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Biomedical subjects

J R Wright

Publications and source records attributed to J R Wright.

At least 91 records · Page 5Linked to original sources
PubMed1998

Surfactant protein A inhibits T cell proliferation via its collagen-like tail and a 210-kDa receptor.

Investigation of possible mechanisms to describe the hyporesponsiveness of pulmonary leukocytes has led to the study of pulmonary surfactant and its constituents as immune suppressive agents. Pulmonary surfactant is a phospholipid-protein mixture that reduces surface tension in the lung and prevents collapse of the alveoli. The most abundant protein in this mixture is a hydrophilic molecule termed surfactant-associated protein A (SP-A). Previously, we showed that bovine (b) SP-A can inhibit human T lymphocyte proliferation and interleukin-2 production in vitro. Results presented in this investigation showed that different sources of human SP-A and bSP-A as well as recombinant rat SP-A inhibited human T lymphocyte proliferation in a dose-dependent manner. A structurally similar collagenous protein, C1q, did not block the in vitro inhibitory action of SP-A. The addition of large concentrations of mannan to SP-A-treated cultures also did not disrupt inhibition, suggesting that the effect is not mediated by the carbohydrate recognition domain of SP-A. Use of recombinant mutant SP-As revealed that a 36-amino acid Arg-Gly-Asp (RGD) motif-containing span of the collagen-like domain was responsible for the inhibition of T cell proliferation. A polyclonal antiserum directed against an SP-A receptor (SP-R210) completely blocked the inhibition of T cell proliferation by SP-A. These results emphasize a potential role for SP-A in dampening lymphocyte responses to exogenous stimuli. The data also provide further support for the concept that SP-A maintains a balance between the clearance of inhaled pathogens and protection against collateral immune-mediated damage.

Animals↗
PubMed1997

Long-term function of fish islet xenografts in mice by alginate encapsulation.

BACKGROUND: Large, anatomically discrete pancreatic islets, Brockmann bodies (BBs), exist in certain teleost fish. When transplanted under the renal capsules of streptozotocin-diabetic athymic nude mice, BB grafts produce uniform normoglycemia for 50 days and mammalian-like glucose tolerance profiles; however, these very discordant islets reject in 7-8 days when transplanted into euthymic BALB/c mice. METHODS: In the present study, BBs were mass harvested, minced into <1-mm tissue fragments, and encapsulated in alginate-based macrospheres (5 mm diameter) or noodles (0.5x3 cm). Nonencapsulated and encapsulated BB fragments were transplanted intraperitoneally into streptozotocin-diabetic (nonfasting blood glucose >400 mg/dl) nu/nu and BALB/c mice. Glucose levels were monitored at least 3 times a week. RESULTS: Encapsulated BB grafts uniformly survived >50 days (10/10) or >100 days (3/3) in nu/nu recipients. The mean graft survival time was 27+/-13 days in BALB/c recipients (n=7). Daily intraperitoneal administration of 2.5 mg/kg 15-deoxyspergualin, in combination with encapsulation, resulted in uniform long-term BB graft function in BALB/c recipients (n=5). Similarly, long-term function was achieved in four of six BALB/c recipients with daily intraperitoneal administration of 10 mg/kg cyclosporine (two grafts failed after 39 and 45 days). Nonencapsulated BB grafts transplanted intraperitoneally into BALB/c or nu/nu recipients functioned for <7 days; immunosuppression alone did not permit graft survival in BALB/c recipients. In all cases of graft survival of >50 days, grafts were surgically removed from the peritoneal cavity, and blood sugar levels returned to a diabetic state within a few days. Historical sections of grafts, stained with hematoxylin and eosin and immunoperoxidase for insulin, showed viable, well-granulated BB tissue. CONCLUSIONS: This study demonstrates that tilapia BBs are suitable for encapsulation and that encapsulated BBs can be made to function long term in diabetic mice.

Alginates↗
PubMed1997

Functional comparison of mouse, rat, and fish islet grafts transplanted into diabetic nude mice.

Equal volumes of teleost fish (tilapia), Lewis rat, or CD-1 mouse islets were transplanted under the kidney capsules of streptozotocin-diabetic athymic nude mice. Nonfasting blood glucose levels were monitored in recipient mice over a period of 30 days. Mean nonfasting blood glucose levels in recipients of tilapia (n = 7), rat (n = 8), and murine (n = 8) islets were 78.8, 77.0, and 115 mg/dl, respectively. Mean blood glucose levels were significantly higher in recipients of murine islets than in recipients of fish and rat islets. After Day 30, intraperitoneal glucose tolerance tests were performed on recipient mice. Mean fasted blood glucose levels in mouse, rat, and fish islet recipients were 113.3, 89.8, and 72.7 mg/dl, respectively. All three groups of recipient mice had similar glucose tolerance profiles with mean glucose disappearance rates (K values) between 4.3 and 5.7. Tilapia islet grafts resulted in a significantly lower baseline for blood glucose values than either rat or mouse islet grafts.

Animals↗
PubMed1997

Immunophenotyping of insulitis in control and essential fatty acid deficient mice treated with multiple low-dose streptozotocin.

Multiple injections of low-dose streptozotocin induce lymphocytic insulitis and autoimmune diabetes in male CD-1 mice. Prior to the onset of insulitis, macrophages infiltrate the islets (single cell insulitis) and presumably help initiate the lymphocytic response directed at streptozotocin-induced neoantigens on islet beta cells. Essential fatty acid deficiency ameliorates the lymphocytic insulitis and prevents diabetes in this model. We hypothesize that essential fatty acid deficiency, which perturbs eicosanoid pathways and blocks the production of inflammatory mediators such as leukotriene B4, might prevent or diminish the single cell insulitis and, thus, abrogate the lymphocytic response. The purpose of the study was to determine whether essential fatty acid deficiency causes any differences in the immunophenotype or the time course of single cell insulitis or insulitis after low-dose streptozotocin. Three to five essential fatty acid deficient and 3-5 control mice were treated with low-dose streptozotocin and killed on days 0, 3, 5, 8, 10, 12 and 15. Frozen sections of the pancreata were stained using an immunoperoxidase method with antibodies against mouse macrophages, CD4T-lymphocytes and CD8 T-lymphocytes. Sections were assessed for the presence and severity of single cell insulitis and insulitis. Based on cell counts in the most severely involved islet from each pancreas, there was no difference in the single cell insulitis in control and essential fatty acid deficient mice. Islets from control pancreata had a higher mean grade of lymphocytic insulitis. These findings suggest that autoimmune diabetes following low-dose streptozotocin in control mice is the result of both lymphocytic and histiocytic infiltrates with subsequent beta-cell destruction. Our results do not support the hypothesis that the protective effect of essential fatty acid deficiency is due to diminished influx of macrophages into the islets. It is, however, possible that essential fatty acid deficiency deleteriously affects macrophage function and, thus, blunts the lymphocytic response.

Animals↗
PubMed1997

Neuronal-associated tumor necrosis factor (TNF alpha): its role in noradrenergic functioning and modification of its expression following antidepressant drug administration.

Tumor necrosis factor-alpha (TNF alpha) and the alpha 2-adrenergic agonist clonidine regulate norepinephrine (NE) release from noradrenergic nerve terminals in the central nervous system (CNS). In the present study, superfusion and electrical field stimulation were applied to a series of rat hippocampal brain slices in order to investigate the regulation of [3H]-NE release. NE release had been previously determined to be decreased by TNF alpha in a concentration-dependent manner, an effect which was potentiated by the alpha 2-adrenergic antagonist idazoxan. Presently, we demonstrate that similar to alpha 2-adrenergic activation, TNF alpha regulation of NE release in a region of the brain rich in noradrenergic nerve terminals, is dependent upon the frequency of electrical stimulation applied to the hippocampal slice. Furthermore, immunoperoxidase staining has verified our previous findings of constitutive TNF alpha protein in the rat brain. Staining for TNF alpha appears to be largely localized to neurons and neuronal processes, further substantiating the proposal that TNF alpha is either synthesized de novo or is accumulated in and released by neurons. After administration of the tricyclic antidepressant desipramine, tissue sections obtained from the rat hippocampus and locus coeruleus are devoid of neuronal-associated TNF alpha immunoreactivity. TNF alpha localization in neurons and its modification of NE release comparable to alpha 2-adrenergic receptor activation, explains a functional role for the cytokine as a neuromodulator in the CNS.

Animals↗
PubMed1997

Immunomodulatory functions of surfactant.

The possibility that the lipoprotein complex of lung surfactant functions in pulmonary host defense as well as lowering surface tension at the air-liquid interface has been the subject of renewed interest in light of the finding that surfactant proteins A and D (SP-A and SP-D) are members of a family of proteins known as collectins. The collectins, so named because they have in common an NH2-terminal collagen-like domain and a COOH-terminal lectin (carbohydrate binding) domain, are found in both lung and serum and participate in "innate" immunity, acting before induction of an antibody-mediated response. In vitro, many of the collectins stimulate phagocytosis, chemotaxis, and production of reactive oxygen and regulate cytokine release by immune cells. It has been known for several years that surfactant lipids suppress a variety of immune cell functions, most notably lymphocyte proliferation, which, conversely, is augmented by SP-A. Thus surfactant lipids and proteins may be counterregulatory, and changes in lipid-to-protein ratios may be important in regulating the immune status of the lung. That these ratios change in disease states is clear, but it is not known whether the alterations are a cause or an effect. Important future studies with mice in which the SP-A and SP-D genes have been ablated will help clarify the role of surfactant in immune function.

Animals↗
PubMed1997

Surfactant protein A (SP-A) mediates attachment of Mycobacterium tuberculosis to murine alveolar macrophages.

Attachment of Mycobacterium tuberculosis organisms to alveolar macrophages (AMs) is an essential early event in primary pulmonary tuberculosis. Surfactant protein A (SP-A) is a nonimmune opsonin present in the alveolar spaces that binds carbohydrate residues such as mannose. It was hypothesized that SP-A attaches to M. tuberculosis and serves as a ligand between M. tuberculosis and AMs. [125I]SP-A was found to bind to M. tuberculosis in a time- and [Ca2+]-dependent manner with a Kd of 1.9 x 10(-9) M and an apparent number of 6.3 x 10(2) SP-A binding sites/organism. Further, deglycosylated SP-A had minimal binding to M. tuberculosis, indicating that sugar moieties are important in this interaction. SP-A specifically binds to a 60-kD cell-wall protein from M. tuberculosis. SP-A-mediated attachment of 51Cr-labeled M. tuberculosis organisms to AMs is dependent on time, SP-A concentration, and Ca2+. M. tuberculosis attachment to murine AMs in the absence of SP-A was 12.8 +/- 0.9%; however, in the presence of 5 microg/ml SP-A the attachment increased to 38.6 +/- 2.9% (P < 0.001). SP-A-mediated attachment was significantly decreased from 38.6 +/- 2.9% to 18.7 +/- 3.3% (P < 0.05) in the presence of antihuman SP-A antibodies. When the attachment assay was repeated in the presence of alpha-methylene-D-mannosepyranosidase (mannosyl-BSA) and type V collagen, SP-A-mediated attachment decreased from 38.6 +/- 2.9% to 16.6 +/- 1.5% (P < 0.001) and 19.1 +/- 1.4% (P < 0.05), respectively. Further, deglycosylated SP-A had only a minimal effect on M. tuberculosis attachment to AMs. These data indicate that SP-A can mediate M. tuberculosis attachment to AMs, and suggest possible underlying mechanisms for this.

Animals↗
PubMed1997

Estimation of (co)variance components for Jersey type traits using a repeatability model.

(Co)variance components for final score and 15 linear types traits of Jersey cows were estimated by multitrait REML using multiple diagonalization and a repeatability model with 34,999 records of 22,354 cows. Multiple diagonalization gave relative off-diagonals (ratio of squared off-diagonals to the product of diagonals) of < 0.1%. Heritabilities and repeatabilities, respectively, were estimated as 0.29 and 0.48 for final score, 0.40 and 0.57 for stature, 0.26 and 0.39 for strength, 0.28 and 0.43 for dairy form, 0.13 and 0.25 for foot angle, 0.13 and 0.25 for rear legs (side view), 0.27 and 0.41 for body depth, 0.31 and 0.52 for rump angle, 0.22 and 0.33 for thurl width, 0.22 and 0.36 for fore under attachment, 0.28 and 0.46 for rear udder height, 0.26 and 0.42 for rear udder width, 0.32 and 0.48 for udder depth, 0.20 and 0.36 for udder cleft, 0.29 and 0.46 for front teat placement, and 0.31 and 0.48 for teat length. Estimates of heritability generally were higher, and estimates of repeatability were lower, than values used previously for USDA genetic evaluations, which were based on data from the 1970s and early 1980s. Final score was highly correlated both genetically and phenotypically with dairy form and rear udder traits. These estimates of heritabilities and (co)variance components are necessary for multitrait genetic evaluation of linear type traits of US Jerseys.

Animals↗
PubMed1997

Application of canonical transformation with missing values to multitrait evaluation of Jersey type.

A multitrait animal model was used to calculate predicted transmitting ability and reliabilities for final score and 15 linear type traits of 225,632 US Jersey cows. Records were adjusted for age and stage of lactation before analysis. The model contained effects for interactions of herd and date scored; year scored, parity, and age; and herd and sire; effects of permanent environment and additive genetics were also included. Of the 381,511 records included, some observations were missing for final score (8%), body depth (43%), and teat length (33%). The evaluation system used a canonical transformation, included several random effects, and estimated missing values with each iteration. Inbreeding was considered in the computations. Convergence was achieved in approximately 50 rounds of iteration. Correlations between animal and sire model predicted transmitting ability ranged from 0.56 to 0.95 and generally were higher for bulls than for cows and for more recent birth years. Genetic trend was strongly positive for dairy form, final score, and rear udder traits (height and width) and negative for udder depth. For other traits, genetic trend was small. This methodology should improve the accuracy of genetic evaluations for type traits of US Jerseys.

Aging↗
PubMed1997

Immunophenotyping fish-to-mouse islet xenograft rejection: a time course study.

UNLABELLED: Tilapia islets, Brockmann bodies (BBs), transplanted under the kidney capsule (KC) of diabetic nude mice provide long-term normoglycemia, but, when transplanted into euthymic mice, reject in about one week. OBJECTIVES: The present study characterizes the cellular infiltrates at several time points during the xenograft rejection process. METHODS: Tilapia BBs were harvested, fragmented, cultured overnight, and then transplanted under the KC of streptozotocin-diabetic Balb/c mice. Glucose levels were measured daily until the mice were killed at 1 (n = 2), 2 (n = 2), 3 (n = 3), and 5 days (n = 3) post transplantation and at the time of BB graft rejection (n = 6). Serial frozen sections of graft-bearing kidneys were stained for murine macrophages (MOMA-2, F4/80, M170), CD4+ (L3T4) T-cells (YTS 191.1), and CD8+ (Ly-2) T-cells (YTS 169.4) by indirect immunoperoxidase; the presence of granulocytes and plasma cells was assessed with H&E stained sections. RESULTS: At 1 day, the grafts have undergone some central necrosis with macrophage infiltration. By 2 days, these changes are very well-developed and granulocytes, almost exclusively eosinophils, begin to surround the graft. At 3 days, rare CD4+ and CD8+ T-cells are seen at the graft kidney interface. Macrophages massively infiltrate the necrotic foci and pepper the graft. At 5 days and at rejection, macrophages and eosinophils predominated in the center of rejecting grafts while CD8+ T-cells and CD4+ T-cells were present at the periphery. Plasma cells were rare. CONCLUSION: We conclude that cell-mediated processes and eosinophils play roles in the rejection of cellular xenografts across this very wide phylogenetic barrier.

Animals↗
PubMed1997

Tilapia Brockmann Bodies: an inexpensive, simple model for discordant islet xenotransplantation.

Brockmann bodies (BBs), large anatomically discrete islet organs found in some teleost fish, are much more easily harvested than pancreatic islets from mammalian donor sources. Tilapia islets, when transplanted into streptozotocin-diabetic athymic nude mice, will produce long-term normoglycemia and mammalian-like glucose tolerance profiles. Our laboratory has used tilapia BBs as an inexpensive model for studying islet xenograft rejection between discordant species. When transplanted into immunocompetent diabetic mice, tilapia BBs reject in roughly 7-8 days. Results to date suggest that tilapia islets are very immunogenic and that encapsulation is necessary to achieve long-term function in euthymic recipients. Continuous, high-dose immunosuppression using 15-DSG is also effective but causes lethal bone marrow suppression. Less aggressive immunosuppression regimens have achieved only modest prolongation of mean graft survival time. Thus far, immunomodulation techniques and transplantation into immune-privileged sites have been ineffective at prolonging graft survival. Tilapia islets currently represent an excellent, inexpensive donor source for discordant islet xenotransplantation studies. In the not distant future, encapsulated islets harvested from transgenic tilapia bearing humanized tilapia insulin genes may also play a role in establishing clinical islet xenotransplantation as a useful treatment modality for type I diabetes mellitus.

Animals↗
PubMed1996

A new abnormality of human vision provides evidence of interactions between cortical mechanisms sensitive to movement and those sensitive to colour.

We present the results of a psychophysical study on a human observer, MW, which describe his abnormal visual responses to moving stimuli. It has been shown previously that this subject has normal vision for stationary, achromatic patterns, but responds highly abnormally to saturated chromatic, and especially red stimuli. We now report that like chromatic stimuli, moving black and white patterns elicit an inhibitory response which extends beyond the visual field area covered by the moving stimulus itself, and suppresses detection of stationary, achromatic patterns. Although both chromatic and moving stimuli generate similar percepts in association with their inhibitory activities, these latter differ in several respects, and we conclude that they have different neural origins. We show that in addition to their separate inhibitory actions on detection of achromatic patterns, movement and colour exert mutually inhibitory effects. Movement is markedly effective in limiting the inhibitory spread associated with colour, regardless of the positions in the visual field of the moving and coloured stimuli. Such spatially diffuse activity is characteristic of higher visual processing in pre-occipital cortical visual areas.

Color Perception↗
PubMed1996

Expression of C-reactive protein by alveolar macrophages.

C-reactive protein (CRP) is well characterized as one of the serum acute phase proteins, the levels of which increase dramatically after infection. CRP has been shown to be involved in multiple immunoregulatory functions. For example, it activates the classical complement cascade, opsonizes bacteria for phagocytosis, and stimulates phagocytic cells. Although CRP is predominantly produced and secreted by hepatocytes, other cells including subsets of lymphocytes, Kupffer cells, and blood monocytes have been shown to synthesize this protein as well. We hypothesized that CRP may be produced in the lung, and therefore it could function directly in pulmonary host defense. Western blot analysis showed that CRP was present in the lung tissue, lung lavage, and alveolar macrophages. This result was further confirmed by immunohistochemical staining of lung sections that showed the localization of CRP in alveolar macrophages. The CRP mRNA was detected subsequently by reverse-transcriptase PCR (RT-PCR), and a single amplified product was obtained from alveolar macrophages as well as from whole lung tissue. Both were the same size as the amplified product obtained from liver mRNA. Furthermore, in situ hybridization with CRP riboprobe demonstrated specific staining of alveolar macrophages both in lung sections and isolated cells. In addition, in situ hybridization showed that CRP mRNA levels in isolated alveolar macrophages were up-regulated by in vitro LPS stimulation. In summary, these results indicate that CRP is produced by alveolar macrophages, and suggest that CRP may be involved in the pulmonary immune response.

Adjuvants, Immunologic↗
PubMed1996

Orientation discrimination is impaired in the absence of the striate cortical contribution to human vision.

We have examined visual discrimination of orientation for bars and edges presented to the 'blind' hemifield of a patient, GY, who has an extensive lesion involving the left striate and prestriate cortex. The patient's residual vision in response to transient light stimulation of his 'blind' hemifield has been well characterized, and it provides discrimination on the basis of differences in target velocity, flicker frequency or colour. We now show that using his residual vision, GY can identify accurately the orientation of a flickering bar, although his performance is sub-normal for bars shorter than 10 deg. He is, however, unable to identify the orientation of a one-dimensional grating presented within a circular aperture, and is unable to detect a grating structure formed by equiluminant coloured bars or by alternating, equiluminant flickering and steady bars. We also show that he has poor orientation discrimination for edges formed by colour contrast, by contrast between moving stimuli or by flicker contrast. We conclude that in the absence of the striate cortical input, the residual mechanisms which provide discriminations for colour, flicker or movement are not well organized for the detection and discrimination of stimulus orientation. We discuss the physiological mechanisms responsible for the various aspects of GY's residual vision.

Adult↗
PubMed1996

Surfactant protein A stimulates phagocytosis of specific pulmonary pathogens by alveolar macrophages.

Surfactant protein A (SP-A) regulates alveolar macrophage function and has been implicated in the mediation of pulmonary host defense. Our goals were to characterize the interaction of SP-A with various pulmonary pathogens, to investigate the mechanism of SP-A-mediated phagocytosis using an assay that distinguishes bound from internalized bacteria by quenching the fluorescence of extracellular bacteria, and to examine further the interactions of SP-A and the structurally homologous protein complement component 1q (C1q) with alveolar macrophages and peripheral blood monocytes. We found that SP-A binds to and increases the phagocytosis of Haemophilus influenzae, Streptococcus pneumoniae, and Group A Streptococcus; SP-A aggregates only H. influenzae. SP-A neither binds to, aggregates, nor stimulates the phagocytosis of Pseudomonas aeruginosa. We have also found that bronchoalveolar lavage stimulates phagocytosis and that this stimulation is reduced by an anti-SP-A antibody. While the enhancement of phagocytosis by SP-A is inhibited in blood monocytes adhered to C1q-coated surfaces, which presumably clusters the C1q receptor on the basal surface of the cell, alveolar macrophages on C1q-coated slides show no significant change in their response to SP-A. In summary, SP-A stimulates the phagocytosis by alveolar macrophages of specific pulmonary pathogens to which it binds, but aggregation is not required for the effect. Additionally, the role of the C1q receptor in the response to SP-A may differ between monocytes and alveolar macrophages.

Animals↗