The four mouse IgG isotypes differ extensively in bactericidal and opsonophagocytic activity when reacting with the P1.16 epitope on the outer membrane PorA protein of Neisseria meningitidis

Mouse monoclonal antibodies (MoAbs) of the four IgG isotypes, all specific for the P1.16 epitope on the meningcoccal PorA protein, were tested for functional activities. The avidities of the antibodies, measured by NH4SCN elution in enzyme-linked immunosorbent assay, showed similar values for all the MoAbs. The serum bactericidal activity (SBA) defined as the lowest concentration of antibodies giving 50% reduction in the number of meningococcal colony-forming units using human serum as complement, showed a hierarchy of IgG3 > IgG2b > IgG2a > IgG1. For the opsonophagocytosis (OP), the hierarchy was IgG3 > IgG2b = IgG2a > IgG1. OP was measured in flow cytometry using log-phase live meningococci as target cells, normal human peripheral blood polymorphonuclear cells (PMNs) as effector cells and human serum as a complement source. The mouse MoAbs were negative in OP when using human PMNs in the absence of complement. The results demonstrate the importance of choosing the right isotype of mouse MoAbs when using them to judge the potential vaccine importance of their corresponding antigen. If such MoAbs should be used for passive vaccination against infectious diseases, the isotype would presumably play an important role for their anticipated clinical effects.     

Degree of fatness after allogeneic BMT for childhood leukaemia or lymphoma

Excess fatness is frequent after childhood ALL treated without BMT. We measured the whole-body percent fat by dual-energy X-ray absorptiometry and the body-mass index (weight/height(2) (kg/m(2)), BMI) in 25 survivors of childhood leukaemia or lymphoma (21 with ALL) who had received TBI and allogeneic BMT a median of 8 years ago (range 4-13). Adjusted for sex and age, the mean BMI was slightly but significantly reduced (0.4 s.d. below predicted) and the whole-body percent fat was significantly increased compared with healthy controls (1.1 s.d. above predicted). Eleven of 25 patients had a percent fat above the 90 percentile of the reference values, which indicates excess fatness. Adjusted for sex and age, a higher percent fat was related to additional cranial irradiation. Controlled for this, the whole-body percent fat seemed to be unrelated to age at BMT, length of follow-up, and previous chemotherapy. Compared with untransplanted ALL survivors treated with cranial irradiation, BMT survivors had significantly reduced BMI but similar whole body percent fat. BMI was a poor measure of body fatness in these patients. In conclusion, survivors of BMT for childhood leukaemia or lymphoma are adipose and slightly underweight and consequently have a substantially reduced lean body mass.     

The principle of delivery of T cell epitopes to antigen-presenting cells applied to peptides from influenza virus, ovalbumin, and hen egg lysozyme: implications for peptide vaccination

Targeting of antigens to antigen-presenting cells (APCs) increases CD4(+) T cell activation, and this observation can be exploited in the development of new vaccines. We have chosen an antigen-targeting approach in which we make recombinant antibodies (Abs) with T cell epitopes in their constant region and APC-specific variable regions. Three commonly used model epitopes, amino acids 110-120 of hemagglutinin, 323-339 of ovalbumin, and 46-61 of hen egg lysozyme, were introduced as loops in the C(H)1 domain of human IgG3. For all three epitopes, we show that the recombinant molecules are secreted from transfected cells. The epitopes are presented to specific T cells, and targeting to IgD on B cells in vitro enhances the presentation efficiency by 10(4) to 10(5) compared with the free peptide. After i.v. injection, the epitopes targeted to IgD are presented by splenic APCs to activate specific T cells, whereas little or no activation could be detected without targeting, even after the amount of antigen injected was increased 100-fold or more. Because a wide variety of T cell epitopes, in terms of both length and secondary structure, can be tolerated in loops in constant domains of Abs, the Ab constant region seems to have the intrinsic stability that is needed for this fusion molecule strategy. It might thus be possible to load the Ab with several different epitopes in loops in different domains and thereby make a targeted multisubunit vaccine.     

Treatment of recurrent neurocardiogenic syncope with cardiac inhibitors with ipratropium bromide

Pharmacological approaches for the treatment of cardioinhibitory vasovagal syncope are controversially discussed in the literature. In acute treatment of neurocardiogenic syncope, anticholinergics (atropine) are used effectively. Randomised and placebo-controlled clinical trials evaluating the preventive significance of anticholinergic agents in the therapy of cardioinhibitory vasovagal syncope are still missing.We report the case of an 18-year-old male patient with recurrent convulsive, cardioinhibitory neurocardiogenic syncope. Vasovagal syncope occurred predominantly as centrally induced syncope triggered by negative emotions such as fear or by seeing blood. Under resting conditions, the patient revealed increased parasympathetic tone with nocturnal bradycardia of 38 beats/min. In the course of head-up tilt table testing a cardioinhibitory syncope with an asystolic pause of 10 seconds occurred without any prodromes after 10 minutes of upright positioning. In order to inhibit parasympathetic tone, medication with ipratropiumbromide was initiated. Time-variant analysis of heart rate variability (autoregressive model) during head-up tilt table testing showed under the medication with ipratropiumbromide a vagal mediated cardioinhibition to 56 beats/min, but no further sinus arrest.Throughout clinical follow-up of 6 months the patient remained syncope-free under the medication. The usefulness of ipratropiumbromide in inhibiting vagal mediated cardioinhibition will be discussed referring to the case report and to studies evaluating anticholinergic agents in the treatment of neurocardiogenic syncope.     

<Emphasis Type="Italic">Streptobacillus moniliformis</Emphasis> septic arthritis: a clinical entity distinct from rat-bite fever?

Background  

Streptobacillus moniliformis is a zoonotic agent associated with rodent contacts. Although it is more commonly reported to cause rat-bite fever with reactive arthritides, it can also lead to pyogenic infection of the joints.     

Fluorouracil (5-FU) induced acute immune haemolytic anaemia

A female patient on Fluorouracil (5-FU) therapy for rectal carcinoma developed acute intravascular haemolysis with her fifteenth drug injection; a similar episode occurred later after a controlled challenge with the drug. A 5-FU-dependent complement-activating IgM antibody, which reacted with RBC in an indirect antiglobulin test, was detected in her serum. The antibody did not react with cord RBC, but a blood group specificity could not be determined. An excess of 5-FU in the indirect antiglobulin tests resulted in inhibition of these reactions.     

Characterization of an antibody to factor VIII in a patient with acquired hemophilia with circulating immune complexes

A 73-year-old previously healthy woman was admitted because of severe bleeding from esophagitic lesions and intraabdominal bleeding following hysterectomy. Acquired hemophilia, probably due to an IgG antibody to factor VIII (64 inhibitor units/ml) was noticed, the VIII:C in the patient's plasma being 18% or normal. Immune complexes isolated by polyethylene glycol precipitation had only a weak factor VIII inhibiting activity whereas IgG purified from the complexes and monomeric IgG present in her plasma exerted a strong inhibition. Removal of the complexes from plasma had no effect on the inhibitor titer thus indicating that only a minor part of the antibody was circulating as immune complexes. Plasma or purified IgG from the patient decreased the VIII:C of normal plasma to 18 og 14%, respectively, total inhibition being impossible to achieve even in antibody excess, probably reflecting residual activity of factor VIII bound to the patient's antibodies. The ristocetin cofactor activity of normal plasma was unaffected by the antibodies. Transfusion of factor VIII concentrate to the patient resulted in therapeutic levels of circulating factor VIII and transfused factor VIII circulated longer than usual. Partial remission of the disease with adequate levels of VIII:C occurred after 3 months.     

Serum interleukin-3 levels following autologous or allogeneic bone marrow transplantation: effects of T-cell depletion, blood stem cell infusion, and hematopoietic growth factor treatment

Engraftment of marrow following autologous or allogeneic bone marrow transplantation (BMT) may be influenced by quantity and function of stem cells. T lymphocytes, supporting microenvironmental cells, and hematopoietic growth factors (HGF). To elucidate the physiologic role of interleukin-3 (IL-3) in the engraftment process, serum IL-3 levels were measured in over 400 samples from 77 transplant recipients before and for up to 3 weeks following transplantation using a novel enzyme- linked immunoabsorbent assay (ELISA) with a sensitivity of > or = 78 pg/mL. Thirty-seven patients received two to three log T-cell-depleted allografts. In the remaining 40 patients (18 autologous marrow, 12 allogeneic marrow, and 10 autologous peripheral blood [PB] stem cell), T cells were not depleted (non-TCD) from the grafts. A burst of IL-3 (peak levels, 1,500 to 6,000 pg/mL) was detected in the immediate posttransplant period between day 0 and day 14 in all non-TCD recipients and in 21 of 37 (57%) of TCD recipients. A strong inverse relationship between IL-3 levels and absolute neutrophil count (ANC) was observed in both non-TCD recipients (r = -.796) and in TCD recipients (r = -.897). However, both peak IL-3 levels and mean IL-3 levels from day 0 through 14 were significantly lower in TCD recipients compared with either autologous or unmodified allogeneic marrow recipients (P < .01). The lowest peak or mean day 0 through 14 IL-3 levels were observed in matched related recipients undergoing the most aggressive (2.5 to 3.0 log) T-cell-depleted BMT. Autografted patients receiving blood stem cell transplants alone or posttransplant granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage colony stimulating factor (GM-CSF) also had significantly lower peak IL- 3 levels (P < .01). In patients receiving TCD grafts, administration of antithymocyte globulin (ATG) posttransplant significantly increased peak IL-3 levels compared with patients not treated with ATG (P < .04). This study shows that endogenous release of IL-3 is strongly associated with myeloid engraftment and inversely related to ANC. Removal of T lymphocytes from donor marrow or acceleration of engraftment by use of stem cells or growth factors appears to blunt the endogenous release of IL-3 whereas use of ATG posttransplant increases IL-3 release.     

Manipulation under joint anesthesia/analgesia: a proposed interdisciplinary treatment approach for recalcitrant spinal axis pain of synovial joint origin

BACKGROUND: Manipulation under joint anesthesia/analgesia (MUJA) is an approach to treatment for patients with chronic, recalcitrant spinal axis pain of synovial joint origin. MUJA is the synthesis of fluoroscopically and corticosteroid agents with targeted, manual mobilizations and/or manipulations of the injected joint(s). DISCUSSION: MUJA should be viewed with guarded optimism because its success is based solely on anecdotal experience. Many physicians (specializing in targeted intraarticular "blocks" of spinal synovial joints) and chiropractors (specializing in manual mobilization and manipulation of spinal synovial joints) in the Tyler, Texas, area have treated more than 1000 patients over a 7-year period with the MUJA protocol. This protocol includes treatment of the atlanto-occipital and lateral atantoaxial joints of the upper cervical spine, the zygapophysial joints of the cervical spine from C2-3 to C6-7, the thoracic spine and the lumbar spine, and the pelvic sacroiliac joints. CONCLUSION: The following patient types are suitable candidates for MUJA: patients with dominant spinal axis pain who have been unable to progress despite the passage of sufficient time (>2 months) and the delivery of prior treatments, including spinal manipulative therapy; patients with pain so severe that standard manipulative therapy cannot be delivered with technical success; and patients with complex problems in whom the diagnosis of synovial joint-mediated spinal pain must be established before the safe delivery of manipulative therapy.     

Telomerase activation in normal B lymphocytes and non-Hodgkin's lymphomas

Activation of telomerase seems to be a prerequisite for immortalization and is found in permanent cell lines and most malignant tumors. Normal somatic cells are generally telomerase negative, except for bone marrow stem cells. Weak activity is also present in peripheral blood cells. In the present study strong telomerase activity was demonstrated in vivo in normal mature cells of the immune system, as well as in malignant lymphomas. Benign lymph nodes had lower telomerase activity than benign tonsils, which exhibited intermediate to high activity comparable with findings in malignant lymphomas. In benign tonsils the activity seemed to be restricted to germinal center B cells. In benign lymphoid tissues telomerase activity correlated with B-cell numbers and cell proliferation, but this was not observed in the lymphoma group. High- grade lymphomas exhibited higher levels of telomerase compared with low- grade cases. The data showed that in vivo activation of telomerase is a characteristic feature of germinal center B cells. Different signals for activation of telomerase are likely to exist, one of them being immune stimulation. The data suggest that telomerase activity in malignant lymphomas can be explained by an "induction and retention" model, ie, transformation occurs in a normal, mature B cell with reactivated telomerase, which is retained in the neoplastic clone.