Biological effects of cyclosporin A: A new antilymphocytic agent

The fungus metabolite cyclosporin A is a small peptide acting as a novel antilymphocytic agent. It strongly depressed appearance of both direct and indirect plaque-forming cells and produced a clear dose-dependent inhibition of haemagglutinin formation in mice upon oral administration. Skin graft rejection in mice and graft-versus-host disease in mice and rats were considerably delayed by cyclosporin A which also prevented the occurrence of paralysis in rats with experimental allergic encephalomyelitis. This compound was not only highly effective in preventing development of Freund's adjuvant arthritis, but in addition improved the symptoms in rats with established arthritis, although it is inactive in acute inflammation. This new agent contrasts with other immunosuppressives and cytostatic drugs in its weak myelotoxicity. Experimental evidence suggests that cyclosporin A, rather than being cytostatic or lympholytic, affects an early stage of mitogenic triggering of the immunocompetent lymphoid cell.Research Institute, Wander, Bern, a Sandoz Research Unit.     

Treatment of atypical leishmaniasis with interferon γ resulting in progression of Kaposi's sarcoma in an AIDS patient

Visceral leishmaniasis (kala-azar) affecting HIV-infected patient is being reported in increasing frequency. A 40-year-old German bisexual patient with full-blown AIDS is described who presented with Kaposi's sarcoma, epigastric pain, diarrhea, and weight loss but without fever.Leishmania amastigotes were initially found in biopsies from stomach, duodenum, and a cutaneous Kaposi's sarcoma lesion but were later also recovered from bone marrow and lymph node. The patient received three courses of a combination of pentavalent antimony and interferon-. In addition to the common side effects such as fever, thrombocytopenia, and elevated amylase and lipase, a vivid progression of the Kaposi's sarcoma was noted. Tumor progression was temporally closely associated with treatment with interferon-. Because this phenomemon has also been observed in other patients, we advise caution when using interferon- in patients with Kaposi's sarcoma.Abbreviations AIDS acquired immunodeficiency syndrome - HIV human immunodeficiency virus - KS Kaposi's sarcoma Correspondence to: H. Albrecht     

A 14,000 MW lipoprotein and a glycolipid-like structure of Borrelia burgdorferi induce proliferation and immunoglobulin production in mouse B cells at high frequencies.

Sonicated preparations of Borrelia burgdorferi are able to stimulate unselected resting BALB/c spleen cells to proliferate and to produce immunoglobulin in vitro. FACS analysis of target cells prestained with an integrated cell-surface marker as well as cell-depletion experiments demonstrate that the majority of responding lymphocytes are B cells. Limiting dilution analyses of resting B cells revealed high frequencies of cells producing IgM (F 1/11-1/62) or IgG (F 1/5-1/163) in response to B. burgdorferi sonicate (B.b. sonicate). These numbers were similar to those obtained with lipopolysaccharide (LPS) (IgM: F 1/20-1/84; IgG: F 1/14-1/85) or a synthetic lipopeptide of Braun's Escherichia coli lipoprotein (IgM: F 1/15, 1/19; IgG: F 1/148, 1/34). The mitogenic structure(s) expressed by B. burgdorferi is distinct from LPS, as similar proliferative responses were obtained with B cells from LPS-resistant (C57BL/10ScCr and C3H/HeJ) and LPS-susceptible (C57BL/10ScSn, C3H/HeN) mice. Furthermore, B-cell mitogenic properties were also found in two distinct fractions of a phenol-chloroform-petroleum ether extract of B. burgdorferi: they consisted of a lipoprotein distinct from the outer surface proteins (Osp) A and B and glycolipid-like structures, respectively. These data suggest that spirochetes express a multitude of distinct structures with mitogenic activity for B cells including various lipoproteins as well as glycolipid(s).     

Differential immune responses to Borrelia burgdorferi in European wild rodent species influence spirochete transmission to Ixodes ricinus L. (Acari: Ixodidae).

Immune responses to Borrelia burgdorferi and their influence on spirochete transmission to Ixodes ricinus were analyzed in the natural European reservoir hosts; i.e., the mouse species Apodemus flavicollis (yellow-necked mouse) and Apodemus sylvaticus (wood mouse) and the vole species Clethrionomys glareolus (bank vole), and, in addition, in the laboratory mouse strain NMRI. Naive and preimmunized rodents were infected either by artificially infected I. ricinus larvae or by intradermal injection of spirochetes. Independent of the species, all animals developed antibodies to various spirochetal antigens. However, antibodies to the outer surface proteins A (OspA) and B (OspB) were not found in recipients infected via ticks. Rodents of the genus Apodemus and of the NMRI strain showed higher levels of B. burgdorferi-specific antibodies than those of the species C. glareolus. The rate of spirochete transmission to noninfected ticks correlated with both the quality and quantity of spirochete-specific antibodies generated in the various species: high levels of spirochete-specific immunoglobulins correlated with low transmission rates. Furthermore, lower transmission rates were observed with rodents expressing antibodies to OspA and OspB (i.e., intradermally infected or immunized) than with those lacking these specificities (i.e., infected via ticks). The study provides evidence that transmission of B. burgdorferi from natural hosts to ticks is controlled by the specificity and quantity of spirochete-reactive antibodies and suggests that immunity to B. burgdorferi in natural reservoir hosts is an important regulatory factor in the horizontal transmission of B. burgdorferi in nature.     

The gene for familial dystonia with myoclonic jerks responsive to alcohol is not located on the distal end of 9q

A gene (DYT1) for susceptibility to early-onset torsion dystonia in Ashkenazi Jewish and Gentile kindreds is situated on chromosome 9q32-q34 in a 6–7 cM span between markers AK1 and ASS. To determine whether transmission of familial dystonia with myoclonic jerks responsive to alcohol was consistent with a gene in this region, we studied the 37 members of a Swedish family, of whom 20 were so affected. A lod score of < −2.00 from a two-point linkage analysis with six DNA markers covering a 30 cM span from D9S26 to D9S10 that included the region of the DYT gene indicated that this gene is not located in this region, and that two or more autosomal loci are responsible for hereditary dystonia in humans.     

The anaplastic variant of centrocytic lymphoma is marked by frequent rearrangements of the bcl-1 gene and high proliferation indices

Ten cases of classic centrocytic lymphoma as defined in the Kiel classification system were investigated for their immunophenotype, their proliferation activity and by means of molecular diagnostics. The findings were compared to those obtained from a group of nine cases of anaplastic centrocytic lymphoma. Both groups showed virtually identical immunohistochemical characteristics with positivity for CD5 and negativity for CD10 and CD23. In the group of anaplastic centrocytic lymphoma, there were considerably higher proliferation indices as documented by staining for the Ki-67 antigen, up to 80% of the tumour cells being positive. Moreover, the cases of anaplastic centrocytic lymphoma had bcl-1 gene rearrangements in eight out of nine cases compared with three out of 10 cases of classic centrocytic lymphoma. DNA analysis was not able to detect bcl-2 gene rearrangement in any case, pointing to a difference compared with lymphomas of germinal centre origin. The coincidence of anaplastic and sometimes blast-like morphology of the tumour cells, high proliferation index and a rearranged bcl-1 gene in nearly all cases of anaplastic centrocytic lymphoma support their classification as high-grade malignant variants of centrocytic lymphoma and suggest a possible role for the bcl-1 locus not only in the origin but also in the progression of centrocytic lymphomas.     

Direct effects of second-generation H1-receptor antagonists on the activation of human basophils

The present study was performed to investigate the putative suppressive effects of H₁-receptor antagonists (HRA) of the second generation (astemizole (AS), cetirizine (CT), loratadine (LO), oxatomide (OX) and terfenadine (TF)) on the mediator release from human basophils activated by two classical stimuli. Anti-IgE-mediated histamine release was inhibited in a dose-dependent fashion by TF (maximum inhibitory value: 33.8±7.6%, 100 μM,n=7), whereas the other HRA exhibited weaker activity. The anti-IgE-induced LTC₄ production was strongly suppressed by TF, LO and OX (92.4±6.3%, 90.8±6.0% and 88.5±5.6%, 100 μM,n=4−5), while As was less active (56.4±4.1%, 100 μM,n=5). Histamine release induced by incubation with grass pollen antigen (0.01%) was inhibited by TF (40.7±4.1%, 50 μM,n=4), but the other HRA showed only low activity. The present findings suggest that some HRA might exhibit direct inhibitory effects on activation of IgE-receptor bearing cells.

     

Protection from experimental autoimmune diabetes in the non-obese diabetic mouse with soluble interleukin-1 receptor

We have evaluated the effects of a treatment with soluble interleukin-1 receptor (sIL-1R) in the accelerated model of autoimmune diabetes induced by cyclophosphamide (CY) in the non-obese diabetic (NOD) mouse. Prior to the CY challenge (350 mg/kg body weight), female euglycemic NOD mice were randomly divided into three groups (A–C). Groups B and C were treated daily from 1 day before to 13 days after the CY challenge with sIL-1R at doses of 0.2 and 2 mg/kg body weight. Group A was treated with PBS. By 2 weeks after CY administration, an acute form of autoimmune diabetes with glycosuria, hyperglycemia and severe insulitis occurred in the majority (13/20, 65%) of the control mice (group A). In contrast, repeated injections with sIL-1R protected NOD mice from insulin-dependent diabetes mellitus (IDDM) development in a dose-dependent fashion; the incidence of IDDM was 53.3% (8/15) in the mice treated with 0.2 mg/kg and only 6.7% (1/15) in those treated with 2 mg/kg. However, none of the doses of the sIL-1R reduced the extent of insulitis in NOD mice. Importantly, the anti-diabetogenic property of sIL-1R may not involve major T cell function impairment; accordingly, in parallel experiments, splenic lymphoid cells from NOD mice not challenged with CY, but treated with 2 mg/kg sIL-1R for 5 consecutive days showed a normal distribution of mononuclear cell subsets and maintained their capacity to secrete interferon-γ and IL-2 and to proliferate in response to polyclonal mitogenic stimulation with concanavalin A.     

Low correlation of human cytomegalovirus DNA amplification by polymerase chain reaction with cytomegalovirus disease in organ transplant recipients

Seventy-five organ transplant recipients underwent prolonged virological and serological follow-up for early detection of human Cytomegalovirus (HCMV) infection after transplantation. HCMV DNA detection by nested polymerase chain reaction (PCR) and HCMV early structural antigen (pp65) detection were carried out in 576 peripheral blood leucocyte (PBL) samples. Furthermore, 563 blood specimens were investigated by a commercially available enzyme-linked immunosorbent assay (ELISA) for the detection of specific immunoglobulins G, M, and A against HCMV structural antigens. In eight of nine symptomatic organ transplant recipients, HCMV DNA was detected in one or more consecutive blood samples. HCMV DNA PCR was also positive in one or more samples from eight patients who never developed HCMV-related symptoms. HCMV pp65 antigen was detected almost exclusively in PBL samples from organ transplant recipients suffering from HCMV disease. However, antigenaemia was not detected in four PCR positive patients presenting clinical signs attributable to HCMV infection. Two of the initially HCMV DNA positive samples were not confirmed by retesting and hybridisation. The results of the present study demonstrate that despite the high specificity of nested PCR, HCMV DNA may be detected in the absence of clinical symptoms attributable to HCMV infection. In asymptomatic reactivation, limited replication of viral DNA may be responsible for positive results of PCR without any clinical relevance. In this context, pp65-antigen detection from PBL seems to have a better prognostic value, but is not always detected when clinical symptoms are present. © 1994 Wiley-Liss, Inc.     

Potentiation of concentric plantar flexion torque following eccentric and isometric muscle actions

In a stretch-shortening cycle (SSC) the concentric muscle action is enhanced by a preceding eccentric muscle action. The hypothesis of the present study is that a preceding isometric action can also have an effect on a following concentric action, but to a lesser degree. A KINetic-COMmunicator II dynamometer was used to test muscle strength of the plantar flexion of the right foot in 20 healthy women. Maximal voluntary torque measurements were made at different angular velocities (120^o s^-1 and 240^o s^-1) and the range of motion of the ankle joint was 78–125^o. The assessment was based on concentric torque output and EMG recording from the gastrocnemius muscle under three different types of testing conditions (concentric actions with and without preceding eccentric or isometric actions, all with maximal efforts). The results showed that preceding muscle actions led to greater concentric torque output (P < 0.01) between 90 and 99^o plantar flexion. However, the increase in the concentric action was significantly (P < 0.01) larger with eccentric than with isometric preceding action, regardless of velocity. The EMG activity of the concentric action showed unchanged or lower values when preceded by a muscle action. In this model our conclusion is that the main reason for larger concentric torque values after a preceding muscle action is that time is sufficient for maximal muscle tension development; in addition, elastic energy is stored, particularly during the preceding eccentric action. Our results show that the effect of preceding muscle actions should be taken into account when measuring isokinetic muscle strength at relatively small angular movements.