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Biomedical subjects

R Benner

Publications and source records attributed to R Benner.

At least 37 records · Page 2Linked to original sources
PubMed1995

Enhanced production of biologically active interleukin-1 alpha and interleukin-1 beta by psoriatic epidermal cells ex vivo: evidence of increased cytosolic interleukin-1 beta levels and facilitated interleukin-1 release.

The expression of interleukin (IL)-1 is altered in psoriatic lesions. However, little is known about the actual production of IL-1 alpha and IL-1 beta by psoriatic epidermal cells (EC). We monitored IL-1 in the extracellular, the membrane and the intracellular compartment of freshly isolated EC from untreated lesional psoriatic (PP) and normal healthy (NN) skin during non-stimulated short-term cultures, representing a psoriasis model ex vivo. Cytokines were measured using bioassays combined with neutralizing antibodies and enzyme-linked immunosorbent assay in parallel. PP EC released significantly increased amounts of biologically active IL-1 alpha and IL-1 beta in a ratio of 3:1, whereas NN EC only released IL-1 alpha. Also, the release of IL-6, but not of TNF-alpha, by PP EC was significantly increased. Membrane-associated IL-1 activity, analyzed using glutaraldehyde-fixed EC, was low and not unique to PP EC. The cytosol of PP EC contained significantly increased levels of immunoreactive IL-1 beta. Furthermore, PP EC displayed loss of membrane integrity, as determined by trypan blue exclusion and release of cytosolic lactate dehydrogenase. This facilitated release of intracellular IL-1. Depletion of CD45+ cells showed that intraepidermal leukocytes did not contribute to the production of IL-1. Our observations show that resident PP EC express enhanced IL-1 production ex vivo, which is due to an increased cytosolic IL-1 beta content and facilitated IL-1 release. This study provides the first evidence that PP EC can produce bioactive IL-1 beta.

Cells, Cultured↗
PubMed1995

Effects of cyclosporine on cytokines and cytokine receptors in psoriasis.

BACKGROUND: Oral cyclosporine is effective in the treatment of recalcitrant psoriasis. However, the precise mechanism(s) are not fully understood. A possible mode of action may be via down-modulation of proinflammatory cytokines that are increased in psoriatic lesions. OBJECTIVE: This study was designed to monitor the effects of cyclosporine treatment on the expression of cytokines, cytokine receptors, and other markers of inflammation in psoriatic skin. METHODS: Ten patients with recalcitrant psoriasis were treated with cyclosporine. The in vivo effects of cyclosporine on cytokines and their receptors were studied by the use of cryostat-cut sections and a panel of antibodies. The in vitro effects were studied with flow cytometry of epidermal cell suspensions prepared from psoriatic lesions and control skin. RESULTS: Clinical improvement was noted in all patients after 2 weeks of cyclosporine treatment. The expression of interleukin-1 beta, interleukin-8, CD25(IL-2R), CD36 and E-selectin were significantly decreased, whereas the number of tumor necrosis factor-receptor-positive epidermal cells was significantly increased in psoriatic lesions. CONCLUSION: Clinical improvement of psoriasis with cyclosporine treatment is accompanied by down modulation of proinflammatory epidermal cytokines and decreased dermal inflammation. Thus besides suppressing cytokine production by the inflammatory infiltrate, the beneficial effect of cyclosporine in psoriasis also depends on the inhibition of the epidermal cytokine network.

Administration, Oral↗
PubMed1995

Hyposensitization in nickel allergic contact dermatitis: clinical and immunologic monitoring.

BACKGROUND: In allergic contact dermatitis (ACD) previously sensitized T cells cause skin damage. If an ubiquitous allergen such as nickel is involved, no effective treatment is available. Down-regulation of this allergic response has been described after antigen presentation in the absence of adequate costimulatory signals. UV exposure can enhance such hyposensitization. OBJECTIVE: The aim of this study was to establish the capability of a hyposensitization procedure to induce antigen-specific tolerance. METHODS: Twenty-one patients with nickel ACD were randomly assigned to either a hyposensitized or control group. A schedule consisting of UVB treatment and subcutaneous nickel sulfate administration (hyposensitization) or UVB only (control) was applied. During the ensuing 2 years, several clinical and immunologic features were monitored. RESULTS: During UVB treatment we observed a significant clinical improvement in both groups that persisted in the hyposensitized group. Except for increased slope variances of specific lymphocyte proliferation in time, no clear changes were seen in the immunologic findings. CONCLUSION: Despite significant clinical improvement induced by UVB, hyposensitization did not induce significant changes in the immunologic findings in patients with nickel ACD.

Adult↗
PubMed1994

Prevention of lethal graft-versus-host disease in mice by monoclonal antibodies directed to T cells or their subsets. II. Differential effectiveness of IgG2a and IgG2b isotypes of anti-CD3 and anti-CD4 moAb.

The effects of rat anti-CD3 and anti-CD4 moAb, of the IgG2a as well as of the IgG2b subclass, on the development of lethal graft-versus-host disease (GVHD) in a fully allogeneic mouse strain combination were compared in vivo. After treatment with these moAb, mice recovered from an initial loss of body weight. Moreover, their survival significantly improved. A single dose of 200 micrograms moAb resulted in a complete and long-term survival, which was not the case after treatment with anti-CD4 IgG2a moAb. A dose of at least 1 mg anti-CD4 IgG2a was necessary to induce a tolerant state. Mice effectively treated were fully repopulated with donor-type cells. Flow cytometric analysis of the recipient spleen cells demonstrated that the moAb caused depletion, modulation or coating of T cells or a combination of these. The moAb with the highest depleting capacity appeared to be anti-CD4 IgG2b moAb. Anti-CD3 IgG2a as well as IgG2b treatment resulted in a strong modulation of CD3 surface proteins, which was found on all days examined. Modulation of CD4 surface antigens did not occur in the case of anti-CD4 IgG2a moAb treatment. Anti-CD4 IgG2b moAb treatment, on the other hand, not only caused some CD4 modulation, but also, quite unexpectedly, a significant modulation of the CD3 molecule. Coating was only observed after treatment with anti-CD4 IgG2a moAb and lasted at least 1 week.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Prevention of lethal graft-versus-host disease in mice by monoclonal antibodies directed against T cells or their subsets. I. Evidence for the induction of a state of tolerance based on suppression.

Lethal GVHD in the fully allogeneic BALB/c (donor)-(C57BL x CBA)F1 (recipient) mouse strain combination could be prevented by a single dose of IgG2b monoclonal antibodies (moAb) directed to T cells. The influence of the time of administration of this moAb after GVHD induction and the effect of anti-T cell subset moAb on the development of GVHD was investigated in this study. Moreover, the state of tolerance in the mice that had become long-term chimeras was examined. Anti-Thy-1 treatment of the recipients 1 day before, 2 h before or 1 day after reconstitution almost completely prevented lethal GVHD. A single dose of 100 micrograms of anti-Thy-1 was as effective as four daily doses of 25 micrograms each. Treatment with a single dose of 25 micrograms or with intervals of 4 days between doses of 25 micrograms was statistically significantly less effective. We injected the recipients with moAb directed to the CD4+ or CD8+ T cells subsets. Using a dose of 100 micrograms moAb, anti-CD4 treatment appeared to be less effective than anti-Thy-1 treatment whereas anti-CD8 treatment was not effective at all. A double dose of anti-CD4 was equally effective as anti-Thy-1 treatment. All mice that became long term survivors remained free of signs of GVHD and were > 99% repopulated with donor type cells. Injection of spleen cells from these BALB/c into (C57BL x CBA)F1 chimeric mice was used to reconstitute lethally irradiated BALB/c, BALB.K and (C57BL x CBA)F1 recipients. Lethal GVHD developed in the BALB.K and (C57BL x CBA)F1 recipients but not in the BALB/c recipients.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Improved survival from potentially lethal graft-vs.-host disease by donor pretreatment with a recipient-specific blood transfusion. II. Evidence for a principal role of the CD4+ T cell subset.

Pretreatment of prospective donors of hemopoietic cells with a single recipient-specific blood transfusion can significantly decrease the morbidity and mortality of potentially lethal graft-vs.-host disease (GVHD) in lethally irradiated, allogeneically reconstituted mice. In a previous report we described the requirements for induction of this blood transfusion effect. In the present study we addressed in particular the mechanism underlying this effect. The beneficial effect of blood transfusion appeared to be due to the white blood cell population in the transfused blood. X-irradiation (20 Gy) of the blood prior to transfusion did not abrogate the effect, which makes a veto cell mechanism unlikely. The blood transfusion effect in this model appeared to be mediated by the CD4+ T cell subset, since purified CD4+ spleen cells from transfused donors caused considerably less morbidity and mortality than naive CD4+ spleen cells. Apparently CD8+ cells were not involved, because their absence did not affect the beneficial effect. This observation was further confirmed by the finding that treatment of recipient mice that were reconstituted with spleen cells from transfused donors with anti-CD8 monoclonal antibody (mAb) did not abrogate the blood transfusion effect. Interestingly, the blood transfusion effect was enhanced by administration of anti-CD4 mAb to the recipients. The anti-CD4 mAb might impair the interaction between T cells and antigen-presenting cells, resulting in functional inactivation.

Animals↗
PubMed1993

Autoimmunity, hyporeactivity to T cell mitogens and lymphoproliferative disorders following neonatal induction of transplantation tolerance in mice.

We have reported that, in A/J (A) (H-2a) mice, a partial tolerance to C57BL/10ScSn (B10) (H-2b) skin allografts and a high incidence of lethal lymphoproliferative disorders (LPD) can be induced by the neonatal i.v. injection of 2 x 10(7) semiallogeneic (B10 x A)F1 spleen cells (SC) (Végh, P., Baranyi, L. and Jánossy, T., Cell. Immunol. 1990, 129: 56). In this study, we show that the incidence and mortality of LPD were continuously growing from 1 month of age until the end of the experiment at 1 year (64% and 36%, respectively). Based on histology, 27% of the diseased mice suffered from lymphoid malignancies. In the remaining cases (73%), reactive histopathological changes were seen in the spleen, lymph nodes (LN), liver and kidneys. The proportion of CD4+ T cells in the spleen and LN as well as that of splenic B cells decreased, while the percentages of mature and immature myeloid cells doubled. The total cell number of each (sub)population, however, was elevated in both lymphoid organs. The cells taking part in the lymphoproliferation were of host (A) and not of donor (F1) origin. Preceding the development of apparent LPD, the SC, LN cell and thymus cell suspensions of 1-month-old tolerized mice showed reduced in vitro proliferative responses to T cell and T cell-dependent B cell mitogens (Con A or PWM), while their reactivity to a T cell-independent B cell mitogen (lipopolysaccharide) was essentially unimpaired. This hyporeactivity seems to be functional, because neither histology nor immunophenotyping by flow cytometry revealed significant alterations in the spleen and thymus of such animals, apart from a slight reduction in the ratio of CD4+/CD8+ T cell subpopulations in the spleen. The in vivo T cell-mediated immune response of the tolerized mice was practically normal to third party CBA/Ca (H-2k) allografts. Antithymocyte autoantibodies (ATA) were detected in the sera of 76% of the tolerized mice at 1 month of age (i.e., even before the mass appearance of LPD). ATA as well as antinuclear Ab were present in 65% of the adult tolerized mice, independently of the presence of LPD. Taken together, in A mice neonatally injected with (B10 x A)F1 SC, a partial, specific allograft tolerance and a chronic host-vs.-graft disease-like syndrome developed. The latter is manifested in hyporeactivity to T cell mitogens, development of autoantibodies and, subsequently, in progressive LPD and lymphoid malignancies.

Animals↗
PubMed1993

MHC-specific graft-protective and delayed-type hypersensitivity (DTH) suppressive activity of a CD4+ CD8+, alpha beta T cell receptor (TCR) positive lymphoma isolated from a tolerant mouse.

Two lymphomas were found in, and isolated from A (H-2a) mice in which permanent transplantation tolerance was induced to CBA (H-2k) histocompatibility antigens by the neonatal injection of (CBAxA)F1 spleen cells. They proved to be of recipient origin and were transferable to syngeneic A mice, growing as disseminated lymphomas (L33 and L46) and killing the recipients rapidly. Analysis of the cell surface antigens disclosed that both lymphomas had an immature T cell phenotype [Thy-1+, CD5+, CD3low, TCR alpha beta low, CD4low, CD8high, heat-stable antigen (HSA) positive, and CD44-, MHC class II-, CD45R-, sIg-, Gr-1-, CD11b-]. Intraperitoneal (i.p.) injection of syngeneic A mice with viable L33 lymphoma cells resulted in a dose-dependent, significant prolongation of the mean survival times of "specific" CBA and MHC-identical B10.BR skin allografts as compared to the survival of appropriate grafts in non-lymphoma-bearing controls. The survival times of third party MHC-incompatible B10 (H-2b) and B10.D2 (H-2d) allografts were only slightly prolonged in A mice inoculated with L33 cells. The graft-protective effect was not abrogated if the proliferative capacity of the L33 cells was blocked by in vitro mitomycin C (MMC) pretreatment. Furthermore, the inoculation of L33 lymphoma into A mice significantly inhibited their DTH response to the sensitizing CBA histocompatibility antigens. In contrast, the L46 lymphoma had no effect on the survival of CBA allografts and the DTH reactivity. These data suggest that the CD4+CD8+TCR alpha beta + L33 T cell lymphoma originating from a neonatally tolerant mouse has a specific immunosuppressive effect on the in vivo reactivity of syngeneic mice to the tolerance-inducing (MHC class I) alloantigens.

Animals↗
PubMed1992

Improved survival from potentially lethal graft-vs.-host disease by donor pretreatment with a recipient-specific blood transfusion. I. Requirements for induction and specificity of the effect.

Pretreatment of prospective donors of hemopoietic cells with a single recipient-specific blood transfusion can significantly decrease the morbidity and mortality of graft-vs.-host disease (GVHD) in lethally irradiated, allogeneically reconstituted mice. This beneficial effect of donor pretreatment could be demonstrated in donor-recipient strain combinations that were H-2 + non-H-2, H-2, or only class II-disparate, but not in the class I-disparate C57BL-B6.C-H-2bm1 strain combination. The effect was proportional to the amount of recipient-strain blood used for transfusion. Donor transfusion with a single dose of 1 ml recipient-specific whole blood resulted in minimum GVHD, lower doses being less or not effective. The interval between donor pretreatment and the use of their hemopoietic cells for reconstitution appeared to be important. The best survival was found at an interval of 4 days. Multiple transfusion was not more effective than a single one. We compared the effectiveness of whole blood and irradiated spleen cells for donor pretreatment. Both protocols have been shown previously to suppress anti-recipient delayed-type hypersensitivity. It appeared that the blood transfusion protocol was superior to the spleen cell protocol. The beneficial effect appeared to be recipient specific, since a third-party blood transfusion did not improve GVHD. We found that the beneficial effect of donor blood transfusion was due to suppression of the anti-host immune response. The donor blood transfusion was able to induce bystander suppression to alloantigens that were not used for the induction of suppression, provided they were co-expressed with the specific alloantigens by the recipients. This also indicates that, although the induction of suppression is specific, the ultimate suppressive effect is non-specific.

Animals↗
PubMed1991

Prevention of lethal graft-vs.-host disease by a single low dose injection of anti-T cell monoclonal antibody to the allograft recipients.

We investigated the capacity of monoclonal antibody (mAb) treatment to prevent graft-vs.-host disease (GVHD) in lethally irradiated, allogeneically reconstituted mice, employing anti-T cell (subset) mAb and a fully allogeneic strain combination. In this strain combination, purified CD4+ cells were able to induce a lethal GVH reaction, whereas purified CD8+ cells were not. In the same strain combination, a single intraperitoneal injection of IgG2b anti-Thy-1 mAb, one day after reconstitution, caused a dose-dependent improvement of the survival. A single injection of a dose as low as 12.5 micrograms per mouse was already effective. Intravenous and intraperitoneal administration of the mAb appeared equally effective. For effective prevention of GVHD the treatment could be postponed until the 4th day after transplantation, but treatment delayed until day 6 was no longer effective. Treatment with IgG2b mAb specific for either helper or cytotoxic T cells also led to improvement of GVHD and survival, but was less effective than treatment with anti-Thy-1 mAb. Clinically, there was a difference in the effectiveness of anti-CD4 and anti-CD8 treatment, since symptoms of GVHD started earlier in the anti-CD8 treated group and the survival was better in the anti-CD4 treated group. These results press for prospective clinical studies employing anti-T cell mAb treatment early after allogeneic bone marrow transplantation, especially in HLA mismatched cases.

Animals↗
PubMed1991

Isolation and molecular characterization of the B cells producing the paraprotein in a case of benign monoclonal gammapathy in C57BL mice.

Benign monoclonal gammapathy (BMG) is defined as a benign monoclonal B cell proliferative disorder characterized by the presence of a persisting component of homogenous immunoglobulins (H-Ig) in the serum. A possible role of antigenic stimulation in the development of BMG has been suggested. From a C57BL mouse, a murine model for BMG, we have isolated clonally related B cells in order to investigate the occurrence of somatic mutations in the variable heavy chain (VH) region of the genes of H-Ig-producing B cell clones. Therefore, B cells were immortalized by hybridoma technology. The hybridomas were screened for resemblance of the serum H-Ig component by Wieme agar electrophoresis, followed by immunoblotting and isoelectrofocusing. Clonal relationship was investigated by Southern blot analysis using a JH probe. In this way we isolated five hybridomas producing an IgG2a, kappa that was identical to the original serum H-Ig component according to testing with anti-idiotypic antisera. mRNA sequencing of four hybridomas showed only one base pair difference in the VH genes. This particular gene belonged to the J558 VH gene family. When compared to the most closely related known VH sequence, three base pair differences were found. The almost complete absence of base pair differences in the VH genes of the four sequenced hybridomas, compared with an independently derived hybridoma, suggests that the same germ-line VH gene has been used and that somatic mutations were infrequent in our BMG clone.

Animals↗
PubMed1991

Hyperthyroid myopathy and the response to treatment.

Hyperthyroidism is accompanied by significant dysfunction of both proximal and distal skeletal muscles. The purpose of this study was to quantitate the degree of muscle weakness in newly diagnosed patients with Graves' disease and to assess the response to treatment. Ten patients were prospectively studied with objective measures of strength and endurance of proximal and distal muscles while hyperthyroid (stage I), after 2 weeks of propranolol (stage II), and about 6 months later when euthyroid (stage III). Propranolol treatment for 2 weeks resulted in a subjective decrease in weakness, which was accompanied by a statistically significant improvement in grip strength (P less than 0.01), shoulder strength (P less than 0.02), and grip endurance (P less than 0.01) but not shoulder endurance. Muscle function further improved and attained control levels when the patients were chemically and clinically euthyroid. In contrast, a control group subjected to the same muscle testing protocol before and after 1 week of propranolol treatment showed no improvement in grip, shoulder strength, or shoulder endurance but had decreased grip endurance (P less than 0.01) and increased subjective weakness. These results confirm that muscle weakness commonly is associated with hyperthyroidism and can be quantitatively profound. In contrast to the effects of beta-blockade in normal controls, propranolol partially improves muscle weakness in thyrotoxic patients. We conclude that thyroid hormone and catecholamines in concert mediate the muscle dysfunction of hyperthyroidism.

Adrenergic beta-Antagonists↗
PubMed1991

Suppression of graft-versus-host reactivity by a single host-specific blood transfusion to prospective donors of hemopoietic cells.

Delayed-type hypersensitivity responses against recipient's histocompatibility antigens can occur early in the course of a graft-versus-host reaction in lethally irradiated allogeneically reconstituted mice. This reactivity could be suppressed by a single host-specific blood transfusion to the prospective donors of allogeneic spleen cells. Maximum suppression was found when the blood transfusion was given 4 or 5 days before the mice were used to reconstitute lethally irradiated hosts. Whole blood and purified white blood cells were capable of inducing suppression, whereas purified red blood cells, plasma, and serum were not. Suppression was already detectable after administration of 1 microliters of whole blood and virtually complete at a dose of 1.0 ml. Irradiation of the blood reduced but did not abrogate its capacity to induce suppression. Purified B and purified T lymphocytes appeared equally effective in inducing suppression. Two helper T cells clones, a Th1 and a Th2 clone, were able to induce suppression as well. A high dose of recombinant IL-2, injected daily for 5 days after reconstitution, did not abrogate or reduce the suppression. Suppression could be induced by H-2 as well as non-H-2 alloantigens, separately or together. A pure H-2-incompatible transfusion was more effective in inducing suppression than a pure non-H-2-incompatible one. Suppression appeared to be a dominant phenomenon and was mediated by a Thy-1+, CD4+, CD8- spleen cell population. This T cell population had its origin in the transfused donor, which excludes the possible involvement of blood-derived "veto-cells."

Animals↗
PubMed1991

The autologous mixed epidermal cell-T lymphocyte reaction is elevated in psoriasis: a crucial role for epidermal HLA-DR+/CD1a- antigen-presenting cells.

The objective of this study was to determine whether epidermal cells (EC) from psoriasis lesions and uninvolved skin could stimulate autologous T lymphocytes in the in vitro autologous mixed epidermal cell-T lymphocyte reaction (autologous MECLR). The functional role of antigen-presenting cell (APC) subsets was concurrently determined in this reaction. Mononuclear cells and purified T lymphocytes from peripheral blood of psoriasis patients showed a clear proliferative response to autologous unpurified epidermal cells from involved as well as uninvolved skin. The autologous mixed leukocyte reaction (MLR) was not elevated in psoriasis patients. In healthy controls and contact allergy patients, T-lymphocyte proliferation was not observed either in the autologous MECLR or in the autologous MLR. The level of proliferation in the autologous MECLR from psoriasis patients correlated to the number of epidermal cells that were added. To exclude the possibility that the observed proliferation in the autologous MECLR in psoriasis was due to the presence of epidermal T lymphocytes that were being stimulated and expanded in vitro, the stimulator EC were gamma irradiated (30 Gy) in some experiments. Preincubation of EC with cyclosporin A (CsA) significantly inhibited the autologous MECLR. The CsA-induced inhibition could be neutralized by the addition of fresh untreated EC to these cultures. This indicated that one of the modes of action of CsA in resolving psoriasis is, as some investigators have already shown, via inhibition of epidermal accessory cell function. In the autologous MECLR, APC from psoriasis skin could initiate this reaction, whereas APC from peripheral blood could not. This occurred in an MHC class II restricted fashion. Depletion experiments showed that Langerhans cells (HLA-DR+/CD1a+) were not the principal stimulators of autologous T lymphocytes in the MECLR. These results indicated that mainly HLA-DR+/CD1a- epidermal cells from psoriasis patients could stimulate autologous peripheral blood T lymphocytes in an MHC class II-restricted fashion.

Adult↗