Synergy between TGF-beta and anti-IgM in growth inhibition of CD5+ B-cell lymphomas.
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Biomedical subjects
D W Scott
Publications and source records attributed to D W Scott.
Dermatologic disorders of Chinese Shar Peis: 58 cases (1981-1989).
A retrospective study on the skin diseases of Chinese Shar Peis was conducted over a 9-year period. Skin disease was found in 58 (49.2%) of the 118 dogs studied. Folliculitis was the most common clinical finding (43 of 58 dogs). In 6 dogs, there was no apparent reason for the folliculitis; however, it was secondary to allergic dermatitis, demodicosis, IgA deficiency, or hypothyroidism in the other dogs. Approximately 20% of the dogs had more than one of these disorders. Serum IgA concentration was measured in 7 dogs and was low in all 7.
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Evaluation of an allergy screening test for use in atopic dogs.
An in-office allergy screening kit was evaluated for its repeatability, sensitivity, and specificity in 21 atopic dogs. Results of this testing were compared with results of a full regionalized allergy test offered by the same manufacturer. Results of the screening kit were repeatable and had high specificity but poor sensitivity. The kit as presently marketed is of questionable value as a diagnostic aid for use in dogs with atopy.
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Cross-linking of surface IgM or IgD causes differential biological effects in spite of overlap in tyrosine (de)phosphorylation profile.
Although displaying similar amounts of surface IgM and IgD, ECH 408-1 cells only succumb to apoptosis after cross-linking of IgM (not IgD), suggesting that different signaling pathways couple to both receptors. Immunoprecipitation studies revealed the presence of several proteins selectively associated with IgM and IgD, thus ruling out that the lack of inhibitory signaling mediated by IgD might be due to membrane expression in the absence of associated proteins belonging to the B cell receptor complex. 32P metabolic labeling and immunoprecipitation studies demonstrated that IgM and IgD are associated with phosphoproteins of 32-33 kDa in an isotype-specific fashion. Kinetic analyses of tyrosine kinase activity showed that cross-linking of surface IgM or IgD resulted in the rapid (1-3 min) phosphorylation of several protein substrates on tyrosine residues, followed by a dephosphorylation step. Isotype-specific changes of the phosphorylation status specifically affected molecules in the 32-33 kDa range, i.e. IgM (not IgD) cross-linking affected a approximately 32-kDa protein, whereas IgD (not IgM) cross-linking induced phosphorylation of a protein exhibiting a slightly lower mobility (33 kDa). These results suggest that isotype-specific immunoglobulin-associated molecules could be involved in the second messenger cascade leading to different biological effects upon IgM and IgD cross-linking.
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Effect of priming with a thymus-independent antigen on susceptibility to B-cell tolerance.
The effects of priming on the susceptibility of B-cell subsets to tolerance induction have been tested in a model system in which anti-immunoglobulin (anti-Ig) has been employed as a surrogate for tolerogen. T-cell-depleted B cells were primed in vitro with fluorescein or trinitrophenylated Ficoll (a thymus-independent (TI) antigen) and then exposed overnight to anti-Ig to attempt to induce B-cell anergy. Primed cells were relatively resistant to this tolerance protocol and resistance was hapten specific. The dose response and kinetics suggested that this process was not due to receptor blockade or modulation, but was an active process. Moreover, this priming for resistance to tolerance was reproduced in vivo upon intraperitoneal treatment with haptenated Ficoll. Such in vivo priming for tolerance resistance was long-lasting and did not occur with a thymus-dependent priming protocol with fluoresceinated hemocyanin. These results are discussed in terms of TI priming to drive B cells into cycle and express novel functional and phenotypic properties.
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Prostaglandin E2 induces apoptosis in immature normal and malignant B lymphocytes.
The purpose of this research was to determine whether prostaglandin E2 (PGE2), a major product of macrophages which can kill certain murine B cell lymphomas, induces death by a necrotic mechanism or by an alternate pathway called apoptosis. CH31 is a phenotypically "immature" B cell lymphoma which resembles immature neonatal B cells in its susceptibility to killing by reagents which cross-link surface immunoglobulin (sIg). In the present study we first show that PGE2, but not the closely related prostanoid, PGF2 alpha, kills CH31 lymphoma cells. In contrast, CH12, a phenotypically "mature" lymphoma which is not negatively affected by sIg cross-linking, is not induced to die after exposure to PGE2. Agarose gel electrophoresis demonstrated that the DNA of PGE2-treated CH31, but not CH12 cells, is cleaved into characteristic 200 base pair oligonucleosomal fragments indicative of an apoptotic mechanism of death. However, a necrotic form of death, indicated by random DNA cleavage which produces a smear following electrophoresis, could be induced by treatment of CH12 or CH31 with anti-class II MHC antibodies and complement. The apoptotic mechanism of CH31 cell killing by PGE2 was confirmed using scanning electron microscopy which demonstrated the unique membrane blebbing and bubbling pathognomonic of this form of death. Finally, using a recently devised flow cytometric method to study apoptosis in heterogeneous cell populations, we compared the ability of anti-IgM, PGE2, or PGF2 alpha to induce apoptosis in B lymphocytes from neonatal or adult mice. Anti-IgM, and to a lesser extent PGE2, but not PGF2 alpha, induces apoptosis in a fraction of neonatal B cells. None of these treatments induced cell death in B lymphocytes from mature mice. Overall, these observations suggest that PGE-secreting cells such as macrophages, which inhabit the B cell microenvironments of lymphoid organs, may eliminate a subset of immature B lymphocytes and may be important in controlling the spread of PGE-sensitive malignant B lymphoma cells.
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Characterization of "modified-self"-induced specific antibody hyporesponsiveness to herpes simplex virus.
Pretreatment of mice iv with syngeneic spleen cells modified with soluble HSV envelope antigens induced an anti-HSV antibody hyporesponsiveness following challenge with infectious virus. The epitope density on the HSV-modified spleen cells was quantitated using a photon-counting spectrofluorimeter so that observed immunological results could be correlated with the HSV antigen dose on the splenocytes. The degree of anti-HSV antibody hyporesponsiveness was found to be related to the epitope density on the HSV-modified spleen cells, but not the number of modified cells used in the pretreatment over the 16-fold range tested. Anti-HSV antibody hyporesponsiveness was induced if 7, but not 3, days had elapsed between pretreatment and challenge. This antibody hyporesponsiveness could be adoptively transferred with T cells. Only mice that had induced an anti-HSV antibody hyporesponsiveness following pretreatment with HSV-modified splenocytes were able to survive an LD50 challenge with infectious virus.
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Can peritoneal B cells be rendered unresponsive?
Ly-1+ B cells have been reported to produce a number of autoantibodies, and to be involved in the selection and regulation of the conventional B cell repertoire. It is not known if these B cells, which are found in high numbers in the peritoneum of normal adult mice, themselves can be regulated. In this study, we evaluated the sensitivity of peritoneal B cells (PBCs) versus conventional splenic B cells to regulation in a model system for tolerance. Normal splenic (conventional) or PBCs (containing both CD5+ and CD5- 'sister' cells) were cultured overnight with either F(ab')2 or intact IgG anti-mouse Ig, washed, and then challenged with fluorescein(FL)-coupled to Brucella abortus (BA), trimethylammonium (TMA)-BA or lipopolysaccharide (LPS), and the IgM responses to the FL and TMA haptens measured. In contrast to spleen cells, which exhibited up to a 90% reduction in anti-FL responsiveness, pretreated PBCs were mostly resistant to this form of tolerance regardless of challenge. The anti-TMA response of PBCs, which reflects the skewed VH11 usage by peritoneal CD5 B cells, was also resistant to tolerance. However, splenic TMA-specific B cells appeared to be sensitive to unresponsiveness induced by anti-Ig. Signaling studies show that PBCs have a blunted initial Ca2+ response, suggesting that the consequence of anti-Ig crosslinking may be defective in these cells. Furthermore, phorbal myristate acetate and/or ionomycin treatment of both PB and splenic B cells led to hyporesponsiveness to LPS challenge. This suggests that PBCs may be defective in a signalling pathway, perhaps involving protein kinase C activation.(ABSTRACT TRUNCATED AT 250 WORDS)
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Direct immunofluorescence testing for immunoglobulin deposits in haired skin, nasal planum and footpads of woodchuck hepatitis virus-infected woodchucks with chronic hepatitis and multiple hepatocellular carcinomas.
The purpose of this study was to determine the frequency of immunoglobulin deposition in the haired skin, footpads, and nasal planums of 10 WHV-infected woodchucks with chronic hepatitis and hepatocellular carcinoma and compare these results with those reported in humans. Immunoglobulin deposition was detected in the skin samples of 3 of 10 woodchucks. Granular deposits were revealed in the superficial dermal blood vessels of the nasal planum, lateral thoracic skin, and footpads in 1 animal each. In 1 of these animals, (lateral thorax) immunoglobulin deposition was concurrently present at the basement membrane zone.
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Bacteria and yeast on the surface and within non-inflamed hair follicles of skin biopsies from cats with non-neoplastic dermatoses.
Coccoid bacteria and/or yeasts were found in the surface keratin or exudate or, rarely, the pilar canal of non-inflamed hair follicles upon light microscopic examination of skin biopsies from 57 of 338 cats (16.9%) with non-neoplastic skin disorders. The presence of these microorganisms did not appear to suggest a specific dermatosis, nor the existence of a clinically relevant infection in the majority of cases.
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Bacteria and yeast on the surface and within non-inflamed hair follicles of skin biopsies from dogs with non-neoplastic dermatoses.
Coccoid bacteria and/or yeasts were found in the surface keratin or exudate and/or in the pilar canal of non-inflamed hair follicles upon light microscopic examination of skin biopsies from 191 of 3,387 dogs (5.6%) with non-neoplastic skin disorders. The presence of surface cocci and/or yeast did not appear to suggest a specific dermatosis, nor the existence of a clinically relevant infection in the majority of cases. However, follicular cocci and/or yeast almost always indicated the presence of a clinically relevant infection.
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Microscopic anatomy of the skin of the woodchuck (Marmota monax): comparison of woodchuck hepatitis virus-infected and non-infected animals.
Thirty-three woodchucks were used in this study. Seventeen animals were healthy adults, not infected with woodchuck hepatitis virus (WHV); 10 were healthy adults infected with WHV; 4 were noninfected neonates; 2 were infected neonates. Within the 4 groups of woodchucks, no histologic differences were detected on the basis of sex or age. Neither were histologic findings different between infected and noninfected woodchucks of similar ages. The average thickness of skin (as measured from the skin surface to the inner limit of the dermis) from the general haired body area was 2394 microns. The skin was thickest on dorsal body areas, and gradually became thinner on ventral body and medial limb areas. The epidermis consisted of 4 layers: stratum basale, stratum spinosum, stratum granulosum, and stratum corneum. A stratum lucidum was present only in the epidermis of the footpads. There was no clear distinction between the superficial dermis and the deep dermis, except for the subtle differences in arrangement and size of collagen fibers. Elastic fibers were seen throughout the dermis, being more prominent in the superficial portion. Both compound and simple hair follicle arrangements were seen, with compound being more common. The arrectores pilorum muscles were largest in the skin over the dorsal body areas. Sebaceous glands were present either within the outer root sheath of hair follicles or in the dense connective tissue surrounding hair follicles. No apocrine sweat glands were found. However, there were abundant eccrine sweat glands in the subcutaneous fat of the footpads.
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Skin disorders of the laboratory woodchuck (Marmota monax): a retrospective study of 113 cases (1980-1990).
An 11-year retrospective study was conducted on the dermatoses occurring in 113 woodchucks from a colony at the College of Veterinary Medicine at Cornell University. Bacterial dermatitis was the most common dermatologic disorder, accounting for 70.2% of the cases. The highest incidence of bacterial dermatitis occurred in September/October prior to hibernation and in February/March during the breeding season. Other dermatoses observed during the study period included Taenia crassiceps infection, microfilarial dermatitis, telogen defluxion, various neoplastic and hyperplastic lesions, and various neonatal conditions associated with trauma and/or bacterial infection. No association was found between any of these dermatoses and the presence of woodchuck hepatitis virus infection.
Alopecia↗
Prevention of B cell clonal deletion and anergy by activated T cells and their lymphokines.
B cell tolerance is described as the absence of a measurable antibody forming response to an antigenic challenge. The establishment of antigen-specific tolerance requires, by definition, engagement of the B cell antigen-specific receptor. However, only in some circumstances does this engagement lead to tolerance, while in others it produces B cell activation and secretion of immunoglobulins. Several mechanisms occur naturally in vivo abrogating the expression of deleterious autoantibodies and contributing to the state of self-tolerance. In this review, we will examine different ways in which B cell tolerance can be broken, focusing on evidence showing that activated-T cells and/or their lymphokines can prevent B cell clonal deletion and thus have a potential role in the pathogenesis of autoimmune diseases. This approach is based on the well-known association of several lymphokines, such as IL-1, IL-2, IL-4, IL-5, and type I interferons, with autoimmune phenomena in vivo.
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Anti-immunoglobulin treatment of murine B-cell lymphomas induces active transforming growth factor beta but pRB hypophosphorylation is transforming growth factor beta independent.
Cross-linking of B-cell membrane immunoglobulin (Ig) receptors induces growth arrest at G1-S, leading to apoptosis and cell death in the immature lymphomas WEHI-231 and CH31, but not in the CH12 B-cell line. In this system, which has been used as a model for B-cell tolerance, we have established that these lymphomas produce active transforming growth factor beta (TGF-beta) when treated with anti-Ig and that their hierarchy of sensitivity to TGF-beta generally correlates with their growth inhibition by anti-Ig. TGF-beta, in turn, has been shown to interfere with the phosphorylation of the retinoblastoma gene product, pRB. Herein, we also demonstrate that in WEHI-231 B-lymphoma cells treated with anti-Ig for 24 h, the pRB protein is found to be predominantly in the underphosphorylated form, as previously reported for cells arrested by the exogenous addition of TGF-beta. However, neutralizing antibodies to TGF-beta failed to prevent growth inhibition by anti-Ig in WEHI-231 and CH31. When WEHI-231 lymphoma cells were selected for growth in TGF-beta, the majority of the TGF-beta-resistant clones remained sensitive to anti-Ig-mediated growth inhibition. In these clones, the retinoblastoma gene product was found to be in the underphosphorylated form after 24-h treatment with anti-Ig, but not with TGF-beta. These data show that anti-Ig treatment of murine B-cell lymphomas stimulates the production of active TGF-beta but that a TGF-beta-independent pathway may be responsible for the pRB underphosphorylation and cell cycle blockade.
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Failure of cyproheptadine hydrochloride as an antipruritic agent in allergic dogs: results of a double-blinded, placebo-controlled study.
Cyproheptadine hydrochloride was administered orally at 0.1 to 0.2 mg/kg/day to 16 dogs with allergic pruritus. No dog improved. Polyphagia was observed in 4 dogs (25%).
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Comparison of the clinical efficacy of two commercial fatty acid supplements (EfaVet and DVM Derm Caps), evening primrose oil, and cold water marine fish oil in the management of allergic pruritus in dogs: a double-blinded study.
Twenty dogs with atopy or idiopathic pruritus were treated in a double-blinded clinical trial with computer-randomized and computer-generated sequences of 4 fatty acid-containing products: evening primrose oil, cold water marine fish oil, DVM Derm Caps, and EfaVet. Each dog received each product for a 2-week period. Five of 20 dogs (25%) had a good-to-excellent reduction in their level of pruritus with at least 1 of the products: evening primrose oil (2 dogs), DVM Derm Caps (1), EfaVet (1), DVM Derm Caps and cold water marine fish oil (1). Only 1 dog experienced a side effect (loose stools). Clinical response to fatty acid supplements appeared to be quite individualized, and independent of age, breed, sex, weight, duration of disease, specific diagnosis, or number of positive intradermal test reactions.
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Nonsteroidal management of canine pruritus with amitriptyline.
Thirty-one dogs with nonlesional pruritus were treated with amitriptyline (1 mg/kg orally q12h) to determine its efficacy in the management of canine allergic pruritus. Seventeen dogs were known to be atopic, 8 were presumed to be atopic, and 6 had pruritus of undetermined etiology. Pruritus was virtually eliminated in 5 (16.1%) dogs, reduced by approximately 50% in another 5 (16.1%) dogs, and not changed in the remaining 21 dogs. Side effects were uncommon.
Amitriptyline↗