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S Thierfelder

Publications and source records attributed to S Thierfelder.

At least 37 records · Page 2Linked to original sources
PubMed1996

[Increased possibility for HIV-associated retinal microangiopathy syndrome in patients with concomitant hepatitis C infection].

BACKGROUND: The etiology of HIV-related retinal microangiopathy syndrome is yet unknown. Several authors postulate direct endothelial-cell infection, an immunocomplex vasculitis caused by HIV-related hypergammaglobulinemia or an increased serum concentration of endothelin as its origin. PATIENTS: 118 patients infected by HIV-1 have been examined (CDC I: 1; CDC II: 42; CDC III: 7; CDC IV: 68). 49 out of them were also infected by hepatitis-C-virus (CDC I: 0; CDC II: 16; CDC III: 4; CDC IV: 29). RESULTS: 26 out of 49 patients with hepatitis-C-co-infection showed HIV-related retinal microangiopathy syndrome (CDC I: 0/0; CDC II: 8/16; CDC III: 2/4; CDC IV: 16/29). In 69 patients without hepatitis-C-infection, HIV-related retinal microangiopathy syndrome was found five times (CDC I: 0/1; CDC II: 2/26; CDC III: 0/3; CDC IV: 3/39). CONCLUSION: Co-infection with hepatitis-C-virus is supposed to enhance the development of retinal microangiopathy syndrome in patients infected by HIV-1.

AIDS-Related Opportunistic Infections↗
PubMed1996

[Magnesium seeding in therapy of pediatric hemangioma of the temporal region, lower eyelid and orbit].

BACKGROUND: Magnesium seeding of haemangiomas is a form of treatment already successfully used in 1900. PATIENT: We report about a male infant with a haemangioma of the left temporal region, underlid and orbit. Maximum depth at the time of indication for magnesium seeding was 28 mm with an intraorbital extension of 7 mm. COURSE OF THERAPY: Magnesium seeding of the haemangioma first lead to a standstill and within 8 weeks to a significant remission. After this period, maximum depth was 6.7 mm without any intraorbital extension. CONCLUSION: Magnesium seeding is a hopeful and low-risked alternative in the therapy of infantile haemangiomas.

Eyelid Neoplasms↗
PubMed1995

Preferential species-restricted heavy/light chain pairing in rat/mouse quadromas. Implications for a single-step purification of bispecific antibodies.

Conventional mouse/mouse or rat/rat hybrid-hybridoma supernatants contain up to 10 different IgG molecules consisting of various combinations of heavy and light chains. Hence, the yield of functional bispecific Ab is low, and purification is often complicated, hampering a general preclinical evaluation of, e.g., bispecific Ab-mediated tumor immunotherapy in animal models. In experiments to overcome this drawback we found that fusion of rat with mouse hybridomas opens the possibility of large scale production of bispecific Ab due to the increased incidence of correctly paired Ab and facilitated purification. In essence, rat/mouse quadroma-derived bispecific Ab have the following advantages: 1) enrichment of functional bispecific Ab because of preferential species-restricted heavy/light chain pairing (observed in four of four rat-mouse quadromas) in contrast to the random pairing in conventional mouse/mouse or rat/rat quadromas, and 2) a possible one-step purification of the quadroma supernatant with protein A. This simple chromatography step does not bind unwanted variants with parental rat/rat heavy chain configuration, and the desired rat/mouse bispecific Ab are retained, which can then easily be separated from parental mouse Ab by sequential pH elution.

Animals↗
PubMed1995

Immunosuppression by Fc region-mismatched anti-T cell antibody treatment.

Formation of anti-antibodies (anti-Ab) is known to counteract immunotherapy with anti-T cell antibodies. Our previously described immunological approach prevented anti-Ab with the consequence of prolonged survival of fully mismatched skin grafts in C57BL/6 mice. These mice were treated with a single priming injection of a monoclonal anti-T cell Ab followed by repeated injections of anti-T cell mAb differing in species origin from the priming mAb. We now show prolonged tolerance to discordant xenogeneic, to bispecific, and even to polyclonal Ab, and demonstrate that the underlying immunosuppressive principle is due to a difference in heavy chain constant region between first and second antibodies, independent of whether or not they share the same idiotype. To examine this phenomenon, a panel of mAb was generated which share the same mouse anti-Thy-1.2 idiotype, but carry a human IgG1(T23), IgG3(T212C8), or mouse IgG2a(MmT1) constant heavy chain region. We found that sequential injection of MmT1 and T23 according to the above treatment schedule induced huIgG1 isotype-specific tolerance to T23, which was similar to that seen when using a primary mAb (MmT5) that was, instead, fully mismatched with T23 in both idiotype and constant region. Thus, differences of idiotype between primary and booster Ab were inconsequential for their ability to inhibit anti-Ab formation. This novel form of induced specific tolerance to anti-T cell Ig survived graft rejection and was still evident 230 days after termination of the T cell depletion protocol. Taken together, these results demonstrate that rechallenge with Fc region-mismatched Ab opens an immunological window that allows for induction of tolerance to immunogenic anti-T cell Ab and prolonged immunosuppression.

Animals↗
PubMed1995

[Measuring retinal nerve fiber density with laser polarimetry in patients with AIDS in comparison with health probands with reference to computer perimetry findings. A pilot study using the nerve fiber analyzer].

BACKGROUND: Several authors postulated a retinal nerve-fiber loss in HIV-infection because of functional alterations (reduced colour sensitivity, alterations in perimetry). This hypothesis has been reevaluated for the first time by means of direct in-vivo measurement of the retinal nerve-fiber-layer thickness by laser polarimetry using the Nerve-Fiber-Analyzer. PATIENTS AND METHODS: Retinal nerve-fiber-layer thickness in 14 eyes of 7 patients has been compared to equally-sided eyes of equally-aged healthy controls. Visual fields showed a bilateral diffuse sensitivity reduction in 5 patients. Visual fields of 2 patients and all healthy controls were normal. RESULTS: A significant difference in measurement values of nerve-fiber-layer thickness did not show between AIDS-patients and healthy controls. There was no correlation between visual field alterations and measurement values of nerve-fiber-layer thickness. CONCLUSION: In AIDS patients, a retinal nerve-fiber loss corresponding to their visual-field alterations has not been found. However, these visual-field alterations may also be explained by central-nervous disorders, lens opacifications or neuro-retinal dysfunctions without nerve-fiber loss.

Acquired Immunodeficiency Syndrome↗
PubMed1995

Unaltered immunoglobulin expression in hybridoma cells modified by targeting of the heavy chain locus with an integration vector.

Chimeric antibodies against the murine T-cell antigen Thy-1.2 were generated in amounts sufficient for in vivo studies by substituting the constant gene segments via homologous recombination in the hybridoma cell. We show that an integration vector targets the heavy chain locus at high frequency even in a non-isogenic situation. Using this vector type, for the first time expression rates were obtained that were identical to the parental hybridoma. The use of the gpt selection marker seems to be crucial for efficient expression, and may overcome a recently claimed drawback of vector integration. A chimeric antibody produced by gene targeting was characterized in vitro and in vivo.

Animals↗
PubMed1995

Suppression of normal and neoplastic human T cells with unconjugated monoclonal antibodies in SCID mouse chimeras.

The aim of this study was to establish a preclinical in vivo model to evaluate the suppressive effect of unconjugated anti-human T (CD3, 5, 7)-cell monoclonal antibodies (mAb) of mouse IgG2a or rat IgG2b isotype. Therefore, severe combined immunodeficient (SCID) mice were transplanted with human peripheral blood lymphocytes (PBL) of healthy donors (hu-PBL-SCID) or with neoplastic T cells of the human T-ALL cell line Jurkat. In preselected hu-PBL-SCID mice with substantial T cell chimerism single antibody injection caused prompt suppression of circulating human T lymphocytes within 2 days followed by occasional T cell recovery during the following weeks. Furthermore, antibody-mediated T cell suppression was measured by prolonged survival of SCID mice that had been injected with Jurkat cells preadapted to cause 100% mortality within 40 days. Injection of preadapted Jurkat cells caused fatal metastasis in lymphoid as well as non-lymphoid organs. The progression of leukemic cells was successfully suppressed when cells and anti-T cell mAb were given i.p. In contrast to control mice, tumor mortality of antibody-treated animals was delayed or completely suppressed. We conclude that SCID mice with reproducible human T cell chimerism are a relevant animal model to test the suppressive effect of anti-human T cell mAb in preclinical studies.

Animals↗
PubMed1994

ATP-sensitive K+ channels in heart muscle cells first open and subsequently close at maintained anoxia.

In ventricular myocardial cells of the guinea pig and the mouse, anoxia caused after a mean latency of 439 +/- 141 s and 129 +/- 23 s (mean +/- S.E.M.), respectively, a large current through KATP-channels. This current disappeared within several seconds when reoxygenating the cells but decayed also completely at maintained anoxia. The kinetics of the latter process, however, were much slower and obeyed an approximately monoexponential time course with time constants in the range of 30 s. The results suggest that in the ischaemic myocardium KATP-channels contribute only to the initial phase of extracellular K+ accumulation.

Adenosine Triphosphate↗
PubMed1994

Immunological approach to inhibit formation of anti-antibodies to allo- and xenogeneic anti-T cell immunoglobulin.

Inhibitory anti-antibodies induced in patients by xenogeneic or even by humanized anti-T cell antibodies remain an unresolved problem. Mice also produce anti-antibodies following injection of xeno- or allogeneic anti-T cell antibodies. Here we report a principle based on sequentially applied anti-T cell antibodies generated in different species, which results in suppressed anti-antibody formation and prolonged immunosuppression. Thus, a single priming injection in mice of mouse (MmT1 or MmT5 differing by idiotype only) or of rat (RmT1) anti-mouse Thy-1 monoclonal antibodies (mAb) or of rat anti-mouse L3T4 + Ly-2 (RmCD4 + CD8) mAb suppressed anti-antibody formation against subsequent booster injections of one of the above antibodies, provided that they differed in species origin from the priming antibody. Correspondingly, a sixfold and longer prolongation of 50% survival of fully mismatched skin grafts was observed. Less or no anti-antibody suppression and little prolongation of graft survival was obtained if the 'first' and the 'second' (and following) antibody injections were of the same species, differing by iso- or idiotype only. Finally, the suppressive principle did not manifest itself at all if the initial antibody injection included both the first and second antibody. These findings are discussed with reference to earlier studies on hapten/carrier effects as well as on immunosuppression attributed to 'non-depleting' rat anti-CD4/CD8 T cell antibodies.

Animals↗
PubMed1994

Anoxia decreases the transient K+ outward current in isolated ventricular heart cells of the mouse.

Transient K+ outward currents (Ito) were measured in enzymatically isolated ventricular mouse heart cells with a patch clamp technique in the whole cell configuration. Exposure of the cells to substrate-free anoxia gradually decreased both the peak and the late Ito. The inactivation time course of Ito was fitted with two exponentials. After 4-10 min of anoxia, the contribution of the fast and slow exponential decreased to 60 +/- 7% and 62 +/- 4% of the control value and recovered after reoxygenation within 1-3 min to 84 +/- 5% and 75 +/- 6% (n = 10; all mean +/- SEM), respectively. The time constants of the exponentials were invariant to anoxia. Voltage dependence of activation and inactivation of Ito were not influenced by anoxia. Application of stimulators of protein kinase A and C, cGMP- dependent protein kinase, or of the oxidant diamide during anoxia did not recover Ito. It is concluded that under conditions of metabolic stress, Ito is reversibly down-regulated leaving inactivation kinetics unchanged. The underlying mechanism is as yet unknown but does neither involve a decreased activity of protein kinase A, protein kinase C, nor c-GMP dependent protein kinase.

Animals↗
PubMed1994

[Clinical studies of reduced accommodation in patients with HIV-1 infection].

PROBLEM Reduced accommodation in HIV-patients has been described. Yet, in literature, statistics on this item cannot be found. PATIENTS AND METHOD In 58 HIV-infected subjects of different infection stages, accommodation was measured using Clement-Clark's accommodometer. Average age was 34.9 years (sigma = 8.3 years) Stages of HIV-infection were defined according to CDC (Centers for Disease Control)-classification. RESULTS The decrease in accommodation did not show any correlation to the stage of HIV-infection neither to its frequency nor to its amount. An antiretroviral therapy may reduce accommodation loss. However, the effect is not statistically significant. Incommodating accommodation loss occurred only in a few cases. CONCLUSION Reduced accommodation is an early ophthalmological symptom of HIV-1-infection. Possible causes of this phenomenon may be either direct neuronal infection by HIV 1, pathologic changes of the lens or the ciliary body.

Accommodation, Ocular↗
PubMed1994

A mouse model for the preclinical evaluation of immunosuppressive effector functions of human isotypes. The human IgG1 isotype is superior to IgG3.

Antibodies against T cells are widely used as immunosuppressive agents in clinical therapy. As effector functions of chimeric or humanized anti-T cell antibodies cannot be predicted in vitro, we compared T cell-depleting effects of human isotypes in vivo with their immunosuppressive consequences in a mouse BMT model. This system is based on chimeric antibodies with a mouse pan T cell specificity and human constant regions. To secure optimal immunosuppression, the specificity for Thy-1.2--one of the best-characterized T cell antigens--was selected, as Thy-1.2-specific antibodies prevent graft-versus-host disease in fully mismatched mice. Chimeric mouse anti-Thy-1.2 antibody with the human IgG1 Fc part was found to be equally effective in preventing graft-versus-host disease mortality as the highly protective anti-Thy-1.2 mouse IgG2a isotype, while human IgG3 was far less effective. This was not predictable by measuring the degree of T cell depletion in peripheral blood. T cell depletion in lymph nodes, however, exactly reflected the results obtained in the BMT system. In addition, this system offers the advantage of assessing the influence of reduced antigen density by using heterozygous Thy-1.2 mice.

Amino Acid Sequence↗
PubMed1994

Prevention of graft-versus-host disease in DLA-haplotype mismatched dogs and hemopoietic engraftment of CD6-depleted marrow with and without cG-CSF treatment after transplantation.

Prevention of graft-versus-host disease by depletion of CD6-positive T cells was studied in the dog. Donors were DLA-homozygous, recipients DLA-heterozygous with one DLA haplotype identical to the donor. Seven control dogs received untreated marrow and died of GvHD after full hemopoietic recovery within 28 days of transplantation. For prevention of GvHD, immunomagnetic separation of T cells with a monoclonal antibody against human CD6 that crossreacted with canine T cells was evaluated. Depletion of CD6-positive cells depleted CD4-positive cells completely, but only part of CD8-positive cells and DR-positive cells. CD6-depleted marrow exhibited strong nonspecific "natural" suppression of the generation of cytotoxic T cells in vitro. Eleven dogs received CD6-depleted marrow. Only 1 dog developed GvHD and died. Sustained engraftment was seen in 8 dogs. Hemopoietic recovery was delayed and slower after transplantation of CD6-depleted marrow than after transplantation of untreated marrow. Four of these dogs were treated with G-CSF, and this accelerated the recovery of leukocytes, but did not prevent rejection. Chimerism was mixed in 7 of 10 evaluable dogs and 1 dog recovered its own hemopoiesis 2 years after transplantation. CD6 depletion prevents GvHD across a DLA-haplotype difference, but rejection and mixed chimerism may occur. Treatment with G-CSF accelerates leukocyte recovery, but cannot prevent rejection.

Animals↗
PubMed1993

Immunohistology and immunocytology of human T-cell chimerism and graft-versus-host disease in SCID mice.

Surprisingly little graft-versus-host disease (GVHD) has been observed in severe combined immunodeficient (SCID) mice injected intraperitoneally (IP) with human blood lymphocytes (hu-PBL-SCID), which raised the question as to whether GVHD in such a distant species is sporadic or suppressed because of immunologic reasons. After screening for blood T-cell chimerism, we hereby describe generalized lethal xenogeneic human GVHD in unconditioned SCID chimeras, which resembles GVHD in SCID mice injected with allogeneic lymphocytes. We adapted an immunocytochemical slide method for minute cell numbers, which allowed us to follow, by multimarker phenotyping of weekly mouse-tail bleeds, the chimeric status of 100 hu-PBL-SCID injected with 10(7) or 10(8) hu-PBL of Epstein-Barr virus- (EBV-) donors. More than half of the mice showed no or less than 2% T cells. However, 13% to 21% developed substantial blood T-lymphocyte chimerism (10% to 80% human CD+ cells) and high mortality. Immunohistology showed more human CD8+ than CD4+ T cells in the splenic white pulp. The cells developed HLA-DR activation markers and infiltrated the red pulp where human B cells also appeared. Expression of activation and proliferation markers increased within 5 to 6 weeks. Many human CD3+ cells were also found in the portal triads of the liver and in the lung, pancreas, and kidney. The thymus also became heavily infiltrated. The intestines and skin of hu-PBL-SCID were less infiltrated by donor cells than in SCID with allogeneic GVHD. The tongue contained almost no human T cells. Our data show that a relatively low overall incidence of human xenogeneic GVHD, even when high numbers of human PBL are injected, is the consequence of a dichotomy between mice with no or transient T-cell chimerism and a minority of mice with high-blood T-lymphocyte chimerism and GVHD mortality.

Animals↗
PubMed1993

Murine anti-mouse T cell monoclonal antibodies elicit anti-antibodies in mice: intra-species immunization model for estimating potential patient sensitization against humanized anti-T cell antibodies.

Humanization of immunosuppressive anti-T cell monoclonal antibodies (mAb) raises the question as to how completely it helps to avoid formation of neutralizing anti-antibodies (anti-Ab) in patients. To get more information on intra-species sensitization against anti-T cell mAb, we produced two immunosuppressive mouse IgG2a anti-mouse Thy-1.2 mAb (MmT1 and MmT5) in AKR/J mice and measured the potential of MmT1 to elicit inhibitory anti-Ab in AKR/J (H-2k), C57BL/6 (H-2b), congenic B10.BR (H-2k) and DBA/2 (H-2d) mice. After one injection once weekly for 4 weeks of 5 micrograms MmT1 (200 micrograms/kg) in C57BL/6 mice, without the use of any adjuvants, high concentrations of anti-Ab directed against MmT1 (300 micrograms/ml) and MmT5 (100 micrograms/ml) were measured by enzyme-linked immunosorbent assay. Similar concentrations of anti-Ab were found in immunized DBA/2 and less in B10.BR mice. No syngeneic anti-Ab could be produced in AKR/J. From the C57BL/6 mice, we raised anti-MmT1+, MmT5- idiotype (IDIO1) and anti-MmT1+, MmT5+ allotype (ALLO1) mAb. An in vivo test system was adapted to measure the inhibitory effects of circulating poly- or monoclonal anti-Ab. It revealed a reduction of in vivo depletion capacity not only of the sensitizing mAb (MmT1), but also of another anti-Thy-1.2 mAb (MmT5), with identical allotype but different idiotype. From this we conclude that intra-species immunization following injection of anti-T cell mAb can produce high titer inhibitory anti-idiotype and anti-allotype antibodies. Implications for hyperchimeric or fully human anti-T cell mAb are discussed.

Animals↗