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Immunostimulating Complexes

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Immunostimulating Complexes Clin Exp Immunol 1995; 102:46-52 Antigen presentation by naive macrophages, dendritic cells and B cells to primed T lymphocytes and their cytokine production following exposure to immunostimulating complexes M. VILLACRES-ERIKSSON Swedish University of Agricultural Sciences, Department of Veterinary Microbiology, Division of Virology, Uppsala, Sweden (Received 23 May 1995) SUMMARY Influenza virus envelope proteins incorporated into immunostimulating complexes (iscoms) are taken up and processed by various kinds of antigen-presenting cells (APC), encompassing peritoneal cells (PEC), unfractionated splenocytes, splenic dendritic cells (DC) or B cells. The iscom-pulsed naive APC stimulated primed T cells to proliferate and produce cytokine in vitro. In contrast, only DC and B cells pulsed with the same antigen (Ag) in the micelle form functioned as accessory cells stimulating the primed T cells to proliferate and produce cytokine. In general, iscoms were better inducers of cell proliferation than micelles. Iscoms stimulated more secretion of IL-2 and interferon-gamma (IFN--y) than the micelles, but both antigenic forms stimulated secretion of IL-4. DC and B cells pulsed with iscoms stimulated most efficiently the secretion of IL-2 and IFN--y. DC were superior to the other APC in stimulating primed T cells to secrete IFN--y. On the other hand, micelles stimulated more efficiently than iscoms splenic T cells from micelle- primed as well as iscom-primed mice to secrete IL-10. These data indicate that influenza virus envelope proteins incorporated in iscoms stimulate a broad T cell response, possibly emphasizing a Thl type of response. The same Ag in a micelle form induce a more prominent Th2 type of T cell response. The results indicate that the administration of an Ag in an adjuvant formulation can superimpose a different cytokine profile on the immune response than that induced by the protein Ag alone. Keywords iscoms APC antigen-presentation cytokines adjuvants INTRODUCTION for evolving the one or the other type of immune response are it is conceivable that the cells Several studies have revealed that protective immunity to not yet understood, taking up, to immune pathogenic microorganisms is not primarily determined by processing and presenting antigen (Ag) competent the level but rather by the type of immune response. The cells are crucial for the initiation and outcome of the response. activation of CD4+ T cell subsets For instance, dendritic cells (DC) are required as antigen- preferential helper [1] cells for the of interferon- certain determines whether a or presenting (APC) production secreting cytokines protective reactions and T even a detrimental immune will For gamma (IFN-7y) in allogenic [7] cytotoxic response develop. example, both in vivo and in vitro in human leprosy as well as in murine leishmaniasis, progres- lymphocyte (CTL) response [8,9]. sion of disease is associated with the development of the Th2 Therefore, knowledge of the mechanism of APC activation role in induction of immune is of a of T cell In HIV virus and their the response type response [2,3]. infection, healthy interest for the rational and of a of while primary design development positive individuals display Thl type response, vaccines. to be linked to a efficient progression immunodeficiency may develop- is a 40 nm Th2 Additional Immunostimulating complex (iscom) cage-like ment of a ThO [4] or cytokine response [5]. of A and in which support for this thesis has been provided by the survival of IL-4 particle made up Quil triterpenoids lipids, soluble can be deficient mice infected with MAIDS virus [6]. While the reasons amphipathic proteins incorporated by hydro- phobic interactions [10,11]. In the iscom, a multimeric form of Correspondence: Maria Villacres-Eriksson, Swedish University of the Ag is combined with a built-in adjuvant activity. Several Agricultural Sciences, Department of Veterinary Microbiology, Divi- studies have shown that iscom-borne Ag induces immune sion of Virology, Box 585, Biomedical Center, S-75 123 Uppsala, responses under MHC class I and II restriction [12-161. Sweden. These studies complemented with recent evidence [17] strongly 46 4t 1995 Blackwell Science Ag presentation and cytokine induction by iscoms 47 Table 1. The conditions and detection limit of the immunoassays for cytokines Detection limit Cytokine Coating Blocking Second Ab (pg/ml) IL-2 1 jig/ml pH 9-6 1% BSA 1:3000 50 IL-4 3 pg/ml pH 9-6 5% skimmed milk 1:1000 35 IL-10 4,jg/ml pH 8-2 1% BSA 1:1500 60 IFN-'y l2pg/ml pH 7-4 1% BSA 1:2000 750 indicate that iscom-borne Ag has access to the cytosol of APC. APC or as a source of DC or B cells. Splenocyte suspensions Iscoms as well as its matrix, i.e. the iscom structure devoid of contained 24-25% Thy 1.2+ cells, 48-50% Ig+ cells and 1% protein, stimulate the secretion of IL-1 by murine splenocytes DC as determined by immunofluorescence. For separation of and peritoneal cells [18]. Increased expression of MHC class II DC, 4 x 107 magnetic beads coated with sheep anti-rat anti- molecules, considered to be a requirement for efficient Ag bodies (Dynabeads, Oslo, Norway) were reacted with 2ml presentation, has been observed in primary stimulation of supernatant from the 33D1 hybridoma cell line (ATCC TIB peritoneal cells and also in primed splenocytes upon restimula- 227, MD), which recognize splenic DC [25]. Beads were mixed tion with iscoms, both in vivo and in vitro [19,20]. Some of these with the splenocyte suspensions (100-200 x 106 in 500 ,ul culture data indicate that macrophages have a relevant role in the medium) and incubated for 30 min at 4°C. Detachment of the enhanced immune response to iscom-borne Ag [18,19]. We and bound cells was done by incubation with 10, l Detach-a-Bead others have previously demonstrated that immunization with Ab (Dynabeads) according to the supplier's instructions. The influenza virus iscoms induces the development of T cells yield of DC was routinely 6- 10 x 105 per spleen, and contained secreting IL-2 and IFN--y [21-23]. In this study we designed >98% 33D1+ cells. experiments to compare the effect ofpresenting an Ag in iscoms For the separation of B cells, suspensions depleted of DC with that in micelles by evaluating their capacity to induce APC to stimulate primed T cells. The T cell response was evaluated by measuring Ag-driven cell proliferation and the profile of 50 15 * cytokines produced. In this case we consider the profile deter- mined by the production of IL-2 and IFN--y as a Thl type of response and the production of IL-4 and IL-IO as a Th2 profile. 25 MATERIALS AND METHODS Experimental design M 0 Unfractionated splenocyte populations, resident peritoneal 0 0 1 x 2 3 4 5 6 cells (PEC), splenic B cells and splenic DC from naive mice 40 30F(1 on A were used as APC for the experiments the induction of IL-2 .-_ rF(d) and IFN--y. Splenic cell suspensions enriched for T lymphocytes from iscom-primed mice were used as responders. 20 Mice Gnotobiotic BALB/c female mice, 10-12 weeks old, were obtained from the National Veterinary Institute, Uppsala, ' 0' 0 Sweden. 1 2 3 4 5 6 1 2 3 4 5 6 Days of incubation Immunizations Mice were primed subcutaneously with 1 pg influenza virus Fig. 1. The capacity of iscom- or micelle-pulsed APC to stimulate the envelope proteins in iscoms or as micelles, and boosted s.c. 4 proliferation of splenic T cells from iscom-primed mice. The APC used weeks later with the same dose. were: (a) unfractionated spleen cell suspension, (b) peritoneal cells, (c) dendritic cells, (d) B cells. The APC were pulsed with influenza virus Iscoms and micelles envelope Ag in iscoms (E) or as micelles (0). Wells receiving medium Iscoms and micelles containing the envelope proteins from the only (U) were used as background controls. The results are expressed as mean ct/min ± s.d. of 3H-TdR incorporation in triplicate wells, and are influenza virus A/PR/8/34 (HlNl) were prepared by the dia- representative of four separate experiments. 3H-TdR incorporation by method as described before [24]. The preparations were lysis the APC cultured in the absence of T lymphocytes was between 100 and sterile filtered and stored at -70°C. 400 ct/min for the unfractionated spleen cell suspension, and 58 and 199 ct/min for B cells and DC. For peritoneal cells cultured with Preparation ofAPC medium only the values were <200 ct/min at all time points, with Resident PEC were recovered from the peritoneal cavity ofmice micelles the values were 310, 382, 873, 2079 and 84 ct/min from day I to by washing with sterile PBS under aseptic conditions. Single cell 5, and for iscoms the values were 130, 1012, 1663, 4848 and 2488 ct/min suspensions from spleens were either used unfractionated as respectively. * P < 0-05; ** P < 0 005. 1995 Blackwell Science Ltd, Clinical and Experimental Immunology, 102:46-52 48 M. Villacres-Eriksson 1200 1200r (a) (b) 800 800 _ P---.P. 400 k 400 _ - OL IF a=-- m 4r- L T 1 2 3 4 5 6 ( 1 2 3 4 5 6 c1 1200 r (c) 800 400k - .- I L | ) |~~ _r-- 0 1 2 3 4 5 6 0 1 2 4 5 6 Days of incubation Fig. 2. The capacity of iscom- (o) or micelle-pulsed APC (0) to stimulate IL-2 secretion by iscom-primed T cells. Cultures receiving medium only (U) were used as background controls. The APC used were: (a) unfractionated spleen cell suspension, (b) peritoneal cells, (c) dendritic cells and (d) B cells.
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