Walter Fierz

Poor antibody response after tetanus and pneumococcal vaccination in immunocompromised, HIV-infected patients.

Ten patients with symptomatic HIV infection (six with ARC, four with AIDS) received tetanus and 23‐valent pneutnoeoccal vaccination. Anti‐tetanus IgG and IgM, and anti‐pneumococcal IgG against all 23 capsular types of the vaccine were measured on days 0, 11, 17, 30, and 90. Anti‐pneumococcal IgG were simultaneously determined in two plasma pools of 100 healthy unimmunized blood donors and of 112 healthy adults who had previously received a 14‐valent pneumococcal vaccination. Peak IgG responses to both vaccines were observed on day 17; thereafer, the antibody levels gradually fell again. Anti‐tetanus IgG rose from 0.6 U/ml (geometic mean) to 2.0 U/ml on day 17. Anti‐tetanus IgM remained unchanged, Anti‐paeumococcal IgG increased only by 1.14‐fold compared with pre‐vaccination levels (geometric mean of IgG rises against all 23 polysaccharides in 10 patients), and exceeded the upper 95% limit of unvaccinated blood donors in only 30 out of 230 specimens. Pre‐vaceination levels for pneumococcal type‐specific IgG were significantly higher in HIV‐infected patients compared with the pool of unimmunized healthy controls, possibly indicating a higher rate of previous pneumococcal infections in HIV‐seropositive subjects. However, post‐pneumococcai vaccination levels were significantly tower in HIV‐infected patients than in the pool of healthy controls. The increase in anti‐tetanus IgG significantly correlated with the level of CD4 lymphocytes and with in vitro lymphocyte proliferation by pokeweed mitogen (5 μg/ml) and phytohaemagglutinin (2.5 μg/ml), confirming a particularly low vaccination response in patients who were severely immunocompromied.

The role of compartment penetration in PI-monotherapy: the Atazanavir-Ritonavir Monomaintenance (ATARITMO) Trial.

Objectives:To limit exposure to anti-HIV drugs and minimize risk of long-term side effects, studies have looked at the possibility of simplified maintenance strategies. Ritonavir-boosted protease-inhibitor (PI)-monotherapies are an attractive alternative, but limited compartmental penetration of PI remains a concern. Design:Non-comparative 24-week pilot study. Method:Ritonavir-boosted atazanavir (ATV/r) monotherapy administered to fully suppressed patients (>3 month HIV RNA < 50 copies/ml). Plasma was obtained every 4 weeks and cerebrospinal fluid (CSF) and semen at W24. Results:Two patients (7%) failed ATV/r monotherapy. One patient was subsequently identified as a protocol violator since he had a previous history of treatment failure under indinavir. The second patient deliberately decided to stop treatment after W20. Excluding failing patients, individual measurements of HIV RNA in patients having occasional viral ‘blips’ was found in five patients. At W24, 3/20 patients had elevated viral loads in CSF (HIV RNA > 100 copies/ml), and 2/15 in semen, despite viral suppression in plasma (< 50 copies/ml). Samples with elevated HIV RNA (> 500 copies/ml) in CSF were all wild type. The mean ATV drug concentration ratio (CSF/blood, n = 22) was 0.9%. Indicators of altered immune activation (CD8CD38 C-reactive protein) remained unchanged. Conclusion:This study supports previous results indicating the potential use of PI-based mono-maintenance therapies. However, our results in CSF cautions against the uncontrolled use of PI-based monotherapies.

High frequency of non-B subtypes in newly diagnosed HIV-1 infections in Switzerland.

HIV-1 subtypes were determined in newly diagnosed residents of Switzerland. Blood was anonymously collected from patients with a first confirmed positive HIV-1 test result. Viral DNA from the env V3-V5 region was amplified by nested polymerase chain reaction (PCR) and screened for subtype B by heteroduplex mobility assay. All amplicons not identified as B were sequenced. From November 1996 to February 1998, 206 samples were analyzed. Main transmission risks were unprotected heterosexual (55.7%) or homosexual (27.1%) sexual contact or intravenous drug use (12.9%). Subtype B dominated in patients of Swiss, other European, American, or Asian citizenship; particularly high frequencies were found in homosexuals (97%) and drug users (94%). Non-B subtypes including A, C, D, E, F, G, H, a possible B/F recombinant, and a sequence related to J were present in 28.2% (95% confidence interval [CI], 22.9%-35.0%). Non-B were frequent in African citizens (95%), heterosexually infected individuals (44%), and women (43%). Heterosexually infected Swiss males harbored non-B strains in 18% and females in 33%. The results document a change in the epidemiology of newly diagnosed HIV-1 infections in Switzerland: predominance of heterosexual transmission and a high frequency of non-B subtypes.

Immune Mechanisms in Inflammatory Polyneuropathya

I t has been increasingly recognized that a small proportion of patients with the acute Guillain-Barrk syndrome (GBS) have a severe form of the disease with a poor prognosis. Clinical, pathologic, and electrophysiologic studies have demonstrated that axonal degeneration characterizes nerve pathology in these cases. Clinically, the disease reaches peak severity much earlier in these patients than in most other GBS patients, and they require ventilatory assistance more often. In some patients, conduction block occurred at distal sites, whereas in others there was electrophysiologic evidence of widespread muscle denervation. Thus, patients that fulfill all of the established diagnostic criteria for GBS may either-in the majority-have a demyelinating polyneuropathy with conduction slowing or block that is milder and yields better recovery, or have axonal damage with conduction failure, signaling severe disease with slower recovery (TABLE 1). It is unclear at present whether the axonal form is part of the spectrum of GBS

Astrocytes as antigen-presenting cells. Part II: Unlike H-2K-dependent cytotoxic T cells, H-2Ia-restricted T cells are only stimulated in the presence of interferon-γ ☆

Various studies strongly suggest that astrocytes are potent immune-regulating cells. They can be activated to release prostaglandin E, interleukin-1- and interleukin-3-like factors. Cocultivation of antigen-specific T cell lines and astrocytes results in induction of Ia on astrocytes and antigen-specific proliferation of T cells. In the current study, astrocytes were found to be incapable of serving as stimulator cells when unprimed T lymphocytes were used as responders in syngeneic or allogeneic lymphocyte reactions. However, when interferon-gamma (IFN-gamma) was added, astrocytes became Ia positive and potent stimulators in both syngeneic or allogeneic lymphocyte responses. In the presence of IFN-gamma, astrocytes presented antigens to Ia-restricted T hybridoma cells; in contrast hapten was presented to Kb-restricted cytotoxic cloned T cells by astrocytes in the absence of IFN-gamma. Thus, cultured astrocytes do function directly as accessory cells in class I antigen-dependent T cell activation, whereas Ia induction by IFN-gamma is necessary to enable them to present antigen to class II antigen-restricted T cells.

Ritonavir boosted indinavir treatment as a simplified maintenance "mono"-therapy for HIV infection.

Triple combination is currently the fundamental concept for HIV therapy. We evaluated the feasibility of a 48-week maintenance therapy with ritonavir-boosted indinavir in 12 HIV-infected patients. All patients maintained viral suppression (< 50 copies/ml) throughout the study (one drop-out after week 32) and opted to continue on this monotherapy thereafter. At week 48, no changes in fat distribution patterns were detectable using a dual-energy X-ray absorptiometry scan. These results support the further evaluation of mono-maintenance trials.

Ciclosporin A prevents P2 T cell line-mediated experimental autoimmune neuritis (AT-EAN) in rat

Adoptive transfer experimental autoimmune neuritis (AT-EAN) produced in Lewis rats by injection of P2-reactive T lymphocyte line cells offers the unique possibility to study the exclusive contribution of cell-mediated immune responses to the pathogenesis of autoimmune disease of the peripheral nervous system (PNS). It further lends itself to the evaluation of novel therapeutic approaches that may bear relevance to the human acute Guillain-Barré syndrome. The effects of the immunosuppressive agent ciclosporin A on the clinical, electrophysiological and morphological expression of AT-EAN were examined. We found that ciclosporin A suppressed development of the disease. In view of the known actions of ciclosporin A on T cells, these results indicate the requirement of activation and clonal proliferation of T lymphocytes to produce myelin damage in autoimmune diseases of the PNS.

High Proportion of Gamma-Delta T Cell Receptor Positive T Cells in Bronchoalveolar Lavage and Peripheral Blood of HIV-lnfected Patients with Pneumocystis carinii Pneumonias

To investigate the local immunological situation in the lung of HIV-infected patients with Pneumocystis carinii pneumonias (HIV-PCP), we analyzed the proportion and the distribution of lymphocyte subpopulations and their state of activation in bronchoalveolar lavage (BAL) and peripheral blood of 21 HIV-PCP patients (CDC classification group IV) compared to 24 HIV-negative patients with interstitial lung diseases (ILD). Peripheral blood lymphocytes (PBL) and BAL cells were stained with monoclonal antibodies. Two-color cytofluorometric analysis (flow cytometry) was performed with a cytofluorograph (Epics Profile, Coulter Corp., Hialeah, Fla., USA). In BAL from HIV-PCP patients the number of CD3-positive lymphocytes was significantly increased, yet there was no difference in the number of macrophages and neutrophils when compared to patients with ILD. Quantification of lymphocyte subpopulations showed that the increased number of BAL CD3-positive lymphocytes in HIV-PCP patients was mainly due to a significantly increased number of CD8-positive T cells, while the pulmonary CD4-positive T cells were decreased both in relative and absolute numbers. As a consequence, an inverted pulmonary CD4/CD8 ratio resulted for HIV-infected patients with PCP. Analysis of in-vivo-activated T cells in BAL and peripheral blood when measured by the expression of IL-2R, HLA-DR and VLA-1 revealed increased numbers of IL-2R and HLA-DR bearing CD8-positive T cells but significantly decreased numbers of IL-2R and HLA-DR bearing CD4-positive T cells as well as a higher number of CD8/CD57 double positive T cells in HIV-infected individuals when compared to patients with ILD.(ABSTRACT TRUNCATED AT 250 WORDS)

Atypical, cytoplasmic and perinuclear anti‐neutrophil cytoplasmic antibodies in patients with inflammatory bowel disease

Atypical, cytoplasmic and perinuclear anti‐neutrophil cytoplasmic antibodies (x‐, c‐ and pANCA, respectively) are associated with a variety of inflammatory diseases, including inflammatory bowel disease (IBD). Anti‐neutrophil cytoplasmic antibodies are more common in patients with ulcerative colitis (UC) than in patients with Crohns disease (CD). Most publications only refer to p‐ and cANCA in relation to IBD. We have prospectively evaluated the reactivity of sera from 58 patients with IBD and 10 healthy controls against human neutrophils with emphasis on the distinction of the ANCA types. The sera were incubated with ethanol‐ and formaldehyde‐fixed granulocytes to differentiate between c‐, p‐ and xANCA. The results showed that 10 of 24 patients with UC were positive for ANCA, whereas only one of 34 patients with CD was ANCA positive. These results correspond to a sensitivity of 42%, a specificity of 97%, a negative predictive value of 91% and a positive predictive value of 75% in UC. Of the 11 ANCA‐positive sera, two showed a cytoplasmic staining pattern, three showed a perinuclear and six an atypical staining pattern. The disease activity was not correlated to either the ANCA titre or to the presence of ANCA in the serum. In conclusion, ANCA are of limited value in differentiating between UC and CD. Because the majority of ANCA in patients with IBD are xANCA, these ANCA should be explored by not only incubating on ethanol‐fixed granulocytes, but also on formaldehyde‐fixed granulocytes.

Suppression of P2- T cell line-mediated experimental autoimmune neuritis by interleukin-2 receptor targeted monoclonal antibody ART 18

The monoclonal antibody ART 18 directed to the rat interleukin-2 receptor (IL-2 R) was administered to Lewis rats immediately prior to and/or on consecutive days after adoptive transfer of autoreactive P2-T line lymphocytes. The effects of ART 18 and sham treatment on the development of adoptive transfer--experimental autoimmune neuritis (AT-EAN) were assessed by clinical inspection, serial electrophysiological monitoring, and semiquantitative histomorphological analysis. Early injection of ART 18 suppressed AT-EAN while treatment after appearance of clinical signs did not. Since the IL-2 R is expressed exclusively on proliferating T cells activated by antigen, the in vivo application of an IL-2 R-targeted monoclonal antibody allows for more selective immunosuppression of experimental autoimmune disease of the peripheral nervous system than has previously been achieved.