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L D Shultz

Publications and source records attributed to L D Shultz.

At least 127 records · Page 7Linked to original sources
PubMed1994

Preservation of functioning human thyroid "organoids" in the severe combined immunodeficient mouse. III. Thyrotropin independence of thyroid follicle formation.

The severe combined immunodeficient (scid) mouse allows the in vivo reconstitution of thyroid follicles from thyroid monolayer cells when transplanted sc within an extracellular basement membrane matrix. After 2-3 weeks, these human thyroid organoids show an active microfollicular histology and secrete human thyroglobulin into the murine serum in response to the administration of recombinant human TSH. Furthermore, such organoids survive for more than 3 months in this functional state. To assess whether thyroid follicular reconstitution was TSH dependent, we examined organoid follicular reconstruction in T3-induced hyperthyroid scid mice, in which endogenous murine TSH was presumed to be totally suppressed. By providing water with 12 micrograms/ml T3, we increased the murine serum T3 levels from a mean of 1.9 nmol/liter in controls to greater than 12.0 nmol/liter. After 3 weeks, thyroid cells derived from normal human thyroid monolayers were suspended in an extracellular basement membrane matrix, and the suspension was transplanted sc into scid mice (with or without T3-induced hyperthyroidism) and allowed to reconstitute. Histological examination 4 weeks later showed a similar degree of thyroid follicle formation in mice treated with or without T3, indicating that the hyperthyroid state had caused no interference with thyroid follicle reconstitution. This was further confirmed by transmission electron microscopy, which demonstrated normal human thyroid follicle cell polarity in the organoids of both euthyroid and hyperthyroid mice. In addition, using an extracellular basement membrane preparation with reduced growth factor (epidermal growth factor, insulin-like growth factor-I, and platelet-derived growth factor) levels also allowed normal thyroid follicle formation in T3-fed mice. These data demonstrate that in vivo thyroid follicle formation is TSH independent and that extrathyroidal epidermal growth factor, insulin-like growth factor-I, and platelet-derived growth factor may be relatively unimportant. The factors and molecular mechanisms leading to follicular reorganization of adult human thyroid cells remain to be determined, but are likely to depend largely on intrathyroidal growth factor secretion and cell-cell interaction.

Animals↗
PubMed1994

Engraftment of human lymphocytes and thyroid tissue into scid and rag2-deficient mice: absent progression of lymphocytic infiltration.

To study human autoimmune thyroid disease in an animal model we have investigated the in vivo survival of human thyroid tissues and functionality of human lymphocytes in severe combined immunodeficient (scid) mice and recombination-activating gene (rag2) knockout mice. We found successful engraftment of human thyroid tissues in both scid and rag2-deficient mice. However, when peripheral blood mononuclear cells were transplanted ip, human immunoglobulin production was poor in rag2-deficient mice compared to that in scid mice (mean human immunoglobulin G levels at 6 weeks, 0.2 +/- 0.2 microgram/mL in two of eight rag2-deficient mice compared to 20.8 +/- 7.0 micrograms/mL in seven of nine scid mice; P < 0.05). We, therefore, only pursued the further use of scid mice and transplanted them with thyroid tissue from patients with either Graves' disease (four patients) or Hashimoto's thyroiditis (one patient). At the functional level, we observed transiently increased thyroid hormone levels (T4 peaking at 5.4 +/- 0.2 microgram/dL compared to a normal level of 2.6 +/- 0.2 microgram/dL); human autoantibodies to human thyroglobulin, human thyroid peroxidase, and the human TSH receptor were also detected in thyroid-transplanted mice. In contrast to recent reports, histological examination of the thyroid explants showed no increase in the lymphocytic infiltrate compared to the original donor tissue, nor was there any thyroid follicular destruction observed. In fact, many of the transplants demonstrated a marked diminution in the infiltrates over time, with an absence of HLA-DR antigen expression by both T-cells and thyrocytes. Cotransplanted allogeneic thyroid tissues were unremarkable in terms of lymphocytic infiltrates and showed intact morphology. Taken together, these data point to a relative degree of T-cell inactivity within the thyroid explants from the scid mouse. Hence, a factor(s) present in the patient with autoimmune thyroid disease that activates their thyroid-specific T-cells may be absent in this murine model as presently constructed.

Animals↗
PubMed1994

Multiple low-dose streptozocin-induced diabetes in NOD-scid/scid mice in the absence of functional lymphocytes.

The murine severe combined immunodeficiency (scid) mutation was used to assess whether the diabetogenic effects of multiple low-dose streptozocin (MD-STZ) administration required the presence of functional T-cells. An STZ dose as low as 30 mg/kg body wt for 5 days induced hyperglycemia in young NOD/Lt-+/+ male mice, whereas a dose of 50 mg/kg for 5 days was required to elicit comparable hyperglycemia in C.B.-17-+/+ male mice. The greater NOD strain sensitivity was not a function of preexisting insulitis, because insulitis- and diabetes-free NOD male mice congenic for a diabetes-resistant major histocompatibility complex haplotype were equally susceptible to MD-STZ. This was confirmed in NOD-scid/scid and C.B.-17-scid/scid males. Both were completely insulitis-free, and despite the absence of functional T- cells and B-cells, both congenic stocks were as sensitive to MD-STZ as congenic +/+ controls. Indeed, MD-STZ-induced hyperglycemia in NOD-scid/scid male mice was significantly higher than in NOD/Lt-+/+ male mice. The NOD-scid/scid mouse as a recipient of adoptively transferred splenocytes clearly delineated a distinct pathogenesis of spontaneous insulin-dependent diabetes mellitus (IDDM) versus MD-STZ-induced hyperglycemia. Splenocytes from spontaneously diabetic NOD/Lt males, but not those from donors given MD-STZ, readily transferred IDDM, even when host beta-cells were sensitized by a single injection of STZ before adoptive transfer. We conclude that IDDM induced by MD-STZ is not mediated by T-cell- or B-cell-dependent autoimmune mechanisms in a fashion analogous to the spontaneous IDDM characteristic of NOD mice.

Animals↗
PubMed1994

Graves' disease thyroid tissue transplants in scid mice: persistent selectivity in hTcR Va gene family use.

We have analyzed the human T-cell receptor (hTcR) V alpha gene repertoire in thyroid tissue transplants of a patient with hyperthyroid Graves' disease. Blocks of thyroid tissue were transplanted subcutaneously into 10 mice with severe immunodeficiency (scid) and 4 weeks later 5 of the mice were injected intraperitoneally with autologous peripheral blood mononuclear cells (PBMC) (10(7) cells per mouse). After a further 3 weeks, mice were sacrificed and total cellular RNA and cDNA prepared from each of the explants. We used specific olingonucleotides in polymerase chain reactions (PCR) to amplify 18 different human hTcR V alpha gene families and the identity of the PCR fragments was confirmed by Southern blot analysis. Different samples of the donor thyroid tissue consistently expressed 9-10 of the 18 hTcR V alpha gene families screened (V alpha 1-7, 11, 12 & 15). A more marked bias in hTcR V gene family use was seen in each of the explants with a mean of only 2.8 V alpha gene families detected. After 7 weeks of transplantation, the thyroid explants largely reflected some of the same genes seen in the hTcR V gene repertoire of the donor tissue with particularly pronounced expression of V alpha 2 and V alpha 3 gene families. The transplantation of PBMC into the scid mice showed evidence for their accumulation within the transplanted thyroid tissues as judged by the appearance of additional hTcR V gene families expressed in these samples although the specificity of such accumulation remains unclear.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1994

Ultrastructure of macrophages and dendritic cells in osteopetrosis (op) mutant mice lacking macrophage colony-stimulating factor (M-CSF/CSF-1) activity.

The ultrastructural features of macrophages and dendritic cells of mice homozygous for osteopetrosis (op/op) mutation were studied. The mutant mice are characterized by defective differentiation of osteoclasts, monocytes, and tissue macrophages due to the lack of functional macrophage colony stimulating factor (M-CSF/CSF-1) activity. In op/op mice, tissue macrophages were reduced in number and smaller than in normal littermates. Macrophages in op/op mice showed various degrees of phagocytosis but the development of intracytoplasmic organelles and microvillous projections was poor. After administration of CSF-1 daily for 2 weeks, macrophages in op/op mice developed lysosomes and microvillous projections. In the thymic medulla, T-cell zone of lymph nodes, splenic white pulp and epidermis of the op/op mice, the number of dendritic cells was similar to that in normal littermates and the dendritic cells developed a tubulovesicular system typical of interdigitating cells. Birbeck granules in epidermal Langerhans cells were detected in unmanipulated op/op mice, op/op mice injected with CSF-1, and normal littermates or control mice. However, in untreated op/op mice, dendritic cells projected shorter cytoplasmic processes than in normal littermates, normal control mice and CSF-1 injected op/op mice. These results indicate that the differentiation and maturation of tissue macrophages are mediated by CSF-1, but the dendritic cell differentiation is controlled by other factor(s) than CSF-1, most probably by GM-CSF.

Animals↗
PubMed1994

The role of macrophage colony-stimulating factor in hepatic glucan-induced granuloma formation in the osteopetrosis mutant mouse defective in the production of macrophage colony-stimulating factor.

To elucidate the effects of macrophage colony-stimulating factor (M-CSF) on Kupffer cells and monocyte/macrophages in hepatic granuloma formation, we examined granulomas produced by glucan injection in the liver of osteopetrotic mice and littermates with or without M-CSF administration. In the osteopetrotic mice, monocytes were deficient in peripheral blood, and their number did not increase after glucan injection. Hepatic granulomas were formed in the osteopetrotic mice by glucan injection without a supply of blood monocytes. During this process, M-CSF-independent Kupffer cells proliferated, particularly before the granuloma formation, clustered in the hepatic sinusoid, and transformed into epithelioid cells and multinuclear giant cells. In the M-CSF-treated osteopetrotic mice, glucan injection induced an increase in the number of blood monocytes and formed hepatic granulomas at a nearly similar degree to that of littermate mice. Thus, it is concluded that neither monocytes nor M-CSF are necessary for granuloma formation. In contrast, Kupffer cells play a crucial role as granulomas develop in M-CSF-uninjected osteopetrotic mice.

Animals↗
PubMed1994

Acute, lethal, natural killer cell-resistant myeloproliferative disease induced by polyomavirus in severe combined immunodeficient mice.

Infection of severe combined immunodeficient mice, which lack T and B lymphocytes, with polyomavirus (PyV) induced an acute hematological disorder leading to the death of the mice by 2 weeks postinfection. The disease was characterized by a dramatic decrease in megakaryocytes, multiple hemorrhages, anemia, thrombocytopenia, splenomegaly, a massive myeloproliferation and splenic erythroproliferation with a defect in maturation of the myeloid elements similar to that in acute leukemia. This pathology in severe combined immunodeficient mice is very different from that of the well-characterized tumor profiles induced by PyV in normal newborn or nude mice. Viral T and capsid (VP1) antigens and viral genome were detected in some cells in the spleen, but not in the majority of the proliferating myeloid cells. This suggests that the myeloproliferation is induced by some indirect mechanism, such as secretion of growth factors or cytokines by virus-infected cells, rather than by direct transformation by PyV. Neither the spread of PyV, its replication in different organs, nor the pathogenesis or the time of death were altered by depleting natural killer cells in vivo by anti-natural killer cell antibodies. Analysis of the spleen leukocyte population indicated that the cells expressed high levels of class I major histocompatibility complex antigens and were resistant to lysis by activated natural killer cells.

Acute Disease↗
PubMed1993

Anti-CD11b antibody prevents immunopathologic changes in viable moth-eaten bone marrow chimeric mice.

The effect of in vivo treatment with anti-CD11b (MAC-1) antibody (Ab) was examined in an inflammatory disease model, the viable moth-eaten (mev) mutant mouse. The autosomal recessive mev gene occurred spontaneously as a point mutation of the hematopoietic cell protein tyrosine phosphatase in C57BL/6 mice. Homozygotes (mev/mev) develop a chronic myelomonocytic inflammation, involving accumulation of myelomonocytic cells in lungs and skin, resulting in interstitial pneumonitis and severe edema in the paws. These mice also exhibit abnormalities in lymphoid development, thymic atrophy, with T cell and NK cell dysfunction. These inflammatory changes are transferrable by bone marrow cells of mev/mev mice, indicating that mev mutation is due to a stem cell defect in the myelomonocytic pathway. An anti-CD-11b (5C6) Ab inhibited the immunopathologic changes in the bone marrow chimeras, when the Ab treatment was initiated on day -1 or day 0 of the bone marrow transplant. The lungs, paws, and thymus all remained normal after treatment. Furthermore, the Ab also delayed the onset of the mev syndromes when the Ab was given 10 days after the bone marrow transfer. Therefore anti-CD11b Ab inhibited inflammation both prophylactically and therapeutically, and restored normal function of T and NK cells in this disease model. These results support the contention that CD11b molecules expressed in the myelomonocytic cells play a critical role in this naturally occurring inflammatory disease.

Animals↗
PubMed1993

Human bone marrow and umbilical cord blood cells generate CD4+ and CD8+ single-positive T cells in murine fetal thymus organ culture.

Murine fetal thymus lobes isolated from both normal and scid/scid mice can be colonized by donor cells from either human bone marrow or human umbilical cord blood in vitro. Subsequent organ culture results in a transient production of a few CD4+ CD8+ (double-positive) cells and then the accumulation of CD4+ or CD8+ (single-positive) T cells. A significant number of immature T-cell intermediates (e.g., CD8low, CD3-/low cells) were present in early organ cultures, suggesting that these were progenitors of the mature CD3+/high single-positive T cells that dominated late cultures. Depletion of mature T cells from the donor-cell populations did not affect their ability to colonize thymus lobes. However, colonization depended on the presence of CD7+ progenitor T cells. Limiting dilution experiments using mature T-cell populations (human peripheral blood leukocytes, human bone marrow cells, and human umbilical cord blood cells) suggested that thymic organ culture supports the growth of progenitor T cells but does not support the growth of mature human T cells. Each of these donor populations produced single-positive populations with different CD4/CD8 ratios, suggesting that precursor cells from different sources differ qualitatively in their capacity to differentiate into T cells.

Animals↗
PubMed1993

Granulosa cell tumorigenesis in genetically hypogonadal-immunodeficient mice grafted with ovaries from tumor-susceptible donors.

The SWR and SWXJ recombinant inbred strains of mice develop heritable, pubertal onset ovarian granulosa cell (GC) tumors with characteristics similar to those observed for human juvenile GC tumors. We utilized this murine model to determine: (a) whether spontaneous tumorigenesis is an intrinsic property of the susceptible ovary; (b) whether pubertal developmental stage affects tumorigenesis; and (c) whether tumorigenesis depends on extraovarian regulation provided by an immune system or a hypothalamic-pituitary gonadotropin system. To test these questions, ovaries from tumor-susceptible donors were grafted beneath the kidney capsules of hosts with differing immunological and hormonal capabilities. Hosts for these ovarian grafts were: (a) immunologically intact, syngeneic mice; (b) immune-deficient, allogeneic mice homozygous for the severe combined immune deficiency (scid/scid) mutation; and (c) scid/scid mice segregating for the hypogonadal (hpg) mutation, yielding gonadotropin-deficient hpg/hpg scid/scid and gonadotropin replete +/? (hpg/+ or +/+) scid/scid littermates. Donors and hosts of differing ages were used to address questions of developmental effects on tumorigenesis. Grafts were examined 6 to 10 wk after implantation for ovarian morphology and tumor incidence. Results showed that ovary grafts from susceptible female mice formed spontaneous GC tumors equally well in both syngeneic and immune-deficient scid/scid hosts. In each type of host, the incidence of grafts exhibiting spontaneous tumor development declined significantly with increasing age of both donor and host. In addition, prepubertal ovary grafts formed spontaneous tumors in hormonally normal +/? scid/scid but not in hormonally deficient hpg/hpg scid/scid hosts. Finally, treatment of hpg/hpg scid/scid host mice with the androgenic steroid hormone precursor, dehydroepiandrosterone, resulted in GC tumor formation in the tumor-susceptible ovary grafts. We conclude that pubertal onset, spontaneous tumorigenesis in the susceptible ovaries is: (a) independent of an intact immune system; (b) terminated by completion of ovarian maturation as a cyclic organ; (c) not dependent on extraovarian factors unique to the genetically susceptible host; and (d) potentially initiated by androgenic steroids in the absence of an intact hypothalamic-pituitary gonadotropin axis. We hypothesize that ovarian androgens synthesized in response to normal gonadotropin stimulation initiate spontaneous tumorigenesis in the genetically susceptible ovary.

Animals↗
PubMed1993

Mutations at the murine motheaten locus are within the hematopoietic cell protein-tyrosine phosphatase (Hcph) gene.

Mice homozygous for the recessive allelic mutation motheaten (me) or viable motheaten (mev) on chromosome 6 develop severe defects in hematopoiesis. In this paper we present the findings that the me and mev mutations are within the hematopoietic cell protein-tyrosine phosphatase (Hcph) gene. High resolution mapping localized me to an area tightly linked to Hcph on chromosome 6. Abnormalities of the Hcph protein product were demonstrated by Western blot analysis and by activity assays in both me/me and mev/mev mice. Molecular analysis of the Hcph cDNA identified abnormal transcripts in both mutants. DNA sequence analyses of cDNA and genomic clones revealed that both the me and mev mutations are point mutations that result in aberrant splicing of the Hcph transcript. These findings provide the first available animal models for a specific protein-tyrosine phosphatase deficiency, thus facilitating determination of the precise role of this signaling molecule in hematopoiesis.

Animals↗
PubMed1993

Induction of functional follicular dendritic cell development in severe combined immunodeficiency mice. Influence of B and T cells.

Ag injected into immune mice immediately complexes with specific antibody. Immune complexes not phagocytosed by macrophages are transported by Ag transport cells to lymph node follicles for trapping by follicular dendritic cells (FDC). These FDC serve as a long term repository of unprocessed Ag that is believed to maintain both B cell memory and the secondary antibody response. Severe combined immunodeficiency mice lack functional B cells and T cells. Consequently, this mutation also appears to affect the ability to produce Ag-retaining FDC. to assess B and T cell requirements for FDC development and function, severe combined immunodeficiency mice were reconstituted with BM, or mature B and T cells. The development of a FDC reticulum, a three-dimensional network produced by the intertwining of FDC dendrites was assessed by Ag trapping on FDC using the histochemically detectable Ag horseradish peroxidase and quantitated by morphometry. The results showed that bone marrow transplants or B and T cells transferred together supply the required elements for the development of severe combined immunodeficiency FDC reticula that function in Ag trapping and the induction of the germinal center. In contrast, B cells or T cells injected separately induced a minimal development of FDC reticulum. The B and T cell requirements demonstrated here strongly indicate that B-T cell collaboration and the factors these cells produce are essential for FDC development.

Animals↗
PubMed1993

Differentiation of dendritic cell populations in macrophage colony-stimulating factor-deficient mice homozygous for the osteopetrosis (op) mutation.

In op/op mice, immunohistochemical and electron microscopic techniques were used to examine the effects of the OP mutation on dendritic cell populations in lymphoid tissues and skin. In the thymic medulla, T cell zone of lymph nodes, and splenic white pulp of op/op mice, numbers of NLDC-145-positive dendritic cells were not decreased. Compared to the normal littermates, numbers of BM8-positive macrophages were reduced in various tissues of the mutant mice, including the lymphoid tissues. These dendritic cells of op/op mice expressed Ia antigens but not F4/80 and BM8 antigens. Ultrastructurally, the dendritic cells developed a tubulovesicular system typical of interdigitating cells, but they were abnormal in that interdigitation of their cytoplasmic processes was not prominent. In the epidermis of the op/op mice, dendritic cells expressed NLDC-145, F4/80, Ia antigens, and adenosine diphosphatase or adenosine triphosphatase activity, and numbers of NLDC-145-, Ia-, or ADPase-positive dendritic cells were reduced slightly, but these reductions were not significant statistically. Birbeck granules were detected in most of them electron microscopically. These results indicate that nonlymphoid dendritic cells develop in the lymphoid tissues and skin of op/op mouse, suggesting that they are differentiated from granulocyte-macrophage colony-forming cells or earlier hematopoietic cell precursors.

Adenosine Triphosphatases↗
PubMed1993

Preservation of functioning human thyroid organoids in the scid mouse: 1. System characterization.

We have characterized a system for preserving reconstituted human thyroid follicles in vivo by transplanting human thyrocytes into mice with severe combined immunodeficiency (scid mice). Human thyroid organoids were constructed from thyroid monolayer cells derived from both normal and abnormal thyroid tissue, and embedded within a basement membrane preparation which was then transferred sc to scid mice. As early as 4 weeks, and as late as 3 months post transplantation, histological examination of human thyroid organoids demonstrated widespread neofollicle formation and colloid accumulation which stained positive for human thyroglobulin (hTg). Although there were no changes in murine serum T4 levels; the transplanted thyroid epithelial cells secreted hTg into the scid mouse circulation (with an average level of 29 micrograms/L). In addition, hTg release was stimulated in vivo by ip administration of recombinant human TSH (0.1-1.0 IU/mouse) achieving greater than 20-fold increases in scid mouse serum hTg levels. In situ immunohistochemistry showed that thyroid organoids derived from patients with Graves' disease retained scattered lymphocytes in peripolesis with the thyroid epithelial cells; those lymphocytes were identified as human T cells of the memory (CD45RO +), rather than naive, type. These data demonstrate that functioning human thyroid organoids establish in scid mice and remain responsive to TSH stimulation. The system offers a unique opportunity to examine human thyroid-lymphocyte interaction within the confines of a predictable animal model.

Animals↗
PubMed1993

Preservation of functioning human thyroid organoids in the scid mouse: II. Biased use of intrathyroidal T cell receptor V genes.

The severe combined immunodeficiency (scid) mouse, which lacks functional B cells and T cells, has proven a useful model for exploring the survival of transplanted human lymphocytes and thyrocytes. In order to further characterize T cell infiltrates in reconstituted sc human thyroid organoids, we examined for the presence of 18 human T cell receptor (hTcR) V alpha and 21 hTcR V beta gene families using polymerase chain reaction (PCR) analysis. Human TcR V gene activity was confirmed by Southern blot analysis of the PCR fragments from all but one of the thyroid organoids, confirming the continued survival of human T cells within the thyroid organoids. However, only 3.5 out of 18 V alpha and 5.9 out of 21 V beta gene families were detected in these human thyroid organoids indicating a marked bias in T cell survival. Sequencing of the V-D-J regions of the amplified TcR fragments showed that approximately 60% of the sequences were representative of clonally expanded T cells. Hence, these passenger T cells exhibited highly biased use of particular TcR V gene families similar to that observed previously in thyroid tissue and intrathyroidal T cell cultures. Furthermore, variations in the V-D-J regions of sequences from similar V gene families indicated that the V gene region was important in T cell selection rather than the CD3 region.

Animals↗
PubMed1993

Adoptive transfer of diabetes into immunodeficient NOD-scid/scid mice. Relative contributions of CD4+ and CD8+ T-cells from diabetic versus prediabetic NOD.NON-Thy-1a donors.

Precise definition of the role of both CD4 and CD8 T-cell subsets from NOD mice in the adoptive transfer of diabetes has been complicated by the possibility that endogenous T-cells may be recruited. Two newly created NOD congenic stocks, NOD.NON-Thy-1a and NOD/LtSz-scid, have been used as T-cell donors and recipients, respectively, to eliminate contributions from endogenous T-cells and thus to define the requirement for transferred T-cell subsets as a function of underlying diabetes development in the NOD donor. Total T-cells and T-cell subsets prepared from either prediabetic or diabetic NOD.NON-Thy-1a donors were adoptively transferred into 6-wk-old NOD-scid/scid recipients that were monitored for diabetes development. Both flow cytometric and histological analysis of recipient spleen and pancreas after adoptive transfer showed lymphocytes of donor (Thy1.1+) origin exclusively. Total T-cell and enriched CD4+ T-cell preparations from both diabetic and young prediabetic donors transferred diabetes to NOD-scid/scid recipients. However, the mean time to diabetes onset was doubled when CD4+ lymphocytes were isolated from prediabetic versus diabetic donors, and these transfers were complicated by the generation of small but significant numbers of CD8+ cells over time. Enriched CD8+ populations alone were unable to transfer disease. More rigorous exclusion of CD8+ cells by means of anti-CD8 MoAb treatment in vivo of the recipients of enriched CD4+ cells demonstrated a significant difference in the diabetogenic potency of CD4+ lymphocytes from diabetic versus nondiabetic donors. Diabetes was adoptively transferred to 58% of the recipients of enriched CD4+ lymphocytes from diabetic donors. In contrast, none of the recipients of enriched CD4+ lymphocytes from young prediabetic donors developed diabetes after MoAb treatment in vivo. The ability of a T-cell population to produce severe insulitis and sialitis in NOD-scid/scid recipients of T-cells closely paralleled its ability to induce diabetes. In an effort to suppress insulitis by suppression of macrophage migration to the islets, NOD-scid/scid mice were treated with silica in conjunction with adoptive transfer of T-cells from diabetic donors. Chronic silica treatment failed to deplete tissue macrophages and did not prevent diabetes development after transfer of unfractionated T-cells. Evidence is discussed indicating that the age-associated differences in ability of CD4+ T-cells to adoptively transfer diabetes in the absence of the CD8+ T-cells subset is a function of prior, chronic exposure of the CD4+ lymphocytes to beta-cell antigens in the donor.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1993

Epidermal dendritic cell populations in the flaky skin mutant mouse.

Flaky skin (gene symbol: fsn) is an autosomal recessive mouse mutation that causes pathologic changes in the skin yielding a papulosquamous disease resembling human psoriasis. Preliminary studies of epidermal sheets from foot pads of fsn/fsn mice stained for Ia+ Langerhans cells (LC) or Thy-1+ dendritic epidermal cells (Thy-1+ DEC) indicated a rise in LC numbers at the time of weaning, when the skin lesion becomes clinically evident. To further investigate this observation, epidermal sheets were obtained from the ear, dorsal skin, and foot pads from replicates of 6 female mice (both mutants and normal littermates) on weekly intervals from birth to 8 weeks of age. Dorsal skin epidermal thickness was quantitated by computer assisted image analysis and found to be significantly thickened from one week onward in the mutant mice. Using immunofluorescence microscopy, epidermal dendritic cell numbers were determined following staining with antibodies for the following markers: Ia, NLDC-145, and S-100 (for LC) or Thy 1.2 and asialo-GM1 (for Thy-1+ DEC). Use of all 5 markers to evaluate skin from 3 different locations yielded a subtle but significant increase in LC and Thy-1+ DEC in flaky skin mice. Of the three sites evaluated, the dorsal skin and ear epidermal sheets were most informative, which corresponded to the degree of pathological involvement. Mice doubly homozygous for fsn and for the severe combined immunodeficiency (scid) mutation developed the psoriasiform dermatitis. Bone marrow grafts from fsn/fsn homozygotes to homozygous scid/scid mice reproduce the skin lesion. These studies suggest that the psoriasiform dermatitis in the flaky skin mouse mutation is associated with abnormalities at the level of hematopoietic progenitor cells.

Aging↗