvious that the development and differentiation of LC do not require M-CSF.

Animals↗
PubMed1992

Lack of peripherally induced tolerance to established skin allografts in immunologically reconstituted scid mice.

The mechanism by which the antigen-specific immune system distinguishes between foreign antigens (toward which it mounts an immune response) and self-antigens (of which it is tolerant) is not completely understood. Studies using "superantigens" and transgenic mice have allowed investigations into some of the mechanisms of clonal deletion, anergy, and peripheral tolerance. In the present report, we have attempted to develop a new model system to investigate the possible mechanism(s) of peripheral tolerance to allografts. In this system, skin grafts from C57BL/6J (B6; H-2b) mice are grafted onto T- and B-lymphocyte-deficient C.B-17-scid/scid (H-2d; hereafter referred to as scid) mice. Because of their lack of functional lymphocytes, the scid mice readily accept the allogeneic skin grafts. After the allografts healed, the scid mice were reconstituted with T-cell-deficient fetal liver from coisogeneic C.B-17-+/+ mice or bone marrow from weanling congenitally athymic BALB/c-nu/nu (H-2d; hereafter referred to as nude) mice. Upon immunological reconstitution, the scid mice rejected the established B6 skin allografts, suggesting that an immune system developing in the presence of an intact peripheral skin allograft fails to develop tolerance to the peripheral allograft. This model system may be useful for the study of the mechanisms required for the induction of peripheral tolerance.

Animals↗
PubMed1992

Thymic involution in viable motheaten (me(v)) mice is associated with a loss of intrathymic precursor activity.

Mice homozygous for the viable motheaten (me(v)) allele manifest abnormalities in thymocytopoiesis, are severely immunodeficient, and develop autoimmune disorders early in life. Premature thymic involution occurs in me(v)/me(v) mice, and their bone marrow prothymocytes are unable to repopulate the thymus of adoptive recipients following intravenous (i.v.) transfer. However, analysis of thymocytopoiesis following intrathymic (i.t.) adoptive transfer of bone marrow from me(v)/me(v) mice demonstrates the presence of normal numbers of prothymocytes. To investigate intrathymic development in me(v)/me(v) mice, we determined intrathymic precursor cell number and activity. Dual labeling analyses showed that an involuted me(v)/me(v) thymus is relatively enriched (fivefold) in CD4-CD8- thymocytes (intrathymic precursor phenotype) compared with wild-type (+/+) thymus. However, thymocytes from me(v)/me(v) mice were deficient in precursor activity when adoptively transferred i.t. into irradiated recipients. Thymocytes recovered from the involuted thymus of aged or steroid-treated normal mice also displayed reduced precursor activity. However, the phenotypic profile of thymocyte subsets from steroid-treated mice was enriched in single positive cells (mature phenotype) and was distinctly different from the subset distribution of thymocytes in me(v)/me(v) and aged mice. These results suggest that intrathymic precursor activity in me(v)/me(v) mice is decreased, and may be reflective of decreased prothymocyte seeding to the thymus in vivo. In addition, the results suggest that the thymic involution in me(v)/me(v) mice is not due solely to effects of corticosteroids.

Animals↗
PubMed1992

Defective repair of radiation-induced chromosomal damage in scid/scid mice.

The murine severe combined immunodeficiency (scid) mutation interferes with normal recombination of immunoglobulin and T-cell receptor genes. This immunologic defect results in a lack of fully differentiated B and T cells in scid/scid mice. Animals homozygous for the scid mutation also display increased sensitivity to the damaging effects of ionizing radiation. We report here our observations of high frequencies of radiation-induced chromatid interchanges and intrachanges in bone marrow cells and fibroblasts from scid/scid mice. The presence of these aberrant chromosome structures suggests that a delay in strand rejoining underlies the increased sensitivity of scid/scid mice to ionizing radiation. The scid mutation may provide important clues for understanding the relationship between mitotic recombination and DNA repair in higher eukaryotic cells.

Animals↗
PubMed1992

Characteristics of long-term human thyroid peroxidase autoantibody secretion in scid mice transplanted with lymphocytes from patients with autoimmune thyroiditis.

We have explored scid mice as an in vivo model to study lymphocyte function and autoantibody production in patients with autoimmune thyroiditis and thyroid peroxidase (hTPO) autoantibodies. Patient's peripheral blood mononuclear cells (PBMC) were transplanted into scid mice via intraperitoneal injections and human immunoglobulin G (hIgG) and thyroid autoantibody levels in the murine sera were monitored for a minimum of 3 months after transplantation. Human IgG reached maximum serum levels of > 3,000 micrograms/ml (mean +/- SEM = 1,199 +/- 354 micrograms/ml) after an average of 6.5 weeks. In reconstituted mice (hereafter named At-Scid-hu) substantial titers of anti-hTPO of up to 0.51 (ELISA index, normal range < 0.02) were observed over a period of 1-2 months, followed by a gradual decline. Immunization of AT-Scid-hu mice with immunogenic, recombinant human hTPO (rec-hTPO) failed to enhance hTPO-Ab levels. Furthermore, there was no correlation between the magnitude of human IgG in the murine serum and concomitant levels of anti-hTPO. Murine thyroid function was unaffected by the transplantation of PBMC, as evidenced by normal serum thyroxine (T4) levels, and lack of specific pathologic changes in the thyroid. These data indicate, for the first time, the potential for longer-term human thyroid autoantibody secretion in the scid mouse reconstitution model allowing for further investigation of the regulatory factors inpinging on the human B cells surviving in the murine environment.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

CD8+ T lymphocytes are not required for murine resistance to human filarial parasites.

Mice are resistant to the establishment of infection with the nematode parasite Brugia malayi, an etiologic agent of human lymphatic filariasis. We have recently shown that T and B lymphocyte-deficient C.B.-17 scid/scid mice are permissive for infection with this parasite, whereas coisogenic C.B.-17+/+ mice are resistant. This observation suggests that T and B lymphocytes that comprise the antigen-specific immune system orchestrate murine resistance to B. malayi. In order to define the component of the antigen-specific immune response that is responsible for this resistance, we have tested the susceptibility of beta 2M-/- mice to infection with B. malayi L3 larvae. These mice are homozygous for insertional disruption of their B2m genes, which encode beta 2-microglobulin, the small subunit of the major histocompatibility (MHC) antigens. They do not express beta 2-microglobulin and, as a consequence, fail to express the class I major histocompatibility antigens, and they do not develop the CD8+ class I MHC-restricted cytotoxic T cell subset. We find that these mice are completely resistant to B. malayi, indicating that the CD8+ T lymphocyte subset is not an obligate requirement for murine resistance to human filarial parasites.

Animals↗
PubMed1991

Suppressive effects of monocytic cells and transforming growth factor-beta on natural killer cell differentiation in autoimmune viable motheaten mutant mice.

Viable motheaten (mev) mice are homozygous for a recessive single gene mutation at chromosome 6. These mice develop numerous inflammatory and arthritic syndromes and exhibit abnormal B cell functions as well as lower T and NK cell activity. In this study, the differentiation of NK cells in mev mice was examined to elucidate the underlying basis for decreased NK activity. Although NK cells appear to be present in mev mice, their activity was demonstrable only when the spleen cells were enriched by nylon wool passage. Similarly bone marrow cells from these mice could be shown to contain precursors of NK cells when they were passed over nylon wool and transplanted into irradiated recipients. The adherent cells from both the spleen and bone marrow of mev mice suppressed the differentiation of NK cells from normal splenic populations. These suppressive adherent cells were F4/80(+), AsGm-1(+), Qa-5(+), and NK-1.1(+). They were not cytolytic when cultured in IL-2. Antibodies to a number of cytokines, such as IFN-alpha, -beta, and gamma, or TNF-alpha, could not reverse the suppressive effect of the adherent cells. Addition of anti-TGF-beta antibody could, however, overcome the suppression, suggesting that TGF-beta was partly responsible for the defective NK differentiation in the mev mice.

Animals↗
PubMed1991

The immunodeficient scid mouse as a model for human lymphatic filariasis.

The C.B.-17-scid/scid mouse (hereafter referred to as the scid mouse) is homozygous for a recessive mutation at a locus that influences the assembly of intact immunoglobulin and T cell receptor genes. Therefore, scid mice cannot generate functional B or T lymphocytes, are profoundly immunodeficient, and have been reported to be receptive to reconstitution with human immune cells. In the present study, we injected scid mice with infective larvae of the human filarial parasite Brugia malayi. Within 6-10 wk after subcutaneous injection of infective L3 larvae, both male and female worms were observed in various stages of development in 90% of the mice. In animals tested 8 weeks or more after infection, microfilariae were detected in the blood or peritoneal cavity of 52% of the mice examined. Adult worms were observed in the lymphatics of the infected scid mice, where their presence was associated with lymphangitis and lymphangiectasia. These results suggest that the scid mouse model of lymphatic filariasis may be important in investigation of the interaction of the murine, and possibly the human, immune system with the lymphatic filarial parasite.

Animals↗
PubMed1991

Immunological mutants of the mouse.

Mutations at more than 30 loci in mice have been shown to cause deleterious effects on the immune system. Immunologic defects caused by certain of these mutations are determined at the level of hematopoietic progenitor cells or at the level of hematopoietic cell-stromal cell interactions. The immunological mutants described in this paper serve as experimental tools with which to increase our understanding of the development and regulation of the mammalian immune system.

Animals↗
PubMed1991

Phorbol ester responsiveness of murine Ly-1-lineage B cells from normal and viable motheaten mutant mice.

Simultaneous analysis of stimulated cells for surface phenotype and DNA content by flow cytometry was used to delineate the characteristics of murine lymphocytes that respond to phorbol esters. Peritoneal cells that expressed high-density sIgM, Ly-1, Mac-1 and high-density Pgp-1, were preferentially stimulated to enter the S + G2/M phases of the cell cycle by the protein kinase C agonist, phorbol 12-myristate 13-acetate (PMA). Since these phenotypic characteristics correspond well with those of Ly-1-lineage B cells, non-peritoneal sources of Ly-1+ B cells were examined to test the relative role of lineage and environment in determining phorbol ester responsiveness. Splenic sIgM+ lymphocytes from adult mev/mev mice, and Ly-1+ splenic B cells from neonatal normal mice, were stimulated to enter the S + G2/M phases by PMA, although not to the same extent as peritoneal Ly-1+ B cells. These results suggest that responsiveness to phorbol ester, acting alone, is characteristic of murine Ly-1-lineage B cells regardless of tissue of origin; however, a role for environmental influences has not been completely ruled out.

Animals↗
PubMed1991

The SCID-hu mouse and thyroid autoimmunity: characterization of human thyroid autoantibody secretion.

Severe combined immunodeficient (SCID) mice were injected with peripheral blood mononuclear cells (PBMC) from normal individuals and 14 out of 18 had detectable serum human (h) IgG (maximum levels providing a mean +/- SEM 934 +/- 213 micrograms/ml) and IgM (253 +/- 93 micrograms/ml) at 3-6 weeks after transplantation. Serum human immunoglobulin levels were maximum 6-12 weeks after transplantation and declined to low levels over the subsequent 5 months. Human B cells constituted up to 10% and human T cells up to 40% of cells in the peripheral circulation and spleens of these animals 2-3 weeks after transplantation, PBMC, or intrathyroidal (IT) lymphocytes, from 6 patients with Graves' disease and high serum levels of thyroid autoantibodies were transplanted into 30 SCID mice (Graves' SCID-hu). Although serum human immunoglobulins were observed in only low amounts in the animals receiving IT lymphocytes (n = 4), increased levels of hIgG or hIgM were more easily detectable in 19 Graves' SCID-hu mice that received PBMC. The Graves' SCID-hu mice had significantly lower mean levels of hIgG and hIgM than those observed following transplantation of normal PBMC (mean maximum 328 +/- 113 and 32 +/- 21 micrograms/ml, respectively). Six of these 19 mice had detectable human autoantibody to thyroid peroxidase (TPO, as microsomal antigen) between 3 and 8 weeks after transplantation, with titers ranging from 0.05 to 0.39 (normal SCID-hu serum less than 0.02 ELISA Index). No abnormal thyroid hormone (T4 and T3) levels or thyroiditis was seen when compared to normal SCID-hu mice. Immunization of reconstituted SCID mice with recombinant immunoactive human TPO antigen failed to initiate anti-TPO in normal PBMC-treated mice nor did it increase the titer of human anti-TPO in the anti-TPO positive animals. In conclusion we successfully established human thyroid autoantibody secretion in the SCID-hu mouse and characterized the transient nature of the model. Further studies will be required to achieve successful antigen presentation in this system.

Animals↗
PubMed1991

Synthesis of abnormal immunoglobulins by hybridomas from autoimmune "viable motheaten" mutant mice.

Secretory defects in abnormal plasma cells, called Mott cells, that appear in lymphoid tissues of spontaneously autoimmune, "viable motheaten" (mev/mev) mice lead to deposition of immunoglobulin in RER-bound vesicles. Such vesicles have been termed Russel bodies. Cells with Russel bodies can also be observed rarely in normal animals, usually as a result of extreme antigenic loads or pathologic states. To understand why these abnormal cells appear commonly in mev/mev mice, we have established a panel of hybridomas that contain Russell bodies. Using immunochemical analysis and immunoelectron microscopy, we have characterized the secretory defects. Although these hybridoma cells synthesize a normal size heavy chain and it associates with light chain, the Russell bodies have many characteristics of inclusion bodies, which commonly appear in cells synthesizing mutant proteins and often are associated with incompletely or abnormally folded proteins. Pulse-chase experiments showed that immunoglobulins synthesized by these hybridomas accumulate rapidly into insoluble complexes and have an intracellular half life approximately 10 time greater than normal immunoglobulins. The defect affected only the immunoglobulin derived from the mev/mev mice and did not affect the secretion of normal immunoglobulin produced by an IgG1-secreting fusion partner. In addition to accumulating intracellular immunoglobulins, many mutant cell lines also secreted immunoglobulin. Endoglycosidase H digestion was used to determine the state of processing of the N-linked carbohydrates on the immunoglobulin molecules. This analysis demonstrated that the N-linked carbohydrates on the secreted immunoglobulin were resistant to endoglycosidase H digestion, indicating that they were processed normally. The insoluble IgM molecules were sensitive to endoglycosidase H, which is consistent with their localization to the RER. We propose several models by which these abnormal immunoglobulin-secreting cells commonly appear in this autoimmune mutant mouse.

Acetylglucosaminidase↗
PubMed1991

Recapitulation of normal and abnormal BB rat immune system development in scid mouse/rat lymphohemopoietic chimeras.

Mice homozygous for the mutation "severe combined immune deficiency" (C.B17-scid/scid) lack functional T and B lymphocytes and readily accept tumor xenografts. Partial lymphohemopoietic scid/human and mouse/rat chimeras have been described, but complete chimerization with thymic engraftment and generation of donor-origin thymocytes has not been achieved. We now report that low-dose irradiation permits the engraftment of BB rat fetal liver stem cells in scid recipients. We observed that BB rat fetal liver cells injected into irradiated scid mice establish a rat hemopoietic system in the scid mouse bone marrow and populate the scid mouse thymus. These stem cells generated rat-origin thymocytes that migrated to the scid mouse spleen, a peripheral lymphoid organ. Finally, we found that xenogeneic chimeras created using fetal liver cells from the abnormal (lymphopenic, diabetes prone) subline of BB rats recapitulated both the quantitative and phenotypic abnormalities of the donor rat. Xenogeneic lymphohemopoietic chimeras established in scid mice may provide a powerful new tool in the study of immune system development and autoimmunity.

Animals↗
PubMed1991

Hematopoiesis and models of immunodeficiency.

This review focuses on recessive mutations at three loci whose gene products play critical roles in the development and regulation of the murine immune system. These mutations are: severe combined immunodeficiency (scid), osteopetrosis (op), and motheaten (me). The scid mutation blocks differentiation of functional T and B lymphocytes and interferes with DNA repair processes in multiple cell lineages. The normal gene product at this locus performs a critical function during antigen receptor gene rearrangement as well as during repair of double stranded DNA damage. Homozygosity for op causes impaired development of osteoclasts and other macrophage lineage cells. The op mutation is within the macrophage colony stimulating factor (Csfm) structural gene. Deleterious alleles at the me locus affect lymphoid as well as myeloid cell populations, causing severe immunodeficiency accompanied by systemic autoimmune disease. Determination of the product of the wild type allele at the me locus and the mechanisms by which mutations at this locus disrupt the immune system may reveal important new immunoregulatory processes.

Animals↗
PubMed1991

Hairpatches, a single gene mutation characterized by progressive renal disease and alopecia in the mouse. A potential model for a newly described heritable human disorder.

A new murine mutation, hairpatches (Hpt), is on chromosome 4, 18.1 recombination units distal to brown near the interferon alpha and beta chain structural gene complex. On the inbred HPT/Le strain background, Hpt is semi-dominant, and Hpt/Hpt mice die in utero by 6 to 8 days of gestation. Such death in utero is associated with abnormalities of embryonic ectodermal derivatives. However on the (C57BL/6J x C3HeB/FeJ-a/a) segregating hybrid background, Hpt is a fully dominant mutation. HPT/Le Hpt/+ mice can be recognized by 3 to 4 days of age by patches of lightly pigmented skin. These mice show reduced numbers of hair follicles, abnormalities in hair follicle structure, and patchy absence of hair throughout life. By 2 weeks of age, abnormal hair follicle development is accompanied by thickening of the epidermis, reduction in levels of subcutaneous fat, and dermal inflammation. Progressive glomerulosclerosis, resulting in chronic kidney failure, is accompanied by increases in glomerular mesangial matrix, deposition of immune complexes, and glomerular enlargement. Scanning electron microscopic studies revealed abnormalities of podocytes including disorganization, swelling, and fusion of the foot processes. Increase in serum blood urea nitrogen levels accompanies conspicuous renal histopathologic changes. Cardiovascular changes in Hpt/+ mice are evidenced by hypertrophy of the left heart ventricle. Increased systolic blood pressure in these animals was found by 3 months of age. Anemia occurs in Hpt/+ mice by 40 weeks. The Hpt/+ mutation provides a valuable new animal model for chronic kidney disease accompanied by skin abnormalities and ventricular hypertrophy. The pathologic changes caused by this mutation are similar to those reported in affected family members with a newly described autosomal dominant human disease.

Alopecia↗