La définition d'une stratégie vaccinale vis-à-vis des maladies parasitaires a longtemps reposé sur le concept d'antigène spécifiques de stades évolutifs, exposés à la surface du parasite. D'un point de vue évolutif, il semble préférable d'envisager que les structures fonctionnelles essentielles pour le parasite n'obéissent pas à ces critères mais correspondent plutôt à des structures exprimées de manière transitoire à la surface du parasite et avec d'autres topographies pour les autres stades. Enfin, la démonstration qu'un même antigène peut entraîner la production d'anticorps protecteurs et d'anticorps bloquants, amène à reconsidérer l'importance de l'isotype anticorps produit lors d'une immunisation. A l'aide de ces nouveaux concepts, une stratégie vaccinale a pu être développée vis-à-vis des schistosomiases, et son application à d'autres modèles d'infection chronique est discutée.
In Caucasian populations, rheumatoid arthritis (RA) is generally associated with serologic HLA-DR4 specificity. In order to refine this correlation in the HLA-D region, we used six different probes pertaining to this locus: DR beta, DQ beta, DQ alpha, DO beta, DP beta and DP alpha. In this step, pooled RA and control DNA were hybridized with DR beta and DQ beta probes after digestion with 12 different endonucleases. Some bands appeared specific in the RA pool. In fact, with genomic DNA from 13 unrelated typed RA patients and 12 matched or partially matched control cells, these bands were revealed to be related to DR4 and/or DR1, with DR beta and DQ beta probes hybridizing BamHI, EcoRV, PvuII and StuI digests. With other probes, no differences could be related to RA disease. The polymorphism detected by these probes was suggestive of a gradient of decreasing complexity from DR beta to DO beta through DQ beta and DP beta, which could reflect discrete functions of each subregion.
We have recently described an autonomously activated set of T cells in the spleens of normal and "antigen-free" mice which display effector T helper (TH) or T suppressor (TS) activities; we describe here an intrathymic effector T-cell compartment which directly helps or suppresses B-cell responses and appears to be distinct from the peripheral set of effector cells. Splenic effector T cells do not represent recent thymic migrants (because adult thymectomized mice have unaltered levels of effector TH and TS cells in the spleen), nor do intrathymic effector T cells represent circulating peripheral T cells (since thymic effector T cells are B2A2+, while splenic effector T cells are B2A2-). Furthermore, effector TH cells within the two compartments exert differential effector activities: splenic effector TH cells induce B cells to both proliferation and maturation, while thymic effector TH cells are defective in activating B-cell maturation. The present findings extend our studies on "natural" lymphocyte activities in the normal immune system, revealing the existence of two apparently distinct effector T-cell compartments. The potential significance of the intrathymic set of effector cells in repertoire selection is considered.
Reducing host carriage of transmission-stage malaria parasites (gametocytes) is expected to decrease the population-wide burden of malaria. Some malaria disease severity is attributed to the induction of the pro-inflammatory cytokines TNF-α and lymphotoxin-alpha (LT-α), and we are interested in whether anti-malaria interventions which ameliorate the symptoms induced by those cytokines may have the capacity to alter malaria transmission. As many functions of TNF-α and LT-α are exerted through TNF receptor 1 (TNFR1), we investigated the effect TNFR1 blockade exerted on parasite transmission using the rodent malaria Plasmodium chabaudi chabaudi. We found that blocking TNFR1 simultaneously increased gametocyte density and infectivity to mosquitoes, whilst reducing disease severity (weight loss). These transmission-enhancing and severity-reducing effects of TNFR1 blockade were independent of asexual parasite load and were observed for several P. c. chabaudi genotypes. These results suggest that the effects of candidate malaria interventions on infectivity should be examined alongside effects on disease severity so that the epidemiological consequences of such interventions can be evaluated.
In the developing avian and mammalian embryo, haemopoietic cells appear first in transient foci whose function is restricted to discrete periods of embryogenesis. These foci are essentially represented by the yolk sac, intraembryonic dispersed foci and the liver. Haemopoietic cells then repopulate the developing spleen, thymus and bone marrow, organs which persist and develop after birth. In the present review, we describe a number of possible mechanisms controlling specific adhesion, oriented migration and invasiveness of haemopoietic cells. One concerns the high specificity of the interactions of homing receptors on the surface of haemopoietic cells with determinants on vascular endothelium and/or thymic epithelium. A second is the importance of the presence of some macromolecules in the extracellular matrix, such as fibronectin, collagen, laminin and elastin. These components can interact with the haemopoietic cells (and/or induce chemotaxis) via the existence of specific receptors on the surface of the haemopoietic cells. Another mechanism is the activation of the haemopoietic cells through the interactions of cell-chemotactic factor, cell-extracellular matrix and/or cell-thymic epithelium. This activation can lead to: 1) the expression of new specific cell-surface receptors for the target foci; 2) the secretion of specific protease and glycosidase systems active upon the extracellular matrix; and 3) the differentiation of these cells in the thymus.
An anti-Klebsiella pneumoniae K5a capsular polysaccharide vaccine was evaluated as a preventive approach for protecting squirrel monkeys, Saimiri sciureus, in our breeding colony. Based on an 8-month vaccination schedule over a period of more than two years, this vaccine, regardless of the animal's age, resulted in a reduction of this particular bacterial infection and its generally associated fatal outcome. IgG antibody responses in naive and vaccinated animals were monitored over an extended period by radioimmunoassay and showed a marked increase above the initial naturally occurring antibody titres. No side-effects were observed after repeated vaccination of several hundred animals during a two-year period.
In order to characterize the role played by CD4+ T lymphocytes in the immunopathology of acute Trypanosoma cruzi infection, we compared the numbers of blood and tissue parasites and the heart inflammatory reaction in normal and anti-CD4 antibody-treated C3H mice. Treatment of mice with anti-CD4 mAb during acute infection markedly inhibited T-helper-cell-dependent activities, as measured by peritoneal macrophage activation and immunoglobulin secretion by splenic B lymphocytes. After in vivo inactivation of helper T cells, the number of blood and tissue parasites significantly increased, while the inflammatory cellular infiltrates of heart muscles diminished. Our results indicate that CD4+ T lymphocytes play a dual role in the immunopathology of acute experimental Chagas' disease.
The network theory predicts that a subpopulation within the antiidiotypic (anti-Id) antibody response will be the internal image of the priming stimulus. In myasthenia gravis, a portion of the anti-acetylcholine-receptor (anti-AChR) antibody repertoire is directed against the ligand-binding site. These antibodies would be expected to elicit an "anti-idiotype" which is the internal image of the receptor-binding site and hence may also bind cholinergic ligands. We have utilized this theoretical specificity to isolate anti-Id antibodies with AChR-like ligand-binding properties from the serum of 4 myasthenia gravis patients using a choline affinity column. Affinity-purified antibodies from one patient were characterized and found to exhibit binding properties similar to the AChR for various cholinergic ligands.
Anti-acetylcholine-receptor antibodies of IgG and IgM classes and antiidiotypic antibodies were determined in patients with myasthenia gravis at various times after the start of the disease. Patients with a disease duration of less than one year had a higher prevalence of antiidiotypic antibodies (31/32) than patients who had had the disease for more than 5 years (49/79), and the concentration of antiidiotypic antibodies was also higher in patients with early disease (p less than 0.005). The concentrations of antiidiotypic antibodies decreased during progression of the disease concomittant with an increase in IgG anti-receptor antibodies. A change from IgM to IgG anti-receptor antibody production was also found. In two patients, who developed myasthenia after bone-marrow grafting and who were followed before start of disease, antiidiotypic antibodies appeared before anti-receptor antibodies and before symptoms of myasthenia were present. The high prevalence and concentration of antiidiotypic antibodies in early disease indicate that development and expression of antiidiotypic antibodies are important in early myasthenia gravis.
Lepromatous leprosy patients generally have reduced response to Mycobacterium leprae antigens in an in vitro lymphocyte transformation test, which could be due to insufficient generation of reactions or to active suppression of any reaction generated. We could detect 3 types of lack of reactivity: one which could be restored by the addition of supernatants from healthy, PHA-stimulated lymphocyte cultures, one which could not thus be restored and one in which the culture supernatant contained factors able to suppress mitogen responses of healthy cells. We compared responses of cells rom untreated patients, patients treated for 12–20 months with multiple drug therapy and patients with up to 20 years of dapsone treatment; all types of the disease were represented.
Experimental data on thymidine incorporation by T cells as a function of the number of B cells and of the amount of antigen present on B cells are analysed.The data imply that T cells expand only after B cells deliver two signals. One signal is proportional to the antigen present on the surface of B cells and is immunologically specific; the other signal is independent of the antigen present on B cells and therefore is not immunologically specific.
During aging an increased number of CD16+ lymphocytes and an impaired NK cell function have been demonstrated both in fresh and cloned NK cells obtained from the peripheral blood of elderly subjects. Recently, two novel surface molecules have been identified by GL183 and EB6 monoclonal antibodies on subsets of resting or activated NK cells. The expression of GL183 and/or EB6 identifies four distinct phenotypically stable NK subsets: GL183+EB6+, GL183−EB6−, GL183+EB6−, GL183−EB6+. Our study aimed at analyzing the distribution of GL183 and EB6 NK cell subsets in a group of elderly people and at establishing whether a different distribution of these NK lymphocyte subpopulations is related to the altered cytolytic activity found in the elderly. A broad individual variability in the percentages of CD16+GL183+ or CD16+EB6+ cells was observed. Nonetheless, the mean percentage of GL183+ cells in the elderly group showed a significant increase. The cytolytic activity of GL183+ and EB6+ sorted subsets showed a decrease that was almost equally distributed between the two subpopulations. Given the hypothesis of the ability of NK cells to discriminate between self and non self, the decreased cytolytic activity of GL183+ and EB6+ subsets could be related to a generally decreased ability of aging NK cells to recognize specific target cells.
An immunization procedure was developed to induce protection of mice against the gastrointestinal helminth Nippostrongylus brasiliensis. Mice immunized by the oral route with antigens which were released by adult worms during their in vitro survival in a detergent-containing medium and which were entrapped in liposomes were protected against a challenge infection.
The influences of prostaglandin E2 (PGE2), 15-hydroxyeicosatetraenoic acid (15-HETE) and leukotrienes (LT) on the proliferative response of mature (PNA−) and immature (PNA+) mouse thymocytes was investigated. Both PNA+ and PNA− thymocytes proliferated when cultured with concanavalin A plus interleukin-2. PGE2 in concentrations of 10−6 to 10−9 M caused significant inhibition of proliferation of both PNA+ and PNA− thymocytes in these cultures. In contrast, the lipoxygenase products 15-HETE, LTB4, LTC4 and LTD4 caused marked increases in proliferation of PNA+ thymocytes while having no effect on PNA− cells. Therefore, the effect of leukotrienes on thymocyte proliferation depends upon the level of cell maturation and mainly affects immature PNA+ thymocytes.
In this study, we used preparations highly enriched in human natural killer (NK) cells to further characterize the mechanism of target-cell-induced NK inactivation. Highly enriched populations of NK cells were obtained by a newly developed, single-step sheep red blood cell rosette assay. This method, which did not require any incubation steps to facilitate cell contact, permitted a rapid and efficient isolation of NK cells from adherent-cell-depleted peripheral blood lymphocytes. The non-rosetted cells had high NK activity, possessed large granular lymphocyte (LGL) morphology and expressed the NK-associated antigens Leu-11a, Leu-7, OKM1 and NKH-1. In contrast, the rosetted cells had significantly lower NK activity, possessed typical lymphocyte morphology and expressed the T-cell-associated marker OKT3. Next, we examined the ability of these NK-enriched effector cells (ECc) to become inactivated by K562. Functional studies revealed that ECc lost greater than or equal to 95% of their lytic capacity following incubation with K562 at a ratio of 2/1 for 6 h. However, to achieve this level of inactivation, it was essential that the cell suspension be gently mixed every 90-120 min. Inactivation was not due to cell death and did not reflect changes in the percentages of cells bearing the Leu-11a, Leu-7, OKM1 and NKH-1 antigens, but was associated with an increase in cell surface concentration of OKM1. As judged by gross morphology, the percentages of LGL in ECc before and after treatment with K562 were essentially the same. Finally, K562-treated ECc also lost their ability to mediate antibody-dependent cellular cytotoxicity (ADCC), suggesting that both NK-cell-mediated cytotoxicity and ADCC may involve a common lytic pathway.
