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E Montecino-Rodriguez

Publications and source records attributed to E Montecino-Rodriguez.

At least 19 recordsLinked to original sources
PubMed2001

Helper (CD4(+)) and cytotoxic (CD8(+)) T cells promote the pathology of dystrophin-deficient muscle.

Duchenne muscular dystrophy (DMD) and mdx mouse dystrophy result from mutations in the dystrophin gene. Although these mutations are primarily responsible for the defects that underlie the pathology of dystrophinopathies, other factors may contribute importantly to the pathology. In the present investigation, we tested whether T cells present in mdx muscles are activated and contribute significantly to the pathological process. Flow cytometric analyses showed a significantly higher frequency of activated CD44(high) T cells in the blood and muscle of mdx mice when compared to normal B10 mice. However, the frequency of activated T cells was not elevated in mdx lymph nodes, suggesting muscle-specific T cell activation. In vivo antibody-mediated depletions of CD4(+) T cells from mdx mice significantly reduced the amount of histologically discernible muscle pathology by 61% in mdx mice, while depletion of CD8(+) T cells resulted in a 75% decrease in pathology. Finally, adoptive transfer of mdx immune cells in combination with muscle extracts resulted in muscle pathology in healthy murine recipients. These results indicate that T cells promote the mdx pathology and suggest that immune-based therapies may provide benefit to DMD patients.

Adoptive Transfer↗
PubMed2001

Bipotential B-macrophage progenitors are present in adult bone marrow.

According to the current model of adult hematopoiesis, differentiation of pluripotential hematopoietic stem cells into common myeloid- and lymphoid-committed progenitors establishes an early separation between the myeloid and lymphoid lineages. This report describes a rare and previously unidentified CD45R-CD19+ B cell progenitor population in postnatal bone marrow that can also generate macrophages. In addition to the definition of this B-lineage intermediate, the data indicate that a developmental relationship between the B and macrophage lineages is retained during postnatal hematopoiesis.

Animals↗
PubMed2001

Long-term bone marrow cultures provide access to early lymphoid progenitors.

Long-term bone marrow cultures provide defined systems for studying and manipulating hematopoietic progenitors. Myeloid bone marrow cultures harbor early lymphoid progenitors; however, the nature and phenotype of these progenitors has not been investigated. Phenotypic and molecular markers associated with lymphopoiesis were used to characterize the lymphoid population maintained in these cultures. Cells within myeloid cultures expressed genes associated with lymphopoiesis but did not express the B cell-specific lambda5 gene. Flow cytometry demonstrated that cultures lacked cells expressing markers associated with B cell development. Furthermore, rearrangements of immunoglobulin heavy chain diversity (D) and joining (J(H)) gene segments were not detected in the myeloid cultures suggesting that these conditions support early B cell progenitors. Transferring myeloid cultures to conditions optimal for lymphopoiesis resulted in B cell development that temporally recapitulated events in the bone marrow. We also demonstrate that these lymphoid progenitors are targets for retroviral transduction. This study suggests that long-term cultures provide a useful system to access early lymphoid progenitors and study the events that regulate their differentiation.

Animals↗
PubMed2001

Regulation of hematopoiesis by gap junction-mediated intercellular communication.

Gap junctions are intercellular channels formed by individual structural units known as connexins (Cx) that allow the intercellular exchange of small molecules between cells. The presence of Cx protein in bone marrow and thymic stromal cells and the demonstration that these cells are functionally coupled have led to the hypothesis that groups of stromal cells in the bone marrow and thymus form a functional syncytium through which their hematopoietic support capacity is coordinated. The validity of this hypothesis was recently tested in a newly developed strain of mice in which the gene encoding Cx43, the principal Cx expressed in hematopoietic tissues, was disrupted. Studies of myelopoiesis and lymphopoiesis in these Cx43-deficient mice revealed that expression of Cx43 in the bone marrow and thymus is critically important during periods of active hematopoiesis, such as during embryogenesis and after recovery from cytoablative treatments. The clinical implications of these observations, as well as issues that remain to be addressed to understand the mechanism(s) by which gap junctions regulate hematopoiesis, are addressed.

Animals↗
PubMed2000

Expression of connexin 43 (Cx43) is critical for normal hematopoiesis.

Gap junctions are intercellular channels, formed by individual structural units known as connexins (Cx), that allow the intercellular exchange of various messenger molecules. The finding that numbers of Cx43-type gap junctions in bone marrow are elevated during establishment and regeneration of the hematopoietic system has led to the hypothesis that expression of Cx43 is critical during the initiation of blood cell formation. To test this hypothesis, lymphoid and myeloid development were examined in mice with a targeted disruption of the gene encoding Cx43. Because Cx43-/- mice die perinatally, initial analyses were performed on Cx43-/-, Cx43+/-, and Cx43+/+ embryos and newborns. The data indicate that lack of Cx43 expression during embryogenesis compromises the terminal stages of primary T and B lymphopoiesis. Cx43-/- embryos and neonates had a reduced frequency of CD4(+) and T-cell receptor-expressing thymocytes and surface IgM(+) cells compared to their Cx43+/+ littermates. Surprisingly, Cx43+/- embryos/neonates also showed defects in B- and T-cell development similar to those observed in Cx43-/- littermates, but their hematopoietic system was normal at 4 weeks of age. However, the regeneration of lymphoid and myeloid cells was severely impaired in the Cx43+/- mice after cytoablative treatment. Taken together, these data indicate that loss of a single Cx43 allele can affect blood cell formation. Finally, the results of reciprocal bone marrow transplants between Cx43+/+ and Cx43+/- mice and examination of hematopoietic progenitors and stromal cells in vitro indicates that the primary effects of Cx43 are mediated through its expression in the hematopoietic microenvironment.

Animals↗
PubMed2000

NZB mice exhibit a primary T cell defect in fetal thymic organ culture.

Defects in T cell development have been suggested to be a factor in the development of systemic autoimmunity in NZB mice. However, the suggestion of a primary T cell defect has often been by extrapolation, and few direct observations of T cell precursors in NZB mice have been performed. Moreover, the capacity of NZB bone marrow T cell precursors to colonize the thymus and the ability of the NZB thymic microenvironment to support T lymphopoiesis have not been analyzed. To address this important issue, we employed the fetal thymic organ culture system to examine NZB T cell development. Our data demonstrated that NZB bone marrow cells were less efficient at colonizing fetal thymic lobes than those of control BALB/c or C57BL/6 mice. In addition, NZB bone marrow cells did not differentiate into mature T cells as efficiently as bone marrow cells from BALB/c or C57BL/6 mice. Further analysis revealed that this defect resulted from an intrinsic deficiency in the NZB Lin-Sca-1+c-kit+ bone marrow stem cell pool to differentiate into T cells in fetal thymic organ culture. Taken together, the data document heretofore unappreciated deficiencies in T cell development that may contribute to the development of the autoimmune phenotype in NZB mice.

Animals↗
PubMed2000

Humoral and cell-mediated immunity in mice with genetic deficiencies of prolactin, growth hormone, insulin-like growth factor-I, and thyroid hormone.

Prolactin (PRL), growth hormone (GH), insulin-like growth factor-I (IGF-I), and thyroid hormones have been proposed as critical immunoregulatory mediators, and their clinical use is being considered. The precise role played by each of these hormones in the generation of humoral and cell-mediated immune responses was assessed in a panel of mice with mutations that result in a selective reduction of PRL, GH, IGF-I, and/or thyroid hormone production. A surprising result, in view of previous studies indicating an immunoregulatory role for these hormones, was that all mice generated normal humoral and cell-mediated immune responses following challenge with T-independent and T-dependent antigens and with Listeria monocytogenes. A review of these findings in the context of previous data has resulted in the formulation of a working hypothesis proposing that these hormones act as anabolic and/or stress modulating mediators with effects on most cells, including those of the immune system. When considered in this context, it is possible to reconcile the contradictory data.

Animals↗
PubMed1999

Proliferation of bone marrow pro-B cells is dependent on stimulation by the pituitary/thyroid axis.

The frequency and absolute number of pro-B, pre-B, and B cells in the bone marrow of the hypothyroid strain of mice are significantly reduced compared with those of their normal littermates. To investigate why this is the case, various B cell developmental processes were examined in the thyroid hormone-deficient mice. These studies revealed that the frequency of pro-B cells in the S-G2/M phase of the cell cycle was significantly reduced in hypothyroid mice. That thyroid hormone deficiency was responsible for this proliferation defect was established by demonstrating that treatment of hypothyroid mice with thyroxine resulted in a specific increase in the frequency and total number of cycling pro-B cells. The latter effect was paralleled by increases in the frequency and number of bone marrow B lineage cells. Additional in vitro experiments revealed that at least some thyroid hormone effects were directly mediated on the bone marrow. Taken together, these data demonstrate that thyroid hormones are required for normal B cell production in the bone marrow through regulation of pro-B cell proliferation and establish a role for the pituitary/thyroid axis in B cell development.

Animals↗
PubMed1998

Regulation of B and T cell development by anterior pituitary hormones.

Hormones produced by the anterior pituitary gland have been implicated in the regulation of primary lymphocyte development. In order to identify endocrine factors involved in that process, several strains of mice with genetic defects resulting in a selective impairment in the production of one or more anterior pituitary-derived hormones have been analysed. This study has resulted in the classification of endocrine hormones into the following four categories: (i) hormones such as prolactin with no apparent effects on primary lymphopoiesis; (ii) anabolic hormones such as growth hormone and insulin-like growth factor-I whose stimulatory effects on primary lymphopoiesis are non-lineage-specific and related to their actions as systemic mediators of growth and/or differentiation; (iii) hormones such as thyroid hormones that have an obligate role in primary B lymphopoiesis; and (iv) hormones such as oestrogens that act as negative regulators of lymphopoiesis.

Animals↗
PubMed1998

Effects of insulin-like growth factor administration and bone marrow transplantation on thymopoiesis in aged mice.

There has been considerable interest in using hormone replacement therapy to rejuvenate the involuted thymus during aging. GH and insulin-like growth factor-I (IGF-I), a mediator of GH actions, have been of particular interest because of their thymopoietic effects and the fact that their serum concentrations decline during aging. However, treatment of aging rodents with either GH or IGF-I does not restore thymus cellularity to levels present in young animals, suggesting that additional defects might limit the magnitude of their effects. In particular, deficiencies have been reported to accumulate in the bone marrow T cell precursor compartment during aging. In view of this, 18-month-old mice were administered either recombinant IGF-I, bone marrow cells from young mice, or a combination of IGF-I and young bone marrow cells. Thymus cellularity in the latter group of mice was significantly higher than in animals treated with hormone or bone marrow transplantation alone, suggesting that optimal therapies for restoring thymus cellularity must address both endocrine and hematopoietic defects that accumulate during aging. Results from in vitro studies using fetal thymic organ cultures suggest that IGF-I acts by potentiating thymic colonization by bone marrow T cell precursors and/or that the hormone affects some other event soon after thymus colonization.

Aging↗
PubMed1997

Defective mammopoiesis, but normal hematopoiesis, in mice with a targeted disruption of the prolactin gene.

Prolactin (PRL) has been implicated in numerous physiological and developmental processes. The mouse PRL gene was disrupted by homologous recombination. The mutation caused infertility in female mice, but did not prevent female mice from manifesting spontaneous maternal behaviors. PRL-deficient males were fertile and produced offspring with normal Mendelian gender and genotype ratios when they were mated with heterozygous females. Mammary glands of mutant female mice developed a normal ductal tree, but the ducts failed to develop lobular decorations, which is a characteristic of the normal virgin adult mammary gland. The potential effect of PRL gene disruption on antigen-independent primary hematopoiesis was assessed. The results of this analysis indicated that myelopoiesis and primary lymphopoiesis were unaltered in the mutant mice. Consistent with these observations in PRL mutant mice, PRL failed to correct the bone marrow B cell deficiency of Snell dwarf mice. These results argue that PRL does not play any indispensable role in primary lymphocyte development and homeostasis, or in myeloid differentiation. The PRL-/- mouse model provides a new research tool with which to resolve a variety of questions regarding the involvement of both endocrine and paracrine sources of PRL in reproduction, lactogenesis, tumorigenesis and immunoregulation.

Animals↗
PubMed1997

Primary B cell development is impaired in mice with defects of the pituitary/thyroid axis.

There has been considerable speculation that hormones produced in the anterior pituitary gland act as positive regulators of primary B cell development in the bone marrow. In order to identify endocrine factors that have such a role, B cell differentiation was examined in a panel of mice with genetic mutations that result in compromised production of one or more anterior pituitary hormones. This analysis demonstrated that the frequency of B lineage cells is significantly reduced in the dwarf and hypothyroid strains of mice, which have defects in the pituitary/thyroid axis, and that the production of normal numbers of pre-B cells is particularly dependent upon thyroid hormones. B cell development was normal in Little and IGF-I knockout animals, which have defects in the production of growth hormone and/or insulin-like growth factor I. The dependence of B lymphopoiesis on thyroid hormones appeared to be specific for that lineage, as myelopoiesis and thymopoiesis were normal in dwarf and hypothyroid mice. In addition to describing a specific endocrine hormone involved in the regulation of B cell development, these data provide evidence that normal production of bone marrow B lineage cells is dependent on extramedullary signals.

Animals↗
PubMed1997

Thymocyte development in vitro: implications for studies of ageing and thymic involution.

Functional defects that accumulate in the T cell compartment are thought to be responsible for the pronounced immunodeficiency that develops during ageing, and reduced production of T cells by the thymus as it undergoes involution has been suggested to contribute to this phenomenon. Understanding the mechanisms responsible for thymic involution requires a thorough knowledge of how thymopoiesis is regulated. Obtaining such information is dependent upon the availability of defined experimental systems that permit analysis of thymopoiesis at the cellular and molecular levels. Recent advances have been made in the development of such human and murine in vitro systems, and their analysis has the potential to identify thymic microenvironmental signals that regulate T cell production. This information should, in turn, provide a basis for understanding changes in thymopoiesis that occur during ageing. The features of these culture systems are reviewed in this article, and their potential application to the study of T cell production during ageing is discussed.

Aging↗
PubMed1996

Defective B cell development in Snell dwarf (dw/dw) mice can be corrected by thyroxine treatment.

Snell dwarf (dw/dw) mice are deficient in anterior pituitary hormones due to a mutation in the gene encoding the Pit-1 transcription factor. Bone marrow B cell development is also suppressed in the mice, providing circumstantial evidence that one or more anterior pituitary-derived products, or factors induced by them, are required for normal B lymphopoiesis. However, concluding that this is the case is dependent on showing that hormonal treatment of dwarf mice reverses their B cell defects. dw/dw mice were treated with growth hormone (GH), insulin-like growth factor-I (IGF-I), or thyroxine in an attempt to restore bone marrow B lymphopoiesis. GH and IGF-I increased the number of B lineage cells in the bone marrow and spleen but did not restore the frequency of bone marrow pre-B cells to normal. However, bone marrow cellularity in thyroxine-treated dw/dw mice was comparable to that in control animals, and both the frequency and absolute number of B lineage cells had increased to normal or even above normal. Taken together, these data indicate that endocrine factors, especially those regulated by the hypothalamic-pituitary-thyroid axis, are potent B lymphopoietic factors.

Animals↗
PubMed1996

Long-term culture of triple-negative thymocytes.

The role of the thymic microenvironment in regulating events that occur subsequent to the acquisition of CD4, CD8, and the TCR, such as positive and negative selection, has been studied extensively. However, comparatively less is known about how thymic stromal cells regulate growth and differentiation within the CD4-CD8-TCR- triple negative (TN) cell compartment. Long-term culture systems have played a pivotal role in the understanding of microenvironmental regulation of myelopoiesis and B lymphopoiesis, but establishment of comparable cultures for T lineage cells has proved challenging. This report describes a culture system in which a thymic stromal cell line preferentially supports the long-term growth of TN thymocytes. In addition to demonstrating that TN cells have a considerable proliferative potential, the results provide insights into the effects of IL-7 on the growth and/or survival of TN cells and its role in regulating TCR gene rearrangements. The ability of the cultured TN cells to mature into CD4- and/or CD8-expressing thymocytes, some of which express TCR-alpha beta, suggests that the system will be valuable for the identification of microenvironmental stimuli that regulate the maturation of TN cells.

Animals↗
PubMed1996

Thymic stromal cells can support B cell differentiation from intrathymic precursors.

T lineage cells are the predominant intrathymic population, but low numbers of thymic B cells are also present in the thymus. Recent studies describing the contribution of thymic B cells to the shaping of the T cell repertoire have raised the question as to whether they are produced intrathymically and the potential role of the thymic stroma in this process. During the course of studies aimed at testing the B cell developmental potential of CD4-CD8-CD3/TCR- triple-negative thymocytes present in a newly developed, stromal cell-dependent, long term culture system, the ability of selected thymic stromal cells to support distinct stages of B cell development was revealed. Some thymic stromal cell lines maintained cells with B cell developmental potential but could not support their differentiation, while other selected lines efficiently supported the development of surface IgM-expressing cells from triple-negative precursors. Thymic surface IgM+ B cells were generated most efficiently from thymocytes harvested from relatively young mice. Taken together, the results of this study demonstrate that the thymic microenvironment exhibits a functional heterogeneity in its ability to support different stages of B cell development.

Aging↗
PubMed1994

Differential expression of bone marrow stromal cell-surface antigens on myeloid and lymphoid cells.

Two monoclonal antibodies (MAb) that recognize cell-surface determinants present on bone marrow stromal cells have been generated. The 5B3 antibody recognizes a major histocompatibility class I-like molecule. This antigen is coexpressed on all bone marrow B-lineage cells and myeloid progenitors responsive to recombinant granulocyte-macrophage colony-stimulating factor (GM-CSF). The 9D3 antibody recognizes a protein similar in size to those encoded by the Ly-6 locus. A comparable bone marrow staining pattern and inhibition of 9D3 binding to bone marrow cells by anti-Ly-6C antibodies strongly suggests that the 9D3 antigen is Ly-6C. These data provide a further phenotypic characterization of bone marrow stroma and indicate that these cells express cell-surface determinants also present on myeloid and lymphoid cells.

Animals↗