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U Steinhoff

Publications and source records attributed to U Steinhoff.

34 records · Page 2Linked to original sources
PubMed1994

Functional role of type I and type II interferons in antiviral defense.

Mice lacking the known subunit of the type I interferon (IFN) receptor were completely unresponsive to type I IFNs, suggesting that this receptor chain is essential for type I IFN-mediated signal transduction. These mice showed no overt anomalies but were unable to cope with viral infections, despite otherwise normal immune responses. Comparison of mice lacking either type I or type II IFN receptors showed that, at least in response to some viruses, both IFN systems are essential for antiviral defense and are functionally nonredundant.

Alphavirus Infections↗
PubMed1994

Prevention of autoimmune lysis by T cells with specificity for a heat shock protein by antisense oligonucleotide treatment.

T lymphocytes with specificity for the bacterial heat shock protein (hsp) 60 recognize stressed host cells, thus possibly promoting pathogenesis of certain infectious and autoimmune diseases. Here, we show that autoimmune destruction of stressed Schwann cells and macrophages by cytotoxic T lymphocytes raised against mycobacterial hsp60 can be inhibited by the use of hsp60-specific antisense oligodeoxynucleotides (A-ODNs). The inhibitory effect of hsp60 A-ODNs was specific because lysis of murine cytomegalovirus-infected host cells by virus-specific cytotoxic lymphocytes was not affected. Immunoblot analysis and immunoprecipitation studies suggest that different forms of stress increase hsp60 synthesis in Schwann cells and that this neosynthesis is reduced by hsp60 A-ODNs. These findings (i) provide evidence for participation of endogenous hsp60 in the recognition of stressed host cells by mycobacterial hsp60-crossreactive T cells and (ii) suggest the feasibility of inhibiting autoimmune reactions by target-cell treatment with specific A-ODNs.

Animals↗
PubMed1994

Virus or a hapten-carrier complex can activate autoreactive B cells by providing linked T help.

We investigated the mechanism leading to an IgG autoantibody response in two transgenic mouse lines expressing the glycoprotein of vesicular stomatitis virus (VSV-G). Previous experiments have shown that these animals do not mount a transgene-specific IgG response upon stimulation with purified VSV-G or infection with recombinant vaccinia virus expressing VSV-G. However, infection of VSV-G transgenic animals with wild-type vesicular stomatitis virus, serotype Indiana, readily induced VSV-G-specific, neutralizing IgG autoantibodies. We have tested whether this labile state of tolerance reflected differential availability of VSV-G-specific T help. For this, we immunized transgenic mice with the self-antigen VSV-G covalently coupled to sperm-whale myoglobulin (VSV-G-SWM), to provide new T helper epitopes that are linked to the B cell epitope; co-injected uncoupled VSV-G and SWM served as control. High titers of VSV-G specific IgG autoantibodies were detected in serum of mice immunized with VSV-G-SWM but not after co-injection of uncoupled VSV-G and SWM. Transgenic animals depleted of CD4+ T cells prior to injection of VSV-G-SWM failed to mount an IgG response. Priming of transgenic mice with the foreign carrier did not accelerate the IgG autoantibody response to VSV-G-SWM, suggesting that B cells were limiting the rate of the response. Thus, self-reactive B cells could be triggered to produce IgG, if they received linked T help specific for a foreign carrier determinant provided either by a classical carrier determinant or a virus.

Animals↗
PubMed1994

T helper cell unresponsiveness: rapid induction in antigen-transgenic and reversion in non-transgenic mice.

T cell tolerance is usually established by clonal deletion of self-specific T cells in the thymus, or some times, in the periphery. Alternatively, tolerance may also be achieved by induction of clonal T cell unresponsiveness by a poorly understood mechanism called "anergy". We found that transgenic mice expressing a soluble form of vesicular stomatitis virus (VSV) glycoprotein (G) predominantly in liver and kidney exhibited normal B cell responses. VSV-G-specific T help-independent neutralizing IgM responses were within normal ranges, but no T help-dependent neutralizing IgG antibodies were generated upon immunization with recombinant VSV-G protein and recombinant vaccinia virus expressing VSV-G. This demonstrated absence of B cell tolerance but presence of T helper cell unresponsiveness. After adoptive transfer of transgenic spleen cells into thymectomized immuno-incompetent hosts, the unresponsive T helper cells regained function and switched the neutralizing IgM response to IgG, comparably to control T helper cells, within 7 days. Conversely, when naive non-transgenic spleen cells were transferred into transgenic mice, VSV-G-specific T helper cells became unresponsive within 3-4 days. These results suggest that VSV-G-specific T helper cells are rendered unresponsive within a few days in the VSV-G transgenic host also outside of the thymus and that this unresponsiveness was reversed by transfer into antigen-free recipients.

Animals↗
PubMed1994

Localization of T helper cell epitopes in the vesicular stomatitis virus: the nucleoprotein is responsible for serotype cross-reactive T help.

The glycoprotein (G) of vesicular stomatitis virus (VSV) is known to contain the biologically relevant sites for virus-neutralizing antibodies as well as T helper (Th) cell epitopes. The capacity of other VSV proteins to elicit potent Th cell responses has not yet been investigated. Additionally, a short-lived cross-reactivity between the two serologically distinct VSV serotypes Indiana (IND) and New Jersey (NJ) on the T helper cell level has been reported. Here we address the question of whether the VSV nucleoprotein (N) or matrix protein (M) can elicit T help to VSV-G-specific B cells and which of the VSV proteins contains the elements responsible for the IND/NJ cross-reactivity. The N, G, and M of the VSV Indiana serotype produced in a recombinant baculovirus system were assayed for the ability to activate VSV-specific Th cells to induce immunoglobulin class switch of neutralizing antibody responses in vivo in C57BL/6 (H-2b) mice. All three VSV-IND proteins helped in the production of neutralizing IgG antibodies to the homologous VSV-Indiana serotype but only VSV-IND N was able to trigger an IgG response to the heterologous VSV-New Jersey serotype. This data suggest that Th epitope(s) in the VSV-IND N are responsible for the observed cross-reactivity of T helper cells.

Animals↗
PubMed1993

Tolerance induction by clonal deletion of CD4+8+ thymocytes in vitro does not require dedicated antigen-presenting cells.

The cellular requirements of T cell tolerance induction in the thymus by clonal deletion was investigated by using an in vitro assay: thymocytes from mice expressing a transgenic TcR specific for lymphocytic choriomeningitis virus (LCMV) and H-2Db were co-cultured with various H-2b cell types as antigen-presenting cells in the presence of the antigenic LCMV peptide. The results revealed that all cell lines examined including embryonic and transformed fibroblasts, melanoma cells, cortical thymic epithelial cells, lymphomas and neuronal cells induced an antigen dose-dependent deletion of CD4+8+ thymocytes. Similarly, highly enriched accessory cell populations from thymus and spleen (macrophages, dendritic and cortical epithelial cells, i.e. thymic nurse cells) could induce antigen-specific depletion of immature CD4+8+ thymocytes. Depending on the cell type examined micromolar to picomolar concentration of LCMV peptide were required to induce deletion. The effectiveness of deletion by the different cell types did not correlate with their major histocompatibility class I expression level; it was, however, influenced by the presence of ICAM-1 adhesion molecules.

Animals↗
PubMed1991

Heat-shock protein 60: implications for pathogenesis of and protection against bacterial infections.

In this review we have focused on antigenic features of hsp 60 related to: its ubiquitous distribution in the biosphere; its extraordinary homology among various bacteria; its high conservation from prokaryotic to eukaryotic cells; and its abundant expression under stress situations occurring during infection. These unique features make hsp 60 an excellent candidate antigen relevant to protection and pathogenesis of bacterial infections and, perhaps in a broader sense, to surveillance and autoimmunity. We will briefly discuss these possibilities in the following. Acquired resistance. If we assume that bacterial organisms contain some thousand different proteins which all represent potential antigens, the frequency of T cells with specificity for mycobacterial hsp 60 appears surprisingly high. Although, during the course of infection, high levels of hsp may be induced in bacteria, mere abundance appears to be an important though insufficient explanation. In addition, constant boosting by similar hsp 60 cognates from various microbes with which humans come into contact may contribute to dominance. This could easily explain the occurrence of hsp 60-specific T cells in healthy individuals with no clinical history of mycobacterial infections. Involvement of more sophisticated mechanisms, such as the affinity of hsp to other proteins, cannot be excluded (Flynn et al. 1989). Yet dominance does not necessarily mean protection and definite proof that hsp are protective antigens is lacking. Perhaps the immune response against epitopes shared by various mycobacterial pathogens represents a first line of defence preceding a more specific immune response. Such broadly reactive antigens would not qualify as prime candidates for vaccine design. Immunesurveillance. T cells with specificity for epitopes shared by bacterial and human hsp 60 are readily demonstrable and stressed host cells are recognized by hsp 60-specific T cells. Such T lymphocytes are endowed with the capacity to identify host cells stressed by a variety of assaults such as inflammation, infection, trauma, or transformation. Although it has been claimed that hsp-reactive gamma/delta T cells are particularly destined for such surveillance functions (Born et al. 1990, Asarnow et al. 1988), alpha/beta T cells could also participate. Pathogenesis. The mechanisms causing pathogenesis should be similar to those underlying protection and surveillance. In the former case bacterial hsp would be responsible for both induction of immunity and expression of pathogenic reactions; in the latter case an immune response stimulated by conserved regions of bacterial hsp 60 would be converted against a host-derived cognate.(ABSTRACT TRUNCATED AT 400 WORDS)

Amino Acid Sequence↗
PubMed1991

Mycobacterium leprae renders Schwann cells and mononuclear phagocytes susceptible or resistant to killer cells.

Acquired resistance to Mycobacterium leprae, the etiologic agent of leprosy, crucially depends on cellular immune mechanisms. In addition to interleukin-mediated helper functions, killer mechanisms seem to be involved. This study addresses the question of how M. leprae render mononuclear phagocytes and Schwann cells, its natural targets, susceptible or resistant to killer cells. Killer activities were stimulated in peripheral blood mononuclear cells from healthy individuals by incubation with mycobacteria plus interleukin-2. These cells lysed Schwann cells and mononuclear phagocytes which had been pulsed with dead M. leprae, while unpulsed targets remained virtually unaffected. Importantly, targets infected with viable M. leprae were not lysed; furthermore, infection with viable M. leprae as well as gamma interferon stimulation or heat shock caused resistance in otherwise susceptible targets which had been pulsed with dead M. leprae. Thus, M. leprae markedly influenced the effect of killer cells on Schwann cells and mononuclear phagocytes.

Cells, Cultured↗
PubMed1990

Lysis of interferon-gamma activated Schwann cell by cross-reactive CD8+ alpha/beta T cells with specificity for the mycobacterial 65 kd heat shock protein.

Heat shock protein (hsp) 65 is a major T cell antigen of Mycobacterium leprae. The hsp 65 of M. leprae is nearly identical in M. bovis/M. tuberculosis (greater than 95% protein sequence homology) and surprisingly similar in man (65% protein sequence homology). Recently, we had provided evidence in a murine model that CD8+ T cells recognize and lyse Schwann cells presenting M. leprae antigen in the context of major histocompatibility (MHC) class I gene products. Because murine Schwann cells are class I negative, antigen presentation requires prior stimulation with interferon-gamma (IFN-gamma). CD8+ T cells were activated against tryptic fragments of mycobacterial hsp 65. These T cells recognized epitopes of hsp 65 which had been generated through the cytoplasmic class I processing pathway. They were also capable of lysing Schwann cells which had been activated by IFN-gamma and not primed with nominal hsp 65 peptides. In contrast, T cells activated against tryptic ova peptides only lysed Schwann cells which had been both stimulated with IFN-gamma and primed with ova peptides. Evidence is presented that class I (H-2D) restricted, CD8+ alpha/beta T lymphocytes with specificity for the mycobacterial hsp 65 recognize IFN-gamma-stimulated Schwann cells probably because they are specific for a(n) epitope(s) shared by the bacterial hsp and a host cognate. Activation of autoreactive T cells with specificity to shared epitopes could contribute to nerve damage in tuberculoid leprosy which is characterized by low to absent M. leprae in Schwann cells.

Animals↗
PubMed1988

Specific lysis by CD8+ T cells of Schwann cells expressing Mycobacterium leprae antigens.

In vitro cultured murine Schwann cells which were devoid of class I and class II gene products of the major histocompatibility complex expressed class I, though not class II, antigens after stimulation with recombinant interferon-gamma. Recombinant IFN-gamma-stimulated Schwann cells after priming with M. leprae were lysed by antigen-specific CD8+ T lymphocytes in vitro. These findings suggest that specific lysis of M. leprae-infected Schwann cells by CD8+ CTL plays a role in leprosy.

Animals↗
PubMed1988

[The reliability of pulse oximetry monitoring of arterial oxygen saturation in centrally intubated and hypothermic patients].

The present study tests the effectiveness of pulse oximetric measurement in attaining reliable saturation values even in patients with hypothermia and centralization. 20 patients who had all required endoprosthetic surgery of the lower extremities were included in the study. During the process of removing 98 samples for arterial blood-gas analysis, pulse oximetric saturation, heart rate (pulse oximeter and ECG), rectal temperature, peripheral temperature at the back of the fingers, arterial pressure (catheter) and central venous pressure were registered. The results can be summarized as follows: 1. Acute changes in arterial saturation can be very quickly recognized with the help of pulse oximetry. 2. The reliability of pulse oximetric measurement is, in the area examined, dependent neither on the peripheral nor the rectal temperature, nor on the temperature difference between the core and surface temperature of the body, and, therefore not dependent on the degree of centralization. 3. In the area examined, the reliability of pulse oximetric measurement is influenced neither by blood pressure fluctuations nor by intravascular hypo- or hypervolemia. 4. There is merely a sharp increase in the Pulsoximeter when the temperature decreases. The Pulsoximeter still indicates the correct saturation as long as the peripheral pulse rate corresponds to the heart rate on the ECG Monitor.

Aged↗
PubMedDate not supplied

Quantification of magnetic nanoparticles by magnetorelaxometry and comparison to histology after magnetic drug targeting.

Magnetic nanoparticles can be used in medicine in vivo as contrast agents and as a drug carrier system for chemotherapeutics. Thus local cancer therapy is performed with Magnetic Drug Targeting (MDT) and allows a specific delivery of therapeutic agents to desired targets, i.e., tumors, by using a chemotherapeutic substance bound to magnetic nanoparticles and focused with an external magnetic field to the tumor after intraarterial application. Important for this therapeutic principle is the distribution of the particles in the whole organism and especially in the tumor. Therefore we used magnetorelaxometry to quantify ferrofluids delivered after MDT. Tissue samples of some mm3 volume of a VX2 squamous cell carcinoma were measured by magnetic relaxation and the amount of iron was determined using the original ferrofluid suspension as a reference. From this the distribution of the magnetic particles within the slice of tumor was reconstructed. Histological cross-sections of the respective tumor offer the opportunity to map quantitatively the particle distribution and the vascularisation in the targeted tumor on a microscopic scale. Our data show that the integral method magnetorelaxometry and microscopic histological methods can complete each other efficiently.

Animals↗