Review
The Complexities of CD28 and CTLA-4 Signalling: PI3K and Beyond
STEPHEN G. WARD
Abstract. A successful immune response requires a set of non-cognate cell-cell interactions which provide the second „costimulatory” signal to the T cells. The best characterized costimulatory receptor expressed on resting T cells is CD28 which provides poorly-defined cyclosporin-resistant biochemical signal(s) that promote expres- sion of several cytokines/chemokines. Another major effect of CD28 ligation is the promotion of cell survival which is thought to occur via the up-regulation of Bcl-xL expression. SD28 shares its ligands B7.1 and B7.2 with the related CTLA-4, which plays an inhibitory role in T cell activation. Manipulation of CD2B/CTLA-4 interac- tions with their natural ligands has provided exciting results in transplantation and tumor therapy settings and also has potential in the treatment of several diseases such as arthritis and multiple sclerosis, asthma and protection against HIV infection. The biochemical basis for the different functional outcomes of CD2B and CTLA-4 ligation has been the subject of intense investigation over the past few years. This review will focus on our current understanding of the biochemical signals that may be involved in regulating the different functional outcomes of CD2B and CTLA-4, with particular emphasis on the role played by the PI3K-dependent signalling cascade.
Keywords: T cell; CD2B; CTLA-4; PI3K; signalling.alling.
Thymic Peptides and Preparations: an Update
OSCAR J. CORDERO, ALICIA PIŃEIRO and MONTSERRAT NOGUEIRA
Abstract. The possibilities of thymic peptides in human therapy are still being described. Here, we focus on their general characteristics and on recent advances in this area.
Keywords: thymus; thymic peptides; preclinical investigation; therapeutic use; clinical trials.trials.
Tumor Escape from Immune Surveillance
RÉGIS T. COSTELLO, JEAN ALBERT’GASTAUT and DANIEL OLIVE
Abstract. The bases for an efficient anti-tumor immune response begin to be better defined. Nonetheless, neo- plastic cells develop various strategies to escape immune surveillance, which are discussed here in order to better design the therapeutic possibilities of immune manipulation. The absence of specific tumor antigen as well as the weak expression of major histocompatibility complex (MHC) molecules hinder the recognition of the neoplastic cells by T lymphocytes. The defect of expression by the tumor of the ligands for the T cell activation costimu- latory molecules is particularly harmful for the immune response since it induces tolerance. Finally, tumor cells can inactivate effector T lymphocytes through the secretion of inhibitory cytokines, induction of apoptosis or functional inactivation. The multiplicity of the means to oppose an effective anti-tumor response challenges the adaptative mechanisms of the immune system. For example, the natural killer cells target tumor cells not express- ing MHC class I molecules. Numerous possibilities of tumor immunogenicity restoration have been demonstrated at least in vitro, such as stimulation of the cancerous cells by CD4O or cytokine treatment, which could lead to several promising therapeutical approaches.
Keywords: cancer; immunodeficiency; immunotherapy; lymphocyte.hocyte.
Human Acid-Labile Interferon a
EGBERT PIASECKI
Abstract. In acquired immune deficiency syndrome (AIDS) and autoimmune diseases, like systemic lupus erythematosus (SLE), persisting high levels of interferon (IFN) are detectable in plasma. The IFN has been identified as an unusual human acid-labile IFN-a (al-IFN-a). Its properties are similar to that of the known a interferons except sensitivity to acid treatment (pH 2) which is characteristic for IFN-y. The nature of al-IFN-a is not known. Four hypotheses have been presented that suggested that: a) al-IFN-a may be a product of a distinct IFN gene; b) or a posttranscriptionally modified IFN-a molecule; c) the phenomenon of al-IFN-a may be an effect of synergistic action of a mixture of acid-stable IFN-a and acid-labile IFN-y; d) or the effect may be a result of an interaction of acid-stable IFN-a with an unknown factor(s) present in plasma and associated with progression of HIV infection or autoimmune diseases. Neither of the hypotheses have been experimentally proven. To verify the most probable hypothesis of the synergistic interactions between the acid stable and labile IFNs, the experi- ments with the artificial mixtures of nHuIFN-a and rHuIFN-y were performed. The synergistic effect was abolished by the treatment either with pH 2 or with anti-IFN-y antibodies. The residual activity was similar in both cases and corresponded to acid-stable IFN-a. However, al-IFN-y (AIDS serum with high IFN level) was found to be much more sensitive to acid treatment and only negligible effect of anti-IFN-y serum was observed. It suggests that the synergistic effect may be only slightly responsible for the phenomenon of acid lability of IFN-a. Foor explanation of the occurrence of al-IFN-a the hypothesis of existence of a factor(s) interacting with IFN-a should be taken into consideration.
Keywords: interferon; acid-labile interferon a; synergistic action of IFN-a and IFN-y; AIDS; HIV infection; systemic lupus erythematosus; autoimmune diseases.seases.
Substance Abuse and HIV-gp120: Are Opiates Protective?
GEORGE B. STEFANO
Abstract. There has long been a popular conceptual linkage between human immunodeficiency virus (HIV) acquisition and substance abuse involving needles. Indeed, in vitro studies demonstrate that these substances promote the replication of HIV. Included in these in vitro studies is a linkage or association of tissue damage and viral load with the actions HIV envelope protein gp120 with substances of abuse. However, detailed epidemio- logical studies have not supported this association of substance abuse and HIV acquisition, viral load and exacerbated tissue damage. It is with this understanding that we undertake a reevaluation of the in vitro studies within the context of the microvascular immune environment. In this regard, a counter-intuitive hypothesis emerges, namely, that specific substances of abuse may afford a degree of protection from HIV infection. This new hypothesis involves the neural, immune, and vascular signaling molecule nitric oxide.
Keywords: gp120; morphine; monocytes; HIV; immunovascular regulation; nitric oxide. oxide.
Clinical Immunology
Interferon y as Immunomodulator in a Patient with Multiple Myeloma
TERESA KAMIŃSKA, ANNA DMOSZYŃSKA, MARIA CIOCH, IWONA HUS, DARIUSZ JAWNIAK, AGNIESZKA SZUSTER-CIESIELSKA and MARTYNA KANDEFER-SZERSZEŃ
Abstract. We describe here a patient with multiple myeloma, who, while in remission after chemotherapy, received 100 mg of rIFN-’y (Imukin, Boehringer, Ingelheim) subcutaneously 3 times a week for 4 weeks as supportive therapy before autologous peripheral blood stem cell transplantation (PBSCT). The patient was moni- tored for serum IFN, TNF, IL-2 activities and for the ability of peripheral blood leukocytes (PBL) to produce IFN-a/(3, IFN-y, IL-2 and TNF-a after in vitro induction. Changes in the percent of plasma cells in the bone marrow, in the total and differential white blood cell counts, in T cell subsets and NK cells were also monitored. IFN-y yielded no clinical antitumor activity. The number of bone marrow plasma cells increased, however, the percentage of blood and bone marrow NK cells and the CD4/CD8 T cell subset ratio decreased. Monitoring the cytokine production ability of PBL during IFN-’y therapy revealed an increase in IL-2, IFN-’y and TNF-a titers produced upon in vitro induction after 2 weeks of treatment (6 injections of rIFN-y). However, after 9 injections there was a significant decrease in IFN-y and IL-2 production in the PBL, and at the end of therapy ( 12 injections) the decrease not only in IL-2 and in IFN-y but also in IFN-a production was observed. In contrast to these changes, TNF production was strongly enhanced and reached the level observed before the therapy. These data suggest that the schedule of IFN-y therapy in multiple myeloma should perhaps be adapted to become more effective, taking advantage from the immunomodulating activity of IFN-’y.
Keywords: multiple myeloma, rIFN-y therapy; TNF.y; TNF.
Lactoferrin Increases the Output of Neutrophil Precursors and Attenuates the Spontaneous Production of TNF-a and IL-6 by Peripheral Blood Cells
MICHAŁ ZlMECKI, KRYSTYNA SPIEGEL, ANDRZEJ WLASZCZYK, ANDRZEJ KÜBLER and MARIAN L. KRUZEL
Abstract. The aim of this report was to investigate the effects of bovine lactoferrin (BLF) taken orally (per os) by healthy individuals, on selected immune parameters. Three groups of volunteers (7 persons per group) were taken daily for 7 days, one capsule containing 2, 10 or 50 mg of BLF. A control group has taken placebo only. Venous blood was taken for tests a few hours before the first dose of BLF, one day and 14 days after the last dose of the preparation. For the evaluation of BLF action on the immune response system we have chosen 3 parameters: content of neutrophil precursors in the peripheral blood (in percentage), spontaneous production of interleukin 6 (II,-6) and tumor necrosis factor a (TNF-a) by unstimulated blood cell cultures. We found that oral treatment of volunteers with BLF caused a transient (one day after last dose) increase of immature forms of neutrophils in the circulating blood. That increase was more than 2-fold in the case of 10 mg dose. However, statistically significant increases in the percentage of neutrophil precursors were also registered at doses of 2 and 50 mg of BLF. No change in the immature cell content was observed in the placebo group. The treatment with BLF also resulted in a profound decrease of the spontaneous production of IL-6 and TNF-a by cultures of peripheral blood cells. This decrease was significant ( 10 mg/dose) one day following the last dose of BLF and persisted for additional 14 days. These results confirmed our earlier data on the effects of per os treatment with a nutritional preparation containing BLF. Furthermore, we were able to closer establish the optimal dose of BLF affecting selected immune indices.
Keywords: bovine lactoferrin; blood cells; neutrophil precursors; interleukin 6; tumor necrosis factor a.ctor a.
Hydrogen Peroxide in Expired Air Condensate Correlates Positively with Early Steps of Peripheral Neutrophil Activation in Asthmatic Patients
ADAM ANTCZAK, DARIUSZ NOWAK, PIOTR BIALASIEWICZ and MAREK KASIELSKI
Abstract. We have found an increased H202 level in expired air of asthmatic patients. Neutrophils from these subjects generated higher amounts of superoxide radicals after challenge with phorbol esters than those from healthy subjects which may result from an increased activity of NADPH-oxidase. The enhanced Ca2+ mobilisation in neutrophils from asthmatics could be responsible for increased production and subsequent elevated H2O2 concentration in expired breath condensate. In this study we wished to determine whether neutrophils of asthmatic patients have enhanced [Ca ]i response after N-formyl-methionyl-leucyl-phenylalanine – fMLP challenge as compared with cells from healthy donors, and if so, does it correlate with H202 levels in expired air. We examined ? 1 patients, 10 healthy individuals as a control group (mean age 34.3 ± 5.5, 6 males and 4 females) and 11asthmatic subjects (mean age 38.2 ± 7.2, 7 males and 4 females). The rise of [Ca2+]i as an early event of neutrophil activation, was measured spectrofluorimetically with Fura-2-AM. The mean H202 level, measured spectrofluorimetrically in the expired breath of asthmatics, was 20-fold higher than that in healthy control (0.18 ± 0.20 vs. O.OI ± 0.04 pM, p<0.05). [Ca2+]i increase after challenge by fMLP (0[Ca2+]i) was much higher in asthmatics than in control group (205.0 ± 44 vs. 113.0 ± 22 nM, p<0.05, respectively). A strong correlation was observed between H202 and [Ca2+]i and maximal velocity of increase in [Ca2+]i in asthmatics (r = 0.87, p<0.01 and r = 0.64, p<0.05). We conclude that elevated H202 level in the expired breath condensate of asthmatics can be generated by activated neutrophils in the course of mucosal inflammation observed in bronchial asthma.
Keywords: bronchial asthma; hydrogen peroxide in breath condensate; neutrophils; intracellular calcium.alcium.