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I Goldschneider

Publications and source records attributed to I Goldschneider.

At least 55 records · Page 3Linked to original sources
PubMed1986

Studies of thymocytopoiesis in rats and mice. I. Kinetics of appearance of thymocytes using a direct intrathymic adoptive transfer assay for thymocyte precursors.

We describe a quantitative intrathymic (i.t.) adoptive transfer system for detecting thymocyte precursor cells in rats and mice. In this system, the generation of donor-origin thymocytes is analyzed on the FACS after the injection of test cells directly into the thymus of sublethally irradiated, histocompatible, RT-7 (rat) or Ly-1 (mouse) alloantigen-disparate recipients. Like the standard i.v. adoptive transfer assays for prothymocytes, the i.t. transfer assay is time, dose, and irradiation dependent. However, unlike the i.v. assays, the i.t. assay is highly sensitive, independent of cell migration, and specific for T-lineage precursor cells. Thus, the i.t. system requires between 25- and 50-fold fewer precursor cells than do the i.v. systems to generate a given number of donor-origin thymocytes; it detects nonmigratory as well as migratory subsets of precursor cells; it detects prethymic and intrathymic precursor cells with equal facility; and it produces a discrete, self-limited wave of donor-origin thymocytes and peripheral T cells. Moreover, neither hemopoietic nor lymphopoietic stem cell chimerism occurs at extrathymic sites. Comparison of the kinetics of thymocytopoiesis in the i.t. and i.v. transfer systems suggest that the seeding efficiency of prothymocytes in the i.v. assay approximates 0.04; the lag phase of the time-response curve is not due to a delay in the entry of prothymocytes into the thymus; and the relative amount of thymocyte precursor activity in various lymphohemopoietic tissues is highest in bone marrow, lowest (or absent) in lymph node, and intermediate in spleen, blood, and thymus. Moreover, the occurrence of saturation kinetics in the dose-response curve of the i.t. system supports the hypothesis that a finite number of microenvironmental niches for prothymocytes may exist in the thymus. These initial observations will require confirmation and extension in future studies. However, based on the present findings and related observations, we anticipate that the i.t. adoptive transfer system will contribute importantly to the definitive analysis of both normal and abnormal thymocytopoiesis.

Animals↗
PubMed1985

Phenotypic heterogeneity of Gross virus-induced thymic lymphomas in the rat: cellular origins and migratory properties.

Neoplastic thymocytes from rat thymic lymphoma-leukemias induced by the rat-adapted Gross leukemia virus (RAGV) were analyzed for a variety of differentiation markers. The neoplasms from individual rats all expressed the antigenic phenotype MP+, W3/13+, Thy-1+, RT-1+, RT-7+, W3/25-. However, approximately two-thirds of the neoplasms were positive for the OX 8 antigen, and one-third were negative. The OX 8- neoplasms only involved the thymus, whereas approximately 40% of the OX 8+ neoplasms involved the spleen as well as the thymus. Virtually all OX 8+ and OX 8- neoplastic cells contained terminal deoxynucleotidyl transferase (TdT), and both OX 8+ and OX 8- lymphomas expressed the lactate dehydrogenase (LDH)-5' isozyme and the primary, but not the secondary, ADA isozyme. This enzymatic phenotype is characteristic of thymocyte precursors, but not thymocytes. Our results therefore indicate that RAGV-induced lymphomas arise from transformed prethymic TdT+ cells which contain the LDH-5' and the primary ADA isozymes. These preleukemic cells presumably migrate to the thymus where they express the RT-7 pan-T-cell antigen and, in some instances, the OX 8 antigen during the development of overt leukemia. The OX 8+ neoplasms, being more differentiated than their OX 8- counterparts, then migrate to peripheral lymphoid tissues.

AKR murine leukemia virus↗
PubMed1985

Developmental abnormalities of terminal deoxynucleotidyl transferase positive bone marrow cells and thymocytes in New Zealand mice: effects of prostaglandin E1.

The enzyme TdT was used as a marker with which to study the ontogeny of primitive lymphopoietic cells in NZ strain mice. A marked accumulation of abnormally large, rapidly proliferating TdT+ cells was seen in the subcapsular region of the thymus cortex in the NZB and NZB/W mice. This abnormal accumulation of TdT+ thymocytes was most pronounced in the NZB/W hybrid and persisted for at least the first 16 wk of life. In addition, significantly elevated percentages of TdT+ bone marrow cells (presumptive prothymocytes) were present in NZB, NZW, and NZB/W mice between 1 and 4 wk of age, with the highest mean peak levels occurring in the NZB strain. Treatment of both normal and adrenalectomized BALB/c and NZB/W mice with pharmacologic doses (7 to 10 mg/kg) of PGE1 caused a marked, dose-dependent decrease in thymus weight and thymus cell number within 12 to 18 hr. Histologic and cell separation studies showed that this was due to the selective depletion of PNA+ TdT+ cortical thymocytes. Similarly, PGE1 caused a reversible, dose-dependent decrease in the percentage of TdT+ bone marrow cells. In contrast, PGF2 alpha, which is not therapeutically active against autoimmunity in NZB/W mice, had no detectable effect on TdT+ bone marrow cells or thymocytes in BALB/c or NZB/W mice. These results directly document the existence of abnormalities in the development of lymphopoietic precursor cells in the bone marrow and thymus cortex of NZ strain mice prior to the onset of autoimmune phenomena. The results also raise the possibility that the therapeutic efficacy of exogenous PGE1 in autoimmune NZ strain mice may be related, at least in part, to its ability to rectify the abnormal development of these early lymphoid cells.

Adrenalectomy↗
PubMed1984

A selective culture system for generating terminal deoxynucleotidyl transferase-positive (TdT+) lymphoid precursor cells in vitro. I. Description of the culture system.

A primary xenogeneic culture system has been devised that selectively generates undifferentiated TdT+ lymphoblasts from rat bone marrow under conditions that do not support the growth or maintenance of rat colony-forming unit-spleen (CFU-S) or granulocyte/macrophage colony-forming cells (GM-CFC). The culture system requires a mouse bone marrow feeder layer, and a serum supplement that has markedly reduced levels of cortisol. The growth of TdT+ cells can be significantly enhanced by the addition of mesodermalizing factors (e.g., fibroblast growth factor, guinea pig bone marrow extract) to the culture medium, and the serum supplement can be decreased by the addition of selenium, transferrin, and T3. The cultured TdT+ cells are antigenically "null" cells that further resemble their normal counterparts in bone marrow with respect to morphology, size, cortisone sensitivity, and pattern of TdT fluorescence. The TdT+ cells are generated with equal facility from bone marrow of normal and congenitally athymic rats, can be maintained in logarithmic growth for at least 10 mos by serial passage in vitro, and do not cause leukemia when infused into irradiated recipients. Although the lineage relationships of these immature lymphoid cells have not yet been established, our working hypothesis, based on preliminary evidence, is that the cultured TdT+ cells are primitive members of the T cell series.

Animals↗
PubMed1984

Effects of an immunomodulating agent on peripheral blood lymphocytes and subgingival microflora in ligature-induced periodontitis.

The peripheral blood lymphocyte populations and the subgingival levels of black-pigmented Bacteroides species were monitored during the conversion of chronic gingivitis to progressing periodontitis in cynomolgus monkeys. In addition, the effects of an immunomodulating agent, the pentapeptide of thymopoietin (TP5), were determined. After the induction of active periodontitis, proportions of helper T-cells (OKT-4 positive) decreased from 31.5 to 26.4%, and proportions of B-cells (surface immunoglobulin positive) increased from 44.5 to 51.8%. Proportions of suppressor T-cells (OKT-8 positive) remained unchanged, but the numbers of OKT-8-positive cells increased. During this same time period the total cultivable subgingival flora increased from 1.5 X 10(6) to 3.5 X 10(6) per sample, with Bacteroides gingivalis increasing from 5.3 to 16.6% of the total cultivable subgingival flora. After 10 weeks of active periodontitis, animals were treated with either TP5 or placebo. Treatment with TP5 produced an increase in helper T-cells but had no effect on B-cells. The OKT-4/OKT-8 cell ratio, which decreased from 1.3 to 0.8 with disease induction, was increased to 1.1 after TP5 treatment but remained at 0.9 in placebo-treated animals. TP5 had no effect on the total cultivable subgingival flora but significantly decreased the subgingival proportions of B. gingivalis and other black-pigmented Bacteroides species. In this model system, active periodontitis was associated with an increase in B. gingivalis, a decreased helper/suppressor T-cell ratio, and increased levels of B-cells. Treatment with TP5 increased the helper/suppressor T-cell ratio and decreased B. gingivalis levels, suggesting that lymphocyte subsets have the potential to influence subgingival levels of potential periodontal pathogens.

Animals↗
PubMed1984

Identification of thymocyte progenitors in hemopoietic tissues of the rat. I. A quantitative assay system for thymocyte regeneration.

A quantitative adoptive transfer system is described which can be used to precisely monitor the generation of thymocytes and peripheral T cell subsets by precursor cells in hemopoietic tissues of rats. This assay utilizes the rat pan-T cell alloantigens, A.R.T.-1a and A.R.T.-1b, and the fluorescence-activated cell sorter (FACS) to directly enumerate donor- and host-origin thymocytes and T cells in irradiated, histo-compatible recipients. The assay has the advantage over related systems in that it detects more than 95% of total newly-formed thymocytes and T cells at all stages of differentiation; that it is highly sensitive (as few as 1% of the appropriate A.R.T.-1 bearing cells can be detected in cell mixtures); and that it permits selective recovery of donor-and/or host-origin cells for further characterization. The results show that, after a lag period of 10-12 days, the regenerative kinetics of donor-origin thymocytes are linear with respect to time and cell dose, over a range of 2.5 to 50 X 10(6) bone marrow cells. Above a threshold of approximately 400R, the regenerative kinetics of donor-origin thymocytes are independent of irradiation dose, but are inversely related to the age of the recipient. On a per cell basis, bone marrow cells are more efficient than spleen cells at regenerating the thymus. By 4 months after bone marrow cell transfer, permanent chimeras are established in which the proportion of donor-origin T cells approximates that of donor-origin thymocytes, and in which the ratio of presumptive helper (W3/25+) and suppressor/cytotoxic (OX8+) donor-origin T cells is normal. The assay therefore appears to be suitable for following both the purification of prothymocytes from rat hemopoietic tissues and the proliferation and differentiation of their progeny in thymus and peripheral lymphoid tissues.

Animals↗
PubMed1984

Activation of Listeria monocytogenes-induced prekiller T cells by interleukin-2.

Thymus-dependent lymphocytes, or T cells, of rats infected with Listeria monocytogenes acquire a potent cytolytic capability when the cells are restimulated in vitro by Listeria antigens. Activation of such Listeria monocytogenes-dependent cytotoxic T lymphocytes requires both antigen and histocompatible accessory cells, but only when the responder T cells have been specifically depleted of lymphocytes that are responsive to accessory cell alloantigens. When unselected T cells are used, significant activation occurs in specific-antigen-free cultures containing allogeneic accessory cells. This seeming paradox is explained by the fact that a lymphokine generated in mixed leukocyte cultures can promote the terminal differentiation of cytotoxic T lymphocytes precursors. This lymphokine has tentatively been identified as interleukin-2. The results suggest that a three stage process is involved in the activation of Listeria monocytogenes-dependent cytotoxic T lymphocytes. The first stage occurs in response to an immunizing Listeria monocytogenes infection and itself involves two significant events, the polyclonal priming of prekiller cells and the generation of Listeria antigens-specific helper T cells. During the second stage, helper T cells are stimulated by Listeria antigens to release interleukin-2. This process is efficiently executed only in the presence of histocompatible accessory cells. The third stage in the activation process requires neither accessory cells nor antigen and involves the interleukin-2-driven differentiation of prekiller cells.

Animals↗
PubMed1982

Identification of thymocyte progenitors in hemopoietic tissues of the rat. II. Enrichment of functional prothymocytes on the fluorescence-activated cell sorter.

A quantitative thymocyte regeneration assay was used to monitor the isolation of functional prothymocytes from rat bone marrow on the FACS. Two prothymocyte subpopulations were tentatively identified on the basis of their relative resistance to dexamethasone. Both populations were comprised of undifferentiated, medium-size cells that displayed large amounts of Thy-1 antigen. Simultaneous sorting of bone marrow cells according to relative low angle light scatter (size) and relative fluorescence intensity for Thy-1 resulted in enrichments of 112-fold and 260-fold, respectively, in prothymocyte activity in untreated and dexamethasone-treated bone marrow. These prothymocyte-enriched cell fractions contained or approximately 75% of total functional prothymocyte activity in bone marrow, and represented 1.1 and 0.35% of total untreated and dexamethasone-treated bone marrow cells. Using these enriched cell fractions, significant thymocyte regeneration is possible with as few as 2 X 10(4) and 1 X 10(4) bone marrow cells, respectively. The possible relationship of these functional prothymocyte subpopulations with CFU-S and with TdT-positive cells is discussed.

Animals↗
PubMed1982

Thiabendazole (TBZ), an immunohemomodulator. I. Effects on lymph node and spleen.

Previous studies in our laboratory with Thiabendazole (TBZ) indicated that the drug significantly augmented cellular immune responses in mice. The purpose of the present and companion study was to determine which of the cell populations in primary and secondary lymphoid organs and in bone marrow were affected by the in-vivo administration of TBZ. Two major changes in lymph nodes and/or spleens of TBZ-treated mice were detected by histological and quantitative planimetric analysis: (1) expansion of T and B lymphocyte compartments and (2) increase in extramedullary hemopoiesis. The effect on T cells and on hemopoiesis were observed only when TBZ was administered with the thymus-dependent neoantigen, dinitrofluorobenzene (DNFB). The effect on B cells appeared to be antigen-independent. Increased extramedullary hemopoiesis in TBZ + DNFB-treated mice was preceded by a significant increase in pluripotent hemopoietic stem cell activity in bone marrow, as measured by the CFU-S assay. This study indicates that TBZ has significant effects on the development and differentiation of both lymphoid and hemopoietic cells.

Adjuvants, Immunologic↗
PubMed1982

Thiabendazole (TBZ), an immunohemomodulator. II. Effects on thymocytes and prothymocytes.

The purpose of this study was to document the effects of TBZ on the early stages of T cell maturation. The method utilized to quantify presumptive thymocyte progenitors in the bone marrow used the enzyme terminal deoxynucleotidyl transferase (TdT) as a marker. Shifts in thymocyte populations were determined by quantitative planimetry, immunofluorescence for TdT and tritiated thymidine incorporation. When given alone, TBZ produced a marked increase in the number of large, mitotically active lymphoblasts in the thymus cortex. When given with DNFB, a thymus-dependent neoantigen, TBZ produced a significant increase in TdT-positive bone marrow cells. In a companion study, TBZ + DNFB were found to stimulate T cells in lymph node and spleen. Hence, the results indicate that under appropriate conditions, TBZ can stimulate all stages of T cell differentiation in mice.

Adjuvants, Immunologic↗
PubMed1982

Genetic linkage and cell distribution analysis of T cell alloantigens in the rat.

The T cell alloantigens A.R.T.-1, A.R.T.-2, Pta, Ag-F and RT-Ly-2 were examined for linkage to albinism and the haemoglobin variant Hbb, and for cell expression similarities in the rat. The A.R.T.-1 alloantigen was not linked to either A.R.T.-2, albinism or Hbb. The A.R.T.-2 alloantigen was demonstrated to be closely associated to albinism and Hbb with a recombination frequency of approximately 3% with albinism and 1% with Hbb. The four recombinants (out of 104 animals examined) were subsequently analysed with alloantisera to Ag-F, Pta and RT-Ly-2. These alloantisera detected an antigenic system(s) which appeared to co-segregate with A.R.T.-2 in the recombinants studied Characterization of the specific T cell populations expressing each alloantigen demonstrated that removal of the cells bearing any one of the alloantigens removed all the cells expressing any of the other alloantigens. These results demonstrate that the four alloantigenic systems A.R.T.-2, Pta, Ag-F and RT-Ly-2 are located in the same genetic region of linkage group I, and appear to be expressed on the same peripheral T cell subpopulation(s) in the rat.

Animals↗
PubMed1981

Induction of terminal deoxynucleotidyl transferase and Lyt antigens with thymosin: identification of multiple subsets of prothymocytes in mouse bone marrow and spleen.

Thymosin (fraction 5 and synthetic alpha 1 peptide) induced prothymocytes in mouse bone marrow and spleen to express terminal deoxynucleotidyl transferase (TdT; DNA nucleotidylexotransferase; nucleosidetriphosphate:DNA deoxynucleotidylexotransferase, EC 2.7.7.31) or Lyt-1+, 2+, 3+ alloantigens (or both) after brief incubation in vitro. Three antigenic phenotypes were generated: (i) TdT+ Lyt+, (ii) TdT- Lyt+, and (iii) TdT+ Lyt-. The TdT+ Lyt+ phenotype was expressed by 80% of prothymocytes in bone marrow and 30% of prothymocytes in spleen from normal mice. The TdT- Lyt+ phenotype was expressed by 81% of prothymocytes in bone marrow from athymic mice. More than 80% of TdT+ bone marrow cells from normal and athymic mice expressed Lyt antigens after thymosin treatment. We interpret these observations as suggesting that (i) most TdT+ hemopoietic cells in normal and athymic mice are thymocyte progenitors; (ii) two independent lineages of prothymocytes exist, one that expresses TdT and another that does not, (iii) commitment of prothymocytes to the TdT+ cell pathway is partially regulated by a thymic feedback mechanism; and (iv) the bone marrow preferentially produces TdT+ prothymocytes, whereas the spleen may serve as a repository for TdT- prothymocytes. A model of T-cell development is presented in which the thymus functions as a compound organ to process TdT+ and TdT- thymocytes progenitors and to generate two lines of T cells.

Animals↗