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Kenneth Dorshkind

Publications and source records attributed to Kenneth Dorshkind.

At least 19 recordsLinked to original sources
PubMed2006

Aging, B lymphopoiesis, and patterns of leukemogenesis.

The production of B lymphocytes begins to decline steadily early in adult life and is severely compromised in the elderly. This occurrence has been attributed to intrinsic defects in early hematopoietic progenitors and B cell precursors as well as to microenvironmental changes in aged bone marrow. The aim of this review is to present an overview of B lymphocyte senescence and its underlying causes and to discuss its impact on immune function and leukemogenesis in aged individuals.

Adult↗
PubMed2006

New perspectives in B-1 B cell development and function.

In contrast to the predominant population of B-2 B cells produced in the bone marrow, B-1 B cells are a minor population of B lymphocytes that are found in multiple tissues, including the pleural and peritoneal cavities in mice. Although the role of B-1 B cells as effectors of innate-like immunity is widely accepted, their developmental origin has been controversial. This review highlights recent experimental data from murine studies supporting the hypothesis that B-1 B cells belong to a developmental lineage distinct from B-2 B cells, and draws attention to recent studies that have defined new roles for the B-1a and B-1b B-cell subsets in the response to bacteria and self-antigens.

Animals↗
PubMed2006

Identification of a B-1 B cell-specified progenitor.

The B-1 subpopulation of B lymphocytes differs phenotypically and functionally from conventional B-2 B cells. B-1 B cells are proposed to derive from a distinct progenitor, but such a population has not been isolated. Here we identify and characterize a B-1 B cell progenitor whose numbers peaked in fetal bone marrow but were less abundant in postnatal bone marrow. These Lin(-)CD45R(lo-neg)CD19(+) cells responded to thymic stromal lymphopoietin and 'preferentially' reconstituted functional sIgM(hi)CD11b(+)CD5(lo-neg) B-1 B cells, but not sIgM(+)CD11b(-) B-2 B cells, in vivo. These data indicate that the CD45R(lo-neg)CD19(+) population includes B-1 B cell-specified progenitors and support models proposing distinct developmental pathways for B-1 B cells.

Animals↗
PubMed2006

Effects of aging on the common lymphoid progenitor to pro-B cell transition.

The number of common lymphoid progenitors (CLP) and their pre-pro-B and pro-B cell progeny is reduced in old mice, but the age-related changes responsible for these declines have not been fully elucidated. The aim of this study was to provide additional insights into the impact of senescence on early B cell development by analyzing the CLP and pro-B cell compartments under steady-state conditions and after cytoablation with 5-fluorouracil. 5-Fluorouracil subjects the hemopoietic system to acute stress and has the advantage of revealing defects in progenitors that may otherwise be subtle. The data demonstrate significant, age-related defects in the proliferative potential of early B cell precursors and suggest that the ability of CLP to differentiate into pre-pro-B cells is also compromised by senescence. These age-related changes in early B lymphopoiesis do not result from a general defect in HSC or the bone marrow microenvironment that impairs development in all hemopoietic lineages. Instead, data demonstrating that myeloid progenitor number and developmental potential do not decline with age indicate that B lymphopoiesis is particularly sensitive to defects that accumulate during senescence.

Aging↗
PubMed2006

Evolving patterns of lymphopoiesis from embryogenesis through senescence.

Lymphopoiesis occurs throughout adult life, but the number of lymphocytes produced is substantially reduced in old individuals. This commentary will highlight observations suggesting that common mechanisms underlie declines in both B and T cell production and that reductions in lymphopoiesis are initiated much earlier than has generally been appreciated.

Aging↗
PubMed2005

Reassessing the role of growth hormone and sex steroids in thymic involution.

The concomitant decline in growth hormone (GH) and increase in sex steroid production with age is thought to be responsible for thymic involution. If changes in the production of these hormones trigger or sustain thymic involution, that process should be accelerated in little mice, which have a genetic deficiency resulting in reduced production of thymopoietic GH, and delayed in the hypogonadal strain, which fails to produce thymocytotoxic sex steroids. The results indicated that thymic involution in both strains progressed in a manner similar to their normal littermates. That blocking sex steroid production did not delay thymic involution was surprising since castration reportedly increases thymus cellularity. Re-examination of that phenomenon revealed that, while gonadectomy results in increased thymus size, its effects are transient, and the thymus ultimately undergoes involution. Taken together, these data suggest that age-related changes in the endocrine system do not underlie thymic involution.

Age Factors↗
PubMed2005

Transgenic expression of Helios in B lineage cells alters B cell properties and promotes lymphomagenesis.

Helios, a member of the Ikaros family of DNA-binding proteins, is expressed in multipotential lymphoid progenitors and throughout the T lineage. However, in most B lineage cells, Helios is not expressed, suggesting that its absence may be critical for B cell development and function. To test this possibility, transgenic mice were generated that express Helios under the control of an Ig mu enhancer. Commitment to the B cell lineage was unaltered in Helios transgenic mice, and numbers of surface IgM(+) B cells were normal in the bone marrow and spleen. However, both bone marrow and splenic B cells exhibited prolonged survival and enhanced proliferation. B cells in Helios transgenic mice were also hyperresponsive to Ag stimulation. These alterations were observed even though the concentration of ectopic Helios in B lineage cells, like that of endogenous Helios in thymocytes, was well below the concentration of Ikaros. Further evidence that ectopic Helios expression contributes to B cell abnormalities was provided by the observation that Helios transgenic mice developed metastatic lymphoma as they aged. Taken together, these results demonstrate that silencing of Helios is critical for normal B cell function.

Animals↗
PubMed2005

Reevaluating current models of thymic involution.

It is generally accepted that thymic involution commences, or at least accelerates, at puberty due to increases in sex steroid and declines in growth hormone production. As a result of these hormonal changes, the development of the most immature intrathymic progenitors is blocked. However, aspects of this model are now being questioned. The present chapter re-evaluates a number of findings on which traditional models of thymic involution are based and reviews new data that, taken together, indicate a need to revise current views of thymic involution.

Aging↗
PubMed2005

Effects of aging on early B- and T-cell development.

Lymphocyte production in the bone marrow and the thymus is reduced during aging, but why this decline occurs has not been fully elucidated. The ability to isolate hematopoietic stem and progenitor cells using sophisticated flow cytometric strategies and to manipulate them in vitro and in vivo has provided insights into the effects of aging on primary lymphopoiesis. These analyses have showed that intrinsic changes in hematopoietic precursors that affect their proliferative potential are one factor that contributes to the age-related decline in B- and T-cell production. This and other age-related defects may be exacerbated by changes in the lymphopoietic support potential of the bone marrow and thymic microenvironments as well as by age-induced fluctuations in the production of various endocrine hormones. Particular attention with regard to the latter point has focused on changes in the production of sex steroids, growth hormone, and insulin-like growth factor-I. The present review summarizes recent studies of how age-related perturbations affect primary lymphopoiesis and highlights how the data necessitate the reevaluation of a number of existing paradigms.

Aging↗
PubMed2004

Reduction in the developmental potential of intrathymic T cell progenitors with age.

Current models of thymic involution propose that intrinsic developmental defects in intrathymic T cell precursors do not contribute to age-related declines in thymopoiesis. This premise was reassessed in a murine model in light of the recent definition of the early T lineage progenitor (ETP), which appears to be the earliest intrathymic precursor defined to date. The results demonstrate that the frequency of ETP declines with age and their potential to reconstitute the thymus is diminished. These findings are consistent with the fact that ETP from aged mice proliferate less and have a higher rate of apoptosis than their counterparts from young animals. Taken together, these data suggest that age-associated changes in T cell precursors should be considered when attempts to rejuvenate the involuted thymus are made.

Aging↗
PubMed2004

Macrophages and stromal cells phagocytose apoptotic bone marrow-derived B lineage cells.

It has been hypothesized that B cell precursors that undergo programmed cell death due to nonproductive Ig gene rearrangements are cleared from the bone marrow by macrophages. However, a role for macrophages in this process is supported only by micrographs showing their association with apoptotic-appearing, B lineage cells. Functional data demonstrating phagocytosis of apoptotic, bone marrow lymphocytes by macrophages have not been presented, nor have receptors potentially involved in that process been identified. The data in this report demonstrate that macrophages isolated from murine bone marrow efficiently phagocytose apoptotic murine B lineage cells using multiple receptors that include CD14, integrins, class A scavenger receptor, and CD31 (PECAM-1). In addition, the results further reveal a new role for the hemopoietic microenvironment in B cell development in view of data demonstrating that murine bone marrow stromal cells are also capable of clearing apoptotic cells via an integrin-dependent mechanism.

Animals↗
PubMed2004

Got MLL? Definitive hematopoiesis requires MLL gene expression.

A manuscript by Ernst and colleagues in the March 2004 issue of Developmental Cell demonstrates that following hematopoietic stem cell appearance in the AGM, expression of the MLL transcription factor is required for their subsequent differentiation.

Cell Differentiation↗
PubMed2004

Age-related changes in lymphocyte development and function.

The effects of aging on the immune system are widespread and extend from hematopoietic stem cells and lymphoid progenitors in the bone marrow and thymus to mature lymphocytes in secondary lymphoid organs. These changes combine to result in a diminution of immune responsiveness in the elderly. This review aims to provide an overview of age-related changes in lymphocyte development and function and discusses current controversies in the field of aging research.

Aging↗
PubMed2003

Effects of housing on the thymic deficiency in dwarf mice and its reversal by growth hormone administration.

Initial studies on T cell development in the Snell Dwarf (dw/dw) strain of mice, which are deficient in the production of anterior pituitary hormones, have been interpreted to indicate a clear dependence of T cell development on endocrine system-derived factors. However, normal thymopoiesis in this strain has also been reported. The aim of the present study was to reconcile these contradictory data in order to define the role of anterior pituitary hormones in the thymus. The results indicated that if female dw/dw mice are housed together with their normal-sized littermates, thymic cellularity and the frequency of CD4(+)CD8(+) thymocytes are markedly reduced. However, administration of growth hormone could reverse these decreases seen in the double-positive T progenitor cells. Taken together, the data indicate that stress is the unifying parameter that can explain the disparate dw/dw mouse literature and suggest that endocrine effects on the T cell development can best be understood by interpreting the literature in this context.

Animals↗
PubMed2002

B-cell development in the thymus is limited by inhibitory signals from the thymic microenvironment.

B-cell precursors are present in the thymus, and the thymic microenvironment is the source of lymphopoietic factors that include interleukin-7 (IL-7). Despite the fact that intrathymic B-cell progenitors are bone marrow-derived cells, the data in this report demonstrate that these progenitors accumulate at an early pro-B-cell stage of development, cycle less than their bone marrow counterparts, and fail to differentiate efficiently. Additional studies presented herein indicate that these effects are mediated, at least in part, by soluble factors produced by the thymic microenvironment and suggest that they affect the ability of pro-B cells to respond optimally to IL-7. Taken together, these observations demonstrate a specific inhibition of intrathymic B lymphopoiesis, which in turn may explain why lymphoid cell production in the thymus is largely restricted to production of T-lineage cells despite the fact that B-cell precursors and B-lymphopoietic stimuli are present in that organ.

Animals↗
PubMed2002

Impaired development of T lymphoid precursors from pluripotent hematopoietic stem cells in New Zealand Black mice.

Bone marrow cells from autoimmune-prone New Zealand Black (NZB) mice are less efficient at colonizing fetal thymic lobes than cells from normal strains. This study demonstrates that the reduced capacity of NZB bone marrow cells to repopulate the thymus does not result from their inability to migrate to or enter the thymus. Rather, the T lymphopoietic defect of NZB mice is due to an impaired ability of pluripotent hematopoietic stem cells (PHSCs) to generate more committed lymphoid progeny, which could include common lymphoid precursors and/or other T cell-committed progenitors. Although PHSCs from NZB mice were not as efficient at thymic repopulation as comparable numbers of PHSCs from control strains, the ability of common lymphoid precursors from NZB mice to repopulate the thymus was not defective. Similarly, more differentiated NZB T cell precursors included in the intrathymic pool of CD4(-)CD8(-) cells also exhibited normal T lymphopoietic potential. Taken together, the results identify an unappreciated defect in NZB mice and provide further evidence that generation of lymphoid progeny from the PHSCs is a regulated event.

Animals↗