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PubMed1981

Fatal response suggestive of graft-versus-host reaction following transplantation of spleen cells from allogeneic athymic (nude) donors.

Normal female SJL/J mice were exposed to 950 R of total body irradiation (TBI) and transplanted with allogeneic spleen or marrow cells from normal or nude (athymic) C57BL/10 donors. With nude mouse donor marrow, no evidence of graft-versus-host (GVH) response was seen and all SJL/J recipients survived for more than 75 days. In contrast, when spleen cells taken from the same nude C57BL/10 donors were engrafted into SJL/J mice the incidence of fatalities among the recipients was 70% by 60 days. Furthermore, all of the recipients of nude mouse spleen cells showed signs strongly suggestive of GVH response. Comparative fatalities among the recipients of cells from normal donors were 27% for marrow at 60 days and 100% for spleen at 11 days, and these were accompanied by the characteristic signs of GVH response usually seen after transplantation of cells from normal allogeneic donors. Transplantation of normal C57BL/10 marrow mixed with small numbers at normal spleen cells resulted in an increase in the number of fatalities among the SJL/J recipients, and an increase in the severity of the signs of GVH response as compared to that seen following engraftment of normal C57BL/10 marrow alone. However, no such increases in fatalities or severity were observed when similar amounts of nude C57BL/10 spleen cells were engrafted along with normal marrow cells into SJL/J recipients. The results suggest that a factor may exist in nude mouse spleen which in allogeneic transplantation can lead to a fatal response suggestive of GVH reaction, but that nude mouse spleen lacks the T cell-related ability to enhance GVH response that has been previously demonstrated following allogeneic transplantation using normal spleen and marrow donors.

Animals↗
PubMed1987

Induction of transplantation tolerance in rats by spleen allografts. III. The role of T suppressor cells in the induction of specific unresponsiveness.

Heterotopic (WAG x AGUS)F1 spleen allografts survive indefinitely when transplanted to normal AGUS recipients and induce long-term donor-specific unresponsiveness. In this report, we have examined the immune reactivity of spleen graft recipients soon after transplantation, in an attempt to define the immunological mechanisms responsible for the induction of donor-specific unresponsiveness. Unresponsiveness develops as early as one week after splenic transplantation. T cells obtained from the recipient lymph node and spleen exhibit reduced mixed lymphocyte reaction responses to donor (WAG) but respond normally to third-party (PVG) stimulators. In contrast, T cells obtained from the spleen graft are unresponsive to both donor and third-party stimulators. Donor specific T suppressor cells (Ts) appear in the recipient's lymph node and spleen by one week posttransplantation--however, at this time antigen nonspecific suppressor cells predominate in the spleen graft. Only minimal cytotoxic T cell activity could be detected in the spleen graft, with the host spleen and lymph nodes being devoid of cytotoxic T lymphocytes. Sera obtained one or two weeks following splenic transplantation did not contain cytotoxic alloantibodies, and only a very weak response could be detected at one month. These data demonstrate that the unresponsiveness associated with the spontaneous acceptance of spleen allografts is correlated with the early induction of antigen specific Ts in recipient lymphoid tissue and the presence of nonspecific suppressor cells at the graft site.

Animals↗
PubMed1989

The nature of tolerance in adult recipient mice made tolerant of alloantigens with supralethal irradiation followed by syngeneic bone marrow cell transplantation plus injection of F1 spleen cells.

The length of time after syngeneic bone marrow reconstitution when tolerance to alloantigens can be induced in adult mice during T cell differentiation from bone marrow cells was studied by exposing those T cells to (recipient x donor)F1 spleen cells. Supralethally irradiated C3H/He Slc(C3H; H-2k) mice were reconstituted with 1 x 10(7) syngeneic T cell-depleted bone marrow cells and then injected intravenously with 5 x 10(7) (C3H x C57BL/6[B6])F1 (B6C3F1; H-2bxk) or (C3H x AKR/J[AKR])F1 (AKC3F1; H-2kxk) spleen cells at various intervals. In the fully allogeneic combination of B6C3F1----C3H, EL-4 tumor originating from B6 was accepted, and survival of grafted B6 skin was significantly prolonged in the tolerant C3H mice treated with irradiation on day -1 followed by injection of syngeneic bone marrow cells on day 0 plus B6C3F1 spleen cells on days 0, 5, or 10, in a tolerogen-specific manner. In the multiminor histocompatibility antigen-disparate combination of AKC3F1----C3H, AKR skin grafts were permanently accepted in the tolerant C3H mice treated with AKC3F1 spleen cells on days 0, 5, 10, or 15. Immunological parameters, including cytotoxic T lymphocyte activity and delayed foot-pad reaction (DFR), were almost completely suppressed in C3H mice made tolerant of B6 or AKR antigens. A chimeric assay using a direct immunofluorescence method revealed that the tolerant C3H mice given B6C3F1 spleen cells on day 0 were mixed-chimeric for at least 8 weeks after syngeneic bone marrow reconstitution, but not definitely chimeric thereafter. The C3H mice given AKC3F1 spleen cells on day 0 were chimeric even 43 weeks after syngeneic bone marrow reconstitution, but the C3H mice given AKC3F1 spleen cells on day 15 showed temporal chimerism that disappeared within 43 weeks. The untolerant mice were never detectably chimeric. These data suggest that the earlier the timing of the injection of F1 spleen cells after syngeneic bone marrow reconstitution was, the more profound tolerance was induced. Moreover, the stronger the antigenic disparity between donor and recipient, the earlier the injection of F1 spleen cells was required to induce tolerance.

Aging↗
PubMed1990

Elimination of acute GVHD and prolongation of rat pancreas allograft survival with DST cyclosporine, and spleen transplantation.

Allogeneic spleen transplantation has been shown to have a tolerizing effect on pancreas allograft survival in rats. In this study we examined the effect of blood transfusions and cyclosporine administration on both rat pancreas allograft survival and acute graft-versus-host disease in BN recipients of Lewis pancreas-spleen allografts. We found that in this strain combination significant pancreas allograft prolongation occurred when the spleen was included en bloc with the pancreas graft. However, 50% of these recipients developed GVHD and died. A single donor-specific transfusion delivered to BN recipients of Lewis pancreas and pancreas-spleen allografts did not extend graft survival, but precluded the development of GVHD. A short, 6-day, and long, 26-day, course of CsA to recipients of pancreas and pancreas-spleen allografts extended graft and animal survival times, although not indefinitely. All pancreas-spleen recipients of both CsA protocols died following acute GVHD. Combined DST and CsA (short and long-course) administration in pancreas-only allograft recipients was deleterious to graft survival, compared with CsA administration alone. However, in pancreas-spleen recipients, combined DST and CsA had an additive effect. Moreover, in DST and long-course CsA-treated pancreas-spleen recipients, indefinite graft survival occurred with no signs of acute GVHD. The beneficial effect of the spleen allograft on pancreas graft survival was not dependent upon GVHD, since splenic-induced prolongation of pancreas graft survival was observed in the F1-donor to parent-recipient combination.

Acute Disease↗
PubMed1991

The combi-effect--reduced rejection of the heart by combined transplantation with the lung or spleen.

The term combi-effect was introduced to describe the phenomenon of a reduction in rejection of heart grafts after combined transplantation with the lung. In this study in rats we investigated whether the combi-effect was an immunological process and whether it could also be induced by combined transplantation of the heart with the spleen or with a lymphocyte-depleted spleen. Heart and spleen grafts were transplanted into the abdomen; left lungs were transplanted into the thorax of recipient rats. To deplete spleens of their lymphocytes, prospective donor rats were irradiated. Cyclosporine was injected once, on day 2 after transplantation. All heart allografts transplanted alone and treated with cyclosporine were rejected acutely (median survival time [MST] of 14.5 days). In contrast, after combined transplantation of a donor lung or spleen with the heart, almost all heart grafts survived indefinitely. Transplantation of a syngeneic lung or third-party spleen had little effect on heart graft survival (MST of 22.5 days and 26.5 days, respectively). Without cyclosporine treatment, combined transplantation with a donor lung or spleen hardly prolonged heart graft survival. Transplantation of a lymphocyte-depleted spleen with the heart induced a combi-effect in cyclosporine-treated rats that was somewhat weaker: only two of six hearts survived indefinitely. We conclude that in the combi-effect an immunological mechanism reduces rejection of the heart. This mechanism is probably generated by the lymphoid tissue (bronchus-associated lymphoid tissue in lung and white pulp in spleen) in the combined transplant.

Animals↗
PubMed1993

Mechanism of a clinically relevant protocol to induce tolerance of cardiac allografts. Perioperative donor spleen cells plus cyclosporine suppress IL-2 and interferon-gamma production.

Many groups have reported that preoperative injection of donor-derived whole spleen cells or major histocompatibility complex antigens prolongs organ allograft survival in experimental models, but the immunosuppressive mechanism(s) responsible remains unclear. A central, confounding issue is how to reconcile documentation of comparable levels of mRNA for IL-2 in suppressed versus control groups with obvious host hyporesponsiveness. We used a model of tolerance induction involving perioperative injection of donor spleen cells and injection of CsA at day 2 after transplant to analyze the serial expression of several proinflammatory cytokines relevant to development of alloresponsiveness within cardiac allografts and recipients' spleens. Four experimental groups of Lewis rats receiving vascularized heterotopic cardiac allografts from Brown Norway (BN) donors were evaluated: (1) untreated controls; (2) animals receiving intraoperative injection of donor BN spleen cells; (3) those receiving a single injection of CsA on day 2 post-Tx; and (4) animals given the combination of intraoperative BN spleen cells and CsA on day 2 post-Tx. Graft survival was significantly prolonged in Lewis rats receiving the combined spleen cell/CsA therapy (mean 64 days, with 40% of grafts surviving > 100 days, n = 15) compared with acute rejection at about 8 days (range 6-13, n = 20) in each of the 3 control groups (P < 0.0001). By comparison with acutely rejecting allografts in the control untreated group at day 7 post-Tx, allografts in rats receiving the combined perioperative spleen cell/CsA treatment showed (1) significantly reduced graft cellularity and interstitial edema; (2) significantly decreased features of immune activation, including infiltration by mononuclear cells expressing IL-2R or proliferating cell nuclear antigen; (3) decreased intragraft expression of the cytokines IL-2 and IFN-gamma; and (4) suppression of endothelial activation as evidenced by both failure of up-regulation of intracellular adhesion molecule-1 and maintenance of thrombomodulin expression by graft endothelium. Analysis of sections of recipients' spleens showed that spleen cell/CsA therapy led to significant reductions versus untreated controls, in expression of IL-2, IFN-gamma, and IL-2R. Similarly, mixed lymphocyte response cultures showed that responder cells from rats receiving combined therapy proliferated by 93-95% less than untreated animals. Our results suggest that the efficacy of this clinically relevant protocol is associated with suppression of IL-2 or IFN-gamma protein production, and that in the absence of such molecules, it appears that T cell-receptor occupancy by alloantigens readily induces a state of anergy in vivo.

Animals↗
PubMed1981

On the size and tumor involvement of the spleen in Hodgkin's disease.

Fifty-four untreated patients with Hodgkin's disease (HD) subjected to splenectomy were studied with respect to preoperatively assessed spleen size compared to postoperative findings. Before splenectomy, nine patients had "normal sized" spleens, 18 patients had spleens weighing greater than or equal to 200 g and 14/39 spleens were tumor-involved. Nine patients had "enlarged" but unpalpable spleens. Eight of these weighed greater than 200 g and 3/9 spleens showed tumor involvement. Six patients with preoperatively palpable spleens showed tumor involvement, their spleens weighed greater than 660 g. The results confirm the inaccuracy of non-invasive procedures in prediction of spleen size and tumor involvement in HD.

Adolescent↗
PubMed1980

Polyclonal antibody production in murine spleen cells induced by Staphylococcus.

Polyclonal plaque-forming cell (PFC) responses in murine spleen cells induced by Staphylococcus aureus and S. epidermidis were studied. Injection of Balb/c mice with S. aureus strain 248 beta H resulted in the generation of anti-trinitrophenyl (TNP) and anti-sheep red blood cell PFC in their spleens. Cultures of Balb/c mutant yielded many anti-TNP PFC. The larger the number of organisms that were added to the cultures, the better was the PFC response. Both living and killed organisms were capable of inducing the response, but an excess of living 248 beta H organisms in the cultures abrogated the response. All of the organisms (12 strains of S. aureus and 11 strains of S. epidermidis) freshly isolated from patients had the ability to induce the polyclonal PFC response in cell cultures. These organisms stimulated cultured C3H/HcJ mouse spleen cells, which were unresponsive to bacterial lipopolysaccharide (LPS). Cultured cells from the spleens of athymic mice also responded to these organisms, and the number of PFC in nu/nu cell cultures was always greater than in nu/+ cells prepared from a haired litter mate. Moreover, the responses of nu/nu spleen were lower than expected. These findings suggest that the polyclonal PFC response to staphylococci is thymus independent, but that the magnitude of the response is regulated by mature T cells. Cultures of macrophage-depleted spleen cells responded to the organisms to an extent similar to that of the control. The 248 beta H organisms were less capable of stimulating spleen cells of 2-week-old mice (i.e., early maturing B cells) than LPS. However, spleen cells from adult (7-week-old) and aged (9-month-old) mice responded well to both the organisms and LPS. Previous sensitization with the organisms in vivo did not affect any polyclonal responses of spleen cells in vitro to either the organisms or LPS. The role of staphylococcal protein A in the polyclonal PFC response to staphylococci is discussed.

Aging↗
PubMed1983

The amount of white pulp in the spleen; a morphometrical study done in methacrylate-embedded splenectomy specimens.

This report deals with a morphometrical study on 92 surgically removed human spleens, to investigate the composition of spleens which are considered to be normal, i.e. spleens which had ruptured in traffic accidents or which had been incidentally removed during abdominal operations. A comparison was made with 16 spleens with hypersequestration of platelets and to 11 with hyper-sequestration of erythrocytes. Methyl-methacrylate embedding was used because of the superiority of this technique over conventional paraffin embedding. Significant differences were found between both 'normal' groups as to the absolute and relative amount of white pulp as well as the perifollicular red pulp zone. Based also on the few morphometrical reported studies in the literature, spleens removed during abdominal surgery form the best control group. Traumatic rupture of the spleen in traffic accidents might specifically occur in spleens which already contained a stimulated lymphatic compartment. A probably non-specific increase of white pulp was found in splenomegaly of varied aetiology. An expected influence of age on weight and composition of the spleen was not found in our study. The spleen changes in weight and composition only up to 5 years of age. Significant involution at older age was not found in ours nor in other reported larger series.

Adolescent↗
PubMed1979

Morphological studies of the spleen in idiopathic portal hypertension (so-called Banti's syndrome without liver cirrhosis) using light microscopy, scanning electron microscopy and histometry.

Morphological changes in the spleens of patients with idiopathic portal hypertension (IPH) were studied and compared with the normal spleen. The study used (1) light microscopy with histometry, (2) scanning electron microscopy (SEM) of the splenic tissue with histometry and (3) SEM of the spleen vascular replica. Histometrical studies by light microscopy showed that the volume of red pulp of IPH was increased in a unit area and to a total of 12 times the normal in the whole spleen. The white pulp was scanty of lymphocytes and decreased in a unit area but it was increased in the whole spleen. SEM of the white pulp of IPH demonstrated many channels formed by reticulum cells and running parallel with each other along the central artery. This finding presumably corresponds to periarterial fibrosis in light microscopy. SEM histometry demonstrated that the venous sinuses of IPH were small but increased in number and occupied the same percentage area in a unit red pulp area as in the normal spleen. The Billroth cord of IPH was narrowed and occupied by thickened reticulum cells, which may cause increased pooling and destruction of blood cells in the enlarged spleen (hypersplenism). SEM of the tissue and vascular replica demonstrated open arterial termination in the Billroth cord in the spleen of IPH as well as in the normal spleen. Venous sinuses in the replica of IPH ran parallel with each other forming bundles with fewer intercommunications than normal.

Adult↗
PubMed1995

The role of capacitative Ca2+ influx in the alpha 1B-adrenoceptor-mediated contraction to phenylephrine of the rat spleen.

1. The mechanism of contraction to phenylephrine in the rat spleen (mediated via alpha 1B-adrenoceptors) has been studied in functional experiments. 2. The concentration-dependent contraction of the rat spleen to cumulative additions of phenylephrine (pD2 4.8 +/- 0.1) was not significantly reduced by the selective protein kinase C (PKC) inhibitor, calphostin C (10(-6)M) or potentiated by the DAG kinase inhibitor, R59022 (10(-6) M). 3. Contraction of the rat spleen in normal Krebs solution containing Ca2+ (2.5 mM) to a single concentration of phenylephrine (3 x 10(-4) M) produced a maximal response consisting of an initial phasic component and a more slowly developing tonic component. However in Ca(2+)-free Krebs solution (containing EGTA), phenylephrine (3 x 10(-4)M) produced only a phasic contraction which was reduced to 46 +/- 3% maximum response to phenylephrine in normal Krebs solution. 4. In some tissues after the contraction to phenylephrine (3 x 10(-4) M) in Ca(2+)-free Krebs solution (containing EGTA), the phenylephrine was washed out and the tissue was allowed to recover. After 2 h, upon addition of Ca2+ (2.5 mM) to the Krebs solution (EGTA now removed) a tonic contraction developed in the tissue (97 +/- 4% maximum response to phenylephrine). 5. Cyclopiazonic acid produced a tonic contraction of the rat spleen with a maximum effect at 10(-5) M (202 +/- 8% maximum response compared with that to phenylephrine). The contraction to CPA (10(-5) M) was reduced in Ca(2+)-free Krebs solution containing EGTA (30 +/- 4% of the maximum response to phenylephrine). One hour after the end of the contraction in Ca(2+)-free Krebs solution (EGTA now removed), upon addition of Ca2+ (2.5 mM) to the Krebs solution a tonic contraction developed in the tissue (263 +/- 12% maximum response to phenylephrine). 6 In Ca2+-free Krebs solution, after the spleen had been incubated with cyclopiazonic acid for 30 min,the subsequent contraction to phenylephrine (3 x 10-4 M) was reduced from 46+/-3% to 9+/-2%maximum response to phenylephrine.7 Cumulative contractions to phenylephrine and the contraction to cyclopiazonic acid (10-5 M) in the spleen were not significantly affected by nifedipine (10-6 M). The non-selective Ca2+channel blocker,SK&F 96365 (3 x 10-5 M) reduced the maximum response for the cumulative additions of phenylephrine to 35+/-1% and the contraction to CPA (10-5 M) from 202+/-8% to 108+/-8% maximum response to phenylephrine.8 The tyrosine kinase inhibitors genistein (3 x 10-5 M and tyrphostin 23 (10-4 M), reduced the maximum response to phenylephrine in the spleen to 51+/-4% and 44+/-5% respectively and the maximum contraction to cyclopiazonic acid (3 x 10-6 M) in the spleen from 132 +/- 6% to 82 +/-5% and 80 +/- 7% maximum response to phenylephrine respectively without affecting contractions to K+.9 In conclusion, these results are consistent with the contraction of the rat spleen to phenylephrine consisting of an initial phasic contraction due to release of intracellular Ca2+ and a larger tonic contraction due to capacitative Ca2+ influx through non-voltage-gated Ca2+ channels and which may involve a tyrosine kinase. This suggests that inositol triphosphate but not diacylglycerol is involved in the contraction.

Adrenergic alpha-1 Receptor Agonists↗
PubMed1995

Evidence for a functional alpha 1A- (alpha 1C-) adrenoceptor mediating contraction of the rat epididymal vas deferens and an alpha 1B-adrenoceptor mediating contraction of the rat spleen.

1. The alpha 1-adrenoceptor subtype mediating contraction of the rat epididymal vas deferens and rat spleen has been investigated by use of alpha 1-adrenoceptor antagonists that have shown selectivity between the different cloned receptor subtypes. 2. In the rat epididymal vas deferens the potency of noradrenaline and phenylephrine was increased in the presence of neuronal and extra-neuronal uptake blockers, cocaine and beta-oestradiol, but these did not alter that of methoxamine. The order of potency of the agonists in the presence or absence of uptake blockade was noradrenaline > phenylephrine > methoxamine. In the rat spleen the potency of these agonists was not altered in the presence of cocaine and beta-oestradiol, and their order of potency was the same as in the vas deferens. 3. The non subtype selective alpha 1-adrenoceptor antagonist prazosin (up to 1 x 10(-7) M) was found to antagonize contractions to noradrenaline in the vas deferens competitively (pA2 9.2), but only in a non competitive manner in the spleen. Contractions to phenylephrine in the spleen however were competitively antagonized by prazosin (up to 1 x 10(-7) M) with a pA2 of 9.2. This suggests that there is an alpha 1- and a non alpha 1-adrenoceptor response to noradrenaline in the rat spleen. 4. Pretreatment with chlorethylclonidine (10(-4) M for 30 min) did not alter the noradrenaline contractions in the vas deferens, but contractions to noradrenaline and phenylephrine in the spleen were shifted 30 and 300 fold to the right of the control curve, respectively. This suggests that only the contractions in the spleen were mediated by alpha 1B-adrenoceptors. 5. The noradrenaline contractions in the vas deferens were competitively antagonized by WB 4101 (pA29.6), 5-methyl-urapidil (pA2 8.7), phentolamine (pA2 8.3), benoxathian (pA2 9.4), spiperone (pA2 7.5),indoramin (pA2 8.4) and BMY 7378 (pA2 6.7), consistent with the affinities of these antagonists in binding studies on tissue alpha 1A-adrenoceptors. These values correlated best with their published affinities on the expressed alpha 1c-adrenoceptor clone and poorly with those at either the expressed alpha lb- or alpha 1d adrenoceptor clones. Therefore the classical alpha 1A-adrenoceptor appears to be the same as the expressed alpha lc-adrenoceptor clone.6. The phenylephrine contractions in the spleen were competitively antagonized by WB 4101 (pA2 8.1),5-methyl-urapidil (pA2 7.1), phentolamine (pA2 7.3), benoxathian (pA2 7.4), spiperone (pA2 7.9),indoramin (pA2 7.5) and BMY 7378 (pA2 7.4), consistent with the affinities of these antagonists in binding studies on tissue alB-adrenoceptors. The pA2 values correlated best with the published affinities of these compounds on the expressed alb-adrenoceptor clone and poorly with those at either the expressed alpha ld- or alpha lc-adrenoceptor clones. Therefore the alpha lB-adrenoceptor appears to be the same as the expressed alpha lb-adrenoceptor clone.7. The results provide pharmacological evidence that the alpha1-adrenoceptor mediating noradrenaline contractions in the epididymal portion of the rat vas deferens is the alpha 1A-(alpha lC) subtype and that contractions to phenylephrine in the rat spleen are mediated by the alpha 1B-subtype.

Adrenergic alpha-Agonists↗
PubMed1975

Effects of drugs and nerve stimulation on the spleen and arteries of two species of dogfish, Scyliorhinus canicula and Squalus acanthias.

The effects of drugs and nerve stimulation on the spleen of 2 species of dogfish have been examined by experiments with perfused spleens and isolated spleen and artery strips. Adrenaline, noradrenaline and phenylephrine, acting via alpha adrenoceptors, constrict the perfused spleen of both species, thereby releasing erythrocytes, and contract the isolated spleen and artery strips. Phenotolamine competitively antagonizes the excitatory effects of adrenergic agonists. The responses of the spleen to acetylcholine are very irregular, and a rapid desensitization makes evaluation of the mode of action of this drug difficult. In the artery strips acetylcholine produces a dose-dependent contraction. Fluorescent histochemistry reveals well developed adrenergic innervation of the arteries, and a few adrenergic terminals in the spleen. Stimulation of splenic nerves produces normally splenoconstriction in Squalus, which can be blocked by phentolamine but not by atropine. The nervous control of the Scyliorhinus spleen seems to be poor or lacking. It is concluded that the dogfish spleen, and maybe also the arteries, are to a large extent controlled by circulating catecholamines and (in Squalus) also by sympathetic adrenergic fibres.

Acetylcholine↗
PubMed1989

Ah receptor in spleen of rodent and primate species: detection by binding of 2,3,7,8-tetrachlorodibenzo-p-dioxin.

In many species systemic toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is manifested by a generalized wasting syndrome accompanied by a variety of specific organ changes including atrophy of the thymus and spleen. TCDD toxicity in most tissues is thought to be mediated by the Ah receptor. Although the spleen is a prime target for TCDD toxicity, the possible presence of Ah receptor in the spleen has not previously been investigated. Specific binding of [3H]TCDD to Ah receptor in spleen cytosols was assessed by velocity sedimentation on sucrose gradients. Ah receptor was detected in spleen cytosols from adult Rhesus monkeys (mean +/- SEM, 36 +/- 8 fmol/mg cytosol protein), fetal Rhesus monkeys (9 +/- 6), Sprague-Dawley rats (20 +/- 5), C57BL/6J mice (18 +/- 2), New Zealand white rabbits (19 +/- 2), and Hartley guinea pigs (15 +/- 2). Ah receptor was not detectable in spleen cytosol from genetically "nonresponsive" DBA/2J mice or from Golden Syrian hamsters, a species resistant to toxicity of TCDD. Molecular properties of Ah receptor from spleen were similar to those of the receptor from liver of the same species. The high Ah receptor content in spleen cytosols from those species that are most susceptible to TCDD toxicity is consistent with the view that the Ah receptor mediates TCDD toxicity in spleen as well as in other tissues.

Animals↗
PubMed2002

Fatty acid and triacylglycerol utilisation by perfused rat spleen: differential metabolic fate and the effect of endotoxin.

BACKGROUND/AIMS: The spleen uses significant amounts of non-esterified fatty acid (NEFA) and chylomicron (CM)-derived triacylglycerol (TAG); however, its utilisation of very-low-density lipoprotein triacylglycerol (VLDL-TAG), and the effect of endotoxin on lipid assimilation and fate are unknown. This study aims to define spleen utilisation of esterified and non-esterified fatty acid in quiescent and endotoxin-stimulated states. METHODS: Rat spleens were perfused for 2h with glucose (11mM) and either NEFA (oleate; 0.4mM fatty acid), rat CM (0.4mM TAG), or rat VLDL (0.4mM TAG). Lipid oxidation and tissue lipid deposition were measured. RESULTS: Total utilisation of oleate and VLDL-TAG were not significantly different. Utilisation of CM was 2-3 fold greater; however oxidation of CM-TAG (5.5nmols FA/min/gram spleen) was not significantly different from either NEFA or VLDL-TAG. More TAG (CM and VLDL) was deposited as tissue lipid compared to oxidation than NEFA; the pattern of intracellular lipid accumulation of TAG and NEFA also differed. Endotoxin (LPS) did not affect the proportion of lipid oxidised and accumulated or on TAG tissue lipid distribution but it increased the proportion of oleate recovered as tissue TAG and cholesterol ester. Perfusion with CM-TAG significantly decreased heparin-releasable lipoprotein lipase (LPL) activity compared with oleate or VLDL-perfused spleens. LPS increased LPL activity 5-fold in oleate-perfused spleens, but had no effect on VLDL-perfused spleens. CONCLUSION: VLDL-TAG is utilised by spleen to a similar extent as NEFA, but its pattern of metabolic fate resembles that of CM-TAG. Endotoxin affects the pattern of NEFA deposition in tissue lipids but has no significant effect on VLDL utilisation by the spleen.

Animals↗
PubMed1996

Morphometric and histopathologic analysis of lymphoid depletion in murine spleens following infection with Brucella abortus strains 2308 or RB51 or an htrA deletion mutant.

BALB/C mice were inoculated intraperitoneally with suspensions of Brucella abortus strains 2308 or RB51 or an htrA mutant. Spleens were examined on postinoculation day (PID) 2, 4, 7, 10, 15, 21, 30, and 60. Brucellae were cultured in high numbers from the spleens of mice infected with strains 2308 or htrA through PID 60; however, mice infected with strain RB51 cleared the infection between PID 30 and PID 60. Histopathologic changes in spleens from 2308-infected mice were characterized by marked accumulations of macrophages, which expanded marginal zones beginning as early as PID 7 and persisting through PID 60. Morphometric analysis showed a decrease in splenic white pulp in 2308-infected mice at PID 10, which correlated with the peak of bacterial infection. Although this decrease was significant (P < 0.05) when compared with values at the previous (PID 7) and the following (PID 15) time periods, it was not significantly different from white pulp values noted at PID 2 or PID 4 or the values for control spleens. Spleens from RB51-infected mice showed only mild to moderate accumulations of macrophages in marginal zone areas during the peak of RB51 infection (PID 7-10). Morphometric analysis of RB51-infected spleens showed a decrease in white pulp area, which coincided with peak bacterial numbers. However, this decrease was not significant (P > 0.05). Spleens from mice infected with the htrA mutant showed moderate to marked accumulations of macrophages in marginal zone areas, which persisted through PID 60. Multifocal necrosis in lymphoid follicles as early as PID 4 was seen in both htrA and 2308 infection. Morphometric analysis of htrA-infected spleens revealed no significant decrease in white pulp and no obvious correlation with bacterial numbers in the spleen. These results suggest that virulent B. abortus does not induce lymphoid depletion significantly below those values seen in noninfected mice; thus, the possible role of lymphoid depletion in the pathogenesis of brucellosis remains questionable.

Animals↗
PubMed2001

Investigation of human spleen dendritic cell phenotype and distribution reveals evidence of in vivo activation in a subset of organ donors.

Although the mouse spleen dendritic cell (DC) is perhaps the most intensively studied DC type, little has been published concerning its human equivalent. In this report, rare event flow cytometry and in situ immunofluorescence were used to study the surface phenotype and distribution of HLA-DR(+) CD3(-)14(-)16(-)19(-) human spleen DC. Spleens from organ donors with different clinical histories were used. Most (81% +/- 9%; n = 14) spleen DCs expressed high levels of the integrin CD11c. CD11c(+) DCs were distributed in 3 distinct regions-the peri-arteriolar T-cell zones, the B-cell zones, and the marginal zone, where they formed a ring of cells surrounding the white pulp, just inside a ring of CD14(+) red pulp macrophages, apparently more regularly organized than the previously described marginating DC population in the mouse spleen. The T-cell zones contained CD86(+) DCs, among which a subpopulation expressed CD83. These mature/activated CD86(+) DCs represented a minority (12% +/- 8%) of total spleen DCs in most organ donors: most spleen DCs are immature. In 3 of 18 (17%) donors, however, most (54%-81%) of spleen DCs were CD86(+), suggesting that in vivo DC activation had occurred. In one donor, a radical shift in DC distribution from the marginal zone to the T-cell zones was also observed. This activation of spleen DCs in vivo was reminiscent of the effects of experimental microbial product injection in mice, and it seemed to correlate with bacterial infection or multiple trauma. (Blood. 2001;97:3470-3477)

Adult↗
PubMed1983

Aging of natural and acquired immunity of mice. II. Decreased T cell responses to syngeneic tumor cells and parental-strain spleen cells.

Cytolytic T lymphocyte (CTL) functions were compared in mice between the ages of 2 and 30 months. The stimulator cells were H-2 allogeneic spleen or tumor cells, parental-strain spleen cells, or syngeneic tumor cells. Effector cells capable of lysing syngeneic tumor cells were shown to be T cells and not NK cells. The cell-mediated lympholysis (CML) responses by spleen cells of aged mice were near normal against H-2 allogeneic spleen or tumor cells but were defective against syngeneic tumor cells or parental-strain spleen cells. The defective syngeneic tumor CML response was observed at various responder:stimulator ratios and at various days of incubation. The defect was in the nonadherent, and not in the adherent, fraction of spleen cells. Suppressor cells were detected in spleens of 30 month, but not of 18 month old mice. Aged mice were more susceptible than young mice to small inocula of syngeneic C57BL EL-4 lymphoma cells. The immunogenicity of irradiated spleen cells of old mice had not changed for the F1 antiparent CML response. Splenic CML responses of young mice treated with 89Sr demonstrated a similar pattern, i.e., good responses to H-2 allogeneic stimulator cells but poor responses to syngeneic tumor cells or to parental-strain spleen cells. This loss of certain CTL functions influenced by marrow dependent cells can partially explain the increased susceptibility of old animals to tumors.

Age Factors↗