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PubMed1985

The hypersplenic spleen. A contractile reservoir of granulocytes and platelets.

Epinephrine-induced mobilization of noncirculating granulocytes and thrombocytes was evaluated in 13 subjects with marked variation in spleen size and correlated with the sonographically recorded contraction of the spleen. The effects of epinephrine on blood granulocyte and thrombocyte counts correlated highly with splenic contraction but not with spleen size. The findings provide further insight into mechanisms of hypersplenism, suggest that the big spleen of hypersplenism mimics the contractile reservoir function of the spleen of certain animals, and point out that the "marginal" granulocyte pool mobilized by epinephrine is not randomly distributed throughout the body.

Adult↗

PubMed2000

Role of spleen macrophages in the clearance of scrapie agent early in pathogenesis.

The involvement of spleen macrophages in the early stages of scrapie pathogenesis was studied by applying the 'macrophage-suicide technique' to scrapie-infected mice. This method comprises critically the intravenous administration to mice of dichloromethylene disphosphonate encapsulated into liposomes. Depletion of spleen macrophages before scrapie infection induced an increased amount of scrapie inoculum in the spleen, consequently leading to accelerated scrapie agent replication in the early phase of pathogenesis, as followed by PrPres accumulation, a specific hallmark of scrapie. The same effect was observed when spleen macrophages were depleted just before the beginning of scrapie agent replication. These findings suggest that macrophages may partly control scrapie infection in peripheral tissues by sequestration of the scrapie inoculum and may thus impair early scrapie agent replication in the spleen. In addition to macrophages, most follicular dendritic cells and B lymphocytes, which are thought to support scrapie agent replication, were also transiently depleted by dichloromethylene disphosphonate administration. This suggests that a compensatory mechanism is sufficient to ensure the persistence of infection in these early stages of pathogenesis.

Analgesics, Non-Narcotic↗

PubMed1997

Immunohistochemical and structural characteristics of the reticular framework of the white pulp and marginal zone in the human spleen.

BACKGROUND: The reticular framework of the white pulp (WP) and marginal zone (MZ) consists of reticulum cells and reticulin fibers. The antigenic heterogeneity of the reticular framework is well documented in the mouse and rat spleen. The aim of the present study is to characterize the reticular framework of the WP and MZ of the human spleen. METHODS: Nine surgically resected human spleens were investigated. Five of the nine spleens were perfused. Formalin-fixed materials were embedded in paraffin and serial sections prepared for hematoxylin-eosin, silver staining, and immunohistochemical examination. Electron and immuno-electron microscopy were also applied. Using confocal laser scanning microscopy, the reticular framework was analyzed three-dimensionally. RESULTS: The reticulin fibers of the framework were immunostained for type IV collagen in the WP and MZ. The WP was three-dimensionally delimited by the alpha-smooth muscle actin (alpha-SMA)-positive reticulum cells. In the WP, the distribution of alpha-SMA-positive reticulum cells formed the reticular framework of the periarteriolar lymphoid sheath (PALS). They also ensheathed the reticulin fibers. Interdigitating cells (IDCs) were scattered throughout the framework. A few IDCs attached to the framework. In the lymph follicle (LF), reticulum cells were not alpha-SMA-positive. The mesh of follicular dendritic cells (FDCs) was found in the germinal center. In places, the reticulin fibers were involved in the mesh of the FDCs and covered by the cytoplasm of FDCs. In the MZ, alpha-SMA-positive reticulum cells were arranged in a mesh pattern and ensheathed the fine reticulin fibers. CONCLUSION: The reticular framework of the PALS, LF, and MZ is specialized into heterogeneous components in the human spleen. The heterogeneity of the framework may induce the segregation of T and B lymphocytes.

Actins↗

PubMed1977

Spontaneous (pathologic) rupture of the spleen in previously undiagnosed Hodgkin's disease: report of a case with survival.

Spontaneous (pathologic) rupture of the spleen in lymphoma is a rare event. A 38-year-old man with a 6-week history of fever, night sweats, and weight loss, and with known splenomegaly presented in shock as a result of a ruptured spleen. There was no known antecedent trauma. Hodgkin's disease was demonstrated in the spleen and liver. Review of the literature failed to reveal any previous report of spontaneous rupture of the spleen due to undiagnosed Hodgkin's disease. Only one survivor of spontaneous rupture of the lymphomatous spleen has been reported previously.

Adult↗

PubMed1981

Vascular pathways in nonsinusal red pulp--an electron microscope study of the cat spleen.

The red pulp of the cat spleen, including terminal segments of arterial capillaries, pulp venules, and the reticular meshwork, was studied by transmission electron microscopy. Splenic congestion and contraction were produced by barbiturate anesthetic and norepinephrine. Terminal segments of arterial capillaries were ampullary and flared. Blood escaped into surrounding pulp spaces through interendothelial gaps. Pulp venules originated as open-ended vessels in the reticular meshwork near trabeculae and drained into trabecular veins. Venule walls were thin and composed of squamous endothelial cells, a continuous basement membrane, and reticular cells. Venules in congested spleens had many mural apertures, but venules in contracted spleens had few. The interstices of the reticular meshwork in congested spleens contained large amounts of blood, which often was concentrated, many macrophages, lymphocytes, and plasma cells. Fewer blood cells and scant plasma were present in contracted spleens. The vascular arrangements are anatomically open. Blood takes pathways through the reticular meshwork from arterial terminations to pulp venules. Some pathways through the reticular meshwork probably function as closed vascular channels conveying rapidly flowing blood. Other pathways are functionally open and probably contain slowly moving blood that constitutes a reservoir of red cells. Macrophages formed associations with mature red cells and with reticulocytes. Mature red cells were attached to macrophages in a manner indicating erythrophagocytosis. Reticulocyte attachment had a different appearance and likely resulted in reticulocyte sequestration. Platelets bore pseudopodia which would impede their passage through irregular and cell-filled pulp spaces. The change in platelet shape probably is responsible for the formation of the splenic pool of platelets.

Animals↗

PubMed1982

Distribution and identity of the earliest proliferating progeny of colony-forming cells in regenerating murine spleen and bone marrow.

A study was made of the sites of development and the types of cells found in very early hemopoietic colonies in the mouse spleen. Two, 3, and 4 days after transplantation, the proliferating descendants of transplanted bone-marrow cells were identified on radioautographs of spleen sections and on spleen and bone-marrow smears of supralethally irradiated recipient mice which were injected with 3H-TdR at 12, 6, and 0.5 hours before sacrifice. Surprisingly the spleens of nontransplanted, irradiated mice contained proliferating medium and large lymphocytes in the white pulp which increased in numbers during the observation period. The early descendants of transplanted cells that lodged in the spleen could be clearly distinguished from the labeled indigenous cells because they formed discrete nodules or colonies beneath the splenic capsule or in the vicinity of venules and trabeculae of the red pulp. These cells were identifiable on day 2 as transitional cells or unknown hemopoietic blasts and on day 4 included early erythroid cells and small lymphocytes. There was evidence for the traffic of 3H-TdR-labeled cells through the splenic sinusoids.

Animals↗

PubMed1988

Splenic hemopoiesis of the platypus (Ornithorhynchus anatinus): evidence of primary hemopoiesis in the spleen of a primitive mammal.

The generation of blood cells has been observed in the spleen and in the bone marrow of the platypus. Hemopoiesis was found to be far more active in the spleen than in the bone marrow judging by the number of proliferating hemopoietic elements within a unit area of tissue from each organ. Granulocytes, erythroblasts, and megakaryocytes, with the related immature forms for each cell line, were noted in the spleen. In contrast, there were very few examples of immature forms of these cell lines and a complete absence of mature megakaryocytes in the bone marrow. These findings suggest that the spleen is the primary hemopoietic organ in the platypus. Since the platypus is one of two species representing the most primitive existing mammals, it seems likely that the spleen may be the primary hemopoietic organ in mammalian evolution.

Animals↗

PubMed2003

Ineffective erythropoiesis in the spleen of a patient with pyruvate kinase deficiency.

In this study, possible adverse effects of pyruvate kinase (PK) deficiency on the maturation of erythroid progenitors were investigated. A 4-year-old Japanese girl with severe PK deficiency underwent splenectomy to reduce her need for blood transfusions. The spleen was examined a histologically, and the hematopoietic progenitors in the spleen were assayed to evaluate the extramedullary hematopoiesis of this PK-deficient subject. The number of hematopoietic progenitors including CFU-GM, BFU-E and CFU-GEMM in the spleen of the PK-deficient patient was much higher than those found in control spleens, indicating enhanced extramedullary hematopoiesis. TUNEL assay demonstrated apoptotic cells in the splenic red pulp of the PK-deficient patient. The expression of 7A6 antigen was detected in cells isolated from spleen and in cells cultured in vitro, but only in those cells that were positive for glycophorin A. These results provide evidence that the metabolic disturbances in PK deficiency affect not only the survival of red cells but also the maturation of erythroid progenitors, which results in premature cell death, i.e., apoptosis.

Apoptosis↗

PubMed1992

Sequential maturation stages of monoclonal B lineage cells from blood, spleen, lymph node, and bone marrow from a terminal myeloma patient.

In order to fully understand the complexity of the monoclonal B lineage cells in multiple myeloma, it is necessary to evaluate the extent to which these cells are resident in solid lymphoid tissues and the phenotypic differences and similarities as compared to the circulating or bone marrow derived B lineage cells. Peripheral blood mononuclear cells from a patient with multiple myeloma were obtained 8 and 3 days prior to death, and mononuclear cells from lymph nodes, spleen, and bone marrow were obtained at autopsy. Rapid changes in the stage of differentiation of blood late-stage B lineage cells towards mature end-stage plasma cells were observed during the last week prior to death. Lymphoid cells within the blood comprised very few T cells, sub-normal numbers of monocytes, and 80% of B lineage cells which were at a late stage of differentiation. Shortly before death, plasma cells were found in the peripheral blood, indicating progression to plasma cell leukemia. At autopsy, the monoclonal B lineage cells in lymph node, spleen, and bone marrow represented different stages of terminal B cell differentiation. In each tissue, the B lineage cells were at an earlier differentiation stage, as defined phenotypically, than the circulating B lineage cells found in blood 3 days prior to death. Analysis of B cell markers and CD45 was used to define the differentiation stage of the relevant B cell populations, revealing a series of differentiation stages. The least mature B lineage cells (CD45hi) were found in lymph node. However, the CD45 isoform expressed was CD45R0, unlike most normal lymph node B cells. More differentiated B lineage cells (CD45med) were found in the bone marrow, and three sequential stages of pre-plasma cells were found in the spleen (CD45bright, CD45moderate, and CD45low-neg), all of which were CD45R0+. The B cells in normal spleen and bone marrow are CD45RA+. The presence of monoclonal B lineage cells in spleen was confirmed by Southern blotting. The B lineage cells from peripheral blood 3 days prior to death were approaching an end-stage plasma cell stage (CD45low/-). On B lineage cells from the various myeloma tissues, a concomitant loss of CD11b and increasing density of CD29 were observed as a function of progression to terminally differentiated stages.

Antibodies, Monoclonal↗

PubMed1995

Time course of cyclosporine and ist motabolites in blood, liver and spleen of naive Lewis rats: comparison with preliminary data obtained in transplanted animals.

the time course of intravenously administered cyclosporine (1 mg kg-1) and its metabolite AM1, AM9, and AM1c were examined in the blood, liver, and spleen of naive Lewis rats. Cyclosporine concentration versus time data for all three tissues were qualitatively similar, following a biexponential model C = Ae-gamma 1t + Be-gamma 2t with maximum cyclosporine concentrations reached at 1 h. Whole-blood cyclosporine clearance, terminal half-life, mean residence time, steady state volume of distribution, and hepatic extraction ratio (calculated from blood data) were similar to previously reported results. Cyclosporine in the liver showed the largest area under the concentration-time curve, mean residence time, and disposition and terminal half-lives. Spleen cyclosporine mean residence time and and terminal half-life were not significantly different from blood parameters. Metabolites AM1, AM9, and AM1c showed almost parallel time courses in all three tissues. The hydroxylated derivative AM9 was the major metabolite found in all tissues, with twofold greater levels in the liver compared to the blood and spleen. Slightly less AM1 was found in the liver relative to blood and spleen, where it was present in equal amounts. AM1c levels in the liver were not different from those in the spleen and were greater than observed for blood. The results obtained above were reflected in preliminary studies using liver transplanted rats treated with multiple doses of cyclosporine. Both blood and liver biopsy levels of CyA, AM1, and AM9 post-transplant showed twofold to fourfold decreases from day 3 ( samples taken 4 h post-CyA-dose) and concentrations were not significantly different from similarly sampled naive controls. More importantly, the metabolite/CyA ratios did not vary significantly between liver and blood in the two groups. For naive rats, and liver transplanted animals not undergoing rejection, changes in blood cyclosporine levels seem to predict variations in tissue concentrations.

Animals↗

PubMed2007

Development and function of the mammalian spleen.

The vertebrate spleen has important functions in immunity and haematopoiesis, many of which have been well studied. In contrast, we know much less about the mechanisms governing its early embryonic development. However, as a result of work over the past decade-mostly using knockout mice--significant progress has been made in unravelling the genetic processes governing the spleen's early development. Key genetic regulators, such as Tlx1 and Pbx1, have been identified, and we know some of the early transcriptional hierarchies that control the early patterning and proliferation of the splenic primordium. In mouse and humans, asplenia can arise as a result of laterality defects, or the spleen can be absent with no other discernible abnormalities. Surprisingly, given the spleen's diverse functions, asplenic individuals suffer no major haematopoietic or immune defects apart from a susceptibility to infection with encapsulated bacteria. Recent evidence has shed light on a previously unknown role of the spleen in the development and maintenance of specific B cell populations that are involved in the initial response to infection caused by encapsulated bacteria. The lack of these populations in asplenic mice and humans may go some way to explaining this susceptibility.

Animals↗

PubMed1976

Malarial immunodepression in vitro: adherent spleen cells are functionally defective as accessory cells in the response to horse erythrocytes.

The basis for the depressed response of malarial infected mice to horse red blood cells (HRBC) has been studied in vitro. Results presented show that the adherent spleen cells from infected mice (a) are defective in their ability to allow nonadherent spleen cells of both normal and infected mice to respond to HRBC whereas a response does occur with adherent spleen cells from normal mice (b) do not suppress the response of unfractionated spleen cells from normal mice to HRBC (c) contain phagocytic cells as measured by the uptake of neutral red in numbers which are of the same order of magnitude as in adherent spleen cells from normal mice, but which are unable to take up HRBC. We conclude that a splenic adherent cell, probably the macrophage is functionally defective as an accessory cell in the response to HRBC of mice infected with Plasmodium berghei yoelii.

Animals↗

PubMed1979

Immune depression in trypanosome-infected mice. II. Characterization of the spleen cell types involved.

Spleen cells from Trypanosoma congolense-infected mice showed a drastic depression in their capacity to respond to B and T lymphocyte mitogens and to allogeneic spleen cells in mixed lymphocyte cultures. Spleen cells from infected mice were also poor stimulators in mixed lymphocyte cultures. The poor responsiveness or stimulation capacity was not due simply to dilution of relevant B or T lymphocytes by the large number of null cells found in the spleens of infected animals. These null cells expressed approximately eight times more H-2 antigen than spleen cells from normal (uninfected) mice and were devoid of Ia antigens.

Animals↗

PubMed1982

Production of high titers of interferon-gamma by prestimulated murine spleen cells.

Concanavalin A (Con A)-induced interferon-gamma (IFN-gamma) production by murine spleen cells prestimulated with Con A for different periods of time has been studied. Highest titers of antiviral activity were obtained by restimulation of cells that had been prestimulated with Con A for 3 days. These cells produced up to 30 times more IFN than freshly isolated spleen cells stimulated under the same conditions. In an effort to explain this rise in the capacity to produce IFN-gamma, the possibility that it was due to the inactivation of a suppressor cell was excluded. The addition of freshly isolated spleen cells at different concentrations to prestimulated cells did not affect subsequent Con A-induced IFN-gamma production. Separation of freshly isolated or prestimulated spleen cells by velocity sedimentation at unit gravity showed that in the latter case most of the IFN-gamma was produced by a population of large-sized cells not present in the former population. It was concluded from these experiments that prestimulation of spleen cells with Con A gives rise to a population of large-sized cells that produce, upon restimulation with the same mitogen, much higher titers of IFN-gamma than those obtained upon primary stimulation of small resting lymphocytes.

Animals↗

PubMed1984

In vivo regulation of the cytolytic T cell response to hapten-altered self: suppressor T cells induced in the regional lymph nodes by exposure to syngeneic spleen cells.

During the course of examining the in vivo development of the cytotoxic T lymphocyte (CTL) response to hapten-modified self antigens in mice, we have observed that it can be abrogated through prior exposure of the host's regional lymph nodes (LN) to normal syngeneic spleen cells (NSC). Suppression appeared to be antigen nonspecific and was best seen when animals were injected in the footpads with NSC at least 72 h before sensitization for CTL. The ability to prevent the development of the CTL response was restricted primarily to syngeneic splenic T and B cells since syngeneic thymocytes stimulated only partial suppression and syngeneic LN cells, as well as hapten-coupled syngeneic spleen cells, did not at all. Suppression appeared to be a local phenomenon in that the NSC induced transferable suppressor T cells to appear in the popliteal LN draining the footpads but not in spleens. In addition, animals splenectomized prior to injections of NSC showed abrogated CTL responses equivalent to sham-splenectomized animals indicating that the spleen does not contribute to the mechanism of suppression. Finally, when only one footpad was injected with NSC, suppression was seen in the draining popliteal node and not in the contralateral node. Taken together, the evidence suggests that the source of the suppression and the suppressor T cells may be attributed to an in vivo syngeneic mixed lymphocyte reaction occurring between responder cells of the draining LN and injected stimulator spleen cells.

Animals↗

PubMed1989

Ontogenic development of autoantibody repertoires in spleen and peritoneal cavity of normal mice: examples of T cell-dependent and -independent reactivities.

The ontogenic development of B cell clonal precursors (BCP) reactive to bromelain-treated, syngeneic erythrocytes (BrMRC) and to single-stranded DNA has been studied by limiting dilution of both spleen and peritoneal cells. It was found that the frequency of anti-BrMRC BCP in the spleen is very low up to 4 weeks of age and slowly increases thereafter, to reach adult levels by 6-10 weeks. In the peritoneal cavity, no such BCP can be found before 2 weeks, but they occur at a very high frequency already by 3 weeks of age. Injection of adult, normal syngeneic T cells at birth has no apparent effect on the representation of anti-BrMRC BCP in the peritoneal cavity, but brings these to adult levels or even higher in the spleen already at 3 weeks of age. Accordingly, adult athymic (nude) mice contain normal frequencies of BrMRC-specific BCP in the peritoneal cavity but are devoid of such clones in the spleen. In contrast, the frequency of anti-DNA BCP is very high throughout postnatal development in both spleen and peritoneal cavity, of normal and athymic mice, in both resting and naturally activated splenic B cell compartments, and it is independent of T cell transfers into nude animals. These results indicate the role of T cells in the establishment of some clonal specificities in the adult, splenic autoreactive B cell repertoire.

Age Factors↗

PubMed1991

CD3+ T cells in severe combined immune deficiency (scid) mice. I. Transferred purified CD4+ T cells, but not CD8+ T cells are engrafted in the spleen of congenic scid mice.

Young (less than 3 months of age) and old (greater than 1 year of age) C.B-17 scid/scid mice were tested for the presence of immunoglobulin in serum and CD3+ T cells in spleen and peritoneal cavity. In all old severe combined immune deficiency (scid) mice tested we found detectable, but very variable levels of serum immunoglobulin as well as splenic and peritoneal CD3+ T cells comprising 3% to 10% of the nonfractionated cell populations of these organs (n = 10). In contrast, none of the analyzed young scid mice showed any evidence of peripheral lymphocytes. Low numbers (2 x 10(5) to 5 x 10(5) cells/mouse) of highly purified CD4+ cells from congenic C.B-17 or BALB/c donor mice were injected intravenously into young scid recipient mice. A CD4+ T cell population was clearly engrafted when transplanted scid mice were analyzed 8 to 13 weeks after T cell transfer: (a) a CD3+CD4+CD8- T cell population was detectable in the spleens of all recipient scid mice by flow microfluorometry analyses; (b) CD3+CD4+CD8 T cell lines could be grown out of these spleens in vitro; (c) the histological examination revealed evidence of lymphoid cell repopulation in the spleens of all transplanted scid mice and (d) transplanted CD4+ T cell populations could be serially transferred into secondary and tertiary recipient scid mice. These data indicate that scid mice can be constructed in which only the CD4+ T cell compartment is selectively reconstituted. In contrast to the successful engraftment of CD4+ T cell, highly purified congenic CD8+ T cells could not be engrafted into the spleen of scid mice.

Aging↗

PubMed1992

Origin of CD5+ B cells and natural IgM-secreting cells: reconstitution potential of adult bone marrow, spleen and peritoneal cells.

The bulk of natural IgM secretion is currently attributed to peritoneal CD5+ B cells and their progeny, believed to be independent of adult bone marrow precursors. We have compared the capacity of peritoneal or splenic cells from normal adult mice to generate serum IgM after transfer into allotype-congenic, irradiated and bone marrow-protected mice. Recipients of either cell population produced donor-allotype IgM-secreting cells in the spleen, and had donor-derived serum IgM. In both cases as well, recipient IgM secretion recovered to control levels. Since the spleen cell-derived natural IgM production could result from expansion of CD5+ B cells present in the inoculum, we next investigated the ability of Ig- bone marrow (BM) cells (Ig- BM) to reconstitute natural IgM secretion in irradiated mice. This cell population was most efficient in reconstituting donor-derived IgM secretion. The origin and phenotype (IgM, CD5) of B cells present in spleen and peritoneum of recipient mice were also analyzed. In agreement with the high level of donor IgM-secreting cells, transfers of splenic and Ig- BM cells fully reconstitute donor B cells in spleen and peritoneum and inhibit reconstitution from host origin. In contrast, donor peritoneal cells reconstitute B cells very poorly in spleen and allow for reconstitution by host cells. Furthermore, Ig- BM cells as well as splenic or peritoneal donor cells, all reconstitute CD5+ B cells in the peritoneum of recipient mice. Interestingly, the fraction of IgM+ cells of each allotype that differentiate to IgM secretion varies widely, but normal levels of IgM are established even when the number of donor B cells present in the animal is very limited.

Animals↗