The role of IL-5 and allergen-specific IgE in the development of eosinophilic airway inflammation and airway hyperresponsiveness (AHR) was investigated in a murine model. BALB/c mice were sensitized to ovalbumin (OVA) by intraperitoneal injection on Days 1 and 14, followed by airway challenge with OVA on Days 28 and 29. Anti-IL-5 (TRFK-5) or anti-IgE (antibody 1-5) was administered before each airway challenge. Sensitized and challenged mice developed increased OVA-specific IgE serum levels, Th2 cytokine production by peribronchial lymph node (PBLN) cells, increased numbers of eosinophils (predominantly located in the peribronchial regions of the lungs), and increased airway responsiveness to methacholine (MCh). Anti-IgE treatment significantly decreased serum anti-OVA IgE levels and prevented the development of anaphylaxis but failed to affect T cell function, eosinophil airway infiltration, and AHR in sensitized and challenged mice. In contrast, treatment with anti-IL-5 antibody did not affect B cell (Ig serum levels), T cell (cytokine production), or mast cell function (immediate cutaneous reactivity) but completely inhibited development of eosinophilic lung inflammation and AHR. These data identify IL-5-mediated eosinophilia as a major target for development of AHR in this model, with little effect resulting from neutralization of IgE.

T cells play a crucial role in antibodymediated and antibody-independent immunity against Plasmodium falciparum malaria. Therefore, a vaccine immunogen should include parasite-derived B-and T-cell epitopes capable of giving rise to protective responses in both systems. The P.falciparum antigen PfI55/ring-infected erythrocyte surface antigen (RESA), a vaccine candidate, contains immunodominant T-and B-cell epitopes located in the central (5') and C-terminal (3') invariant repeat regions of the molecule. To relate Pfl55/RESA-peptide-specific responses of T cells to function, T cells from P. fakciparum immune donors were activated with peptides corresponding to these immunodominant regions. Activation was measured as induction of interferon-y secretion, T-cell proliferation (DNA synthesis), or transcription and translation of interleukin 4 (IL-4) mRNA.Peptides from both regions were shown to induce interferon-y, IL-4, proliferation, or any combination. In individual donors, there was no correlation between these different activities. Rather, they were negatively correlated, demonstrating the importance of examining multiple parameters of T-cell activation when estimating the proportion of individuals responding to a given epitope. However, IL-4 mRNA and intracellular IL-4 could be induced in T cells of donors who had elevated concentrations ofserum antibodies to the same peptide that was used for T-cell activation. These results suggest that a causal relationship exists between the activation of IL-4-producing T-cell subsets and production of the anti-Pf155/RESA-specific antibodies in individuals in which immunity has been induced by natural infection. This finding has implications that should be considered for the selection of immunogens to be included in a future P. falciparum subunit vaccine and for vaccine development in general.

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B cell switch to IgE expression is mediated by IL-4 and is regarded as a T helper cell-related phenomenon. In this overview we describe that IgE switch can also be induced by mast cell/basophil like cells (from splenic non-B, non-T cells), activated by IgE receptor cross-linking and/or IL-3 which results in IL-4 production by these cells. Furthermore, activated mast cells produce their own growth factors, IL-3 and GM-CSF. Thus, activation of mast cells can provoke an ongoing local allergic reaction as long as antigen confrontation is maintained, a process which is sustained by further IgE production as well as renewal of mast cells. It is furthermore demonstrated that in certain established immune situations the IgE response may become independent of IL-4, namely in the spontaneous in vitro IgE expression of cells from atopic individuals as well as in an in vitro antigen-induced secondary IgE response of spleen cells derived from previously immunized mice. Thus, IgE-switched B cells may persist in vivo and may represent a pool of potentially IgE-producing cells. Finally, a selective inhibiton of the IgE response is described in vitro and in vivo by the use of so-called non-anaphylactic monoclonal anti-IgE antibodies. Such antibodies bind to surface IgE⁺ B cells, but not to IgE-sensitized mast cells, and thereby inhibit IgE responses. Nonanaphylactic antibodies blocked the binding of allergen-specific IgE to mast cells by competing with the Fc_ε on these cells. As a consequence they do not induce but rather prevent allergen-induced mediator release by mast cells. It is believed that corresponding antibodies to human IgE used in the chimeric (humanized) form will represent an attractive possibility to inhibit and/or eliminate IgE-switched B cells in vivo. This may lead to an efficient and isotype-specific suppression of human IgE responses.

A series of 11 different monoclonal antibodies generated against human kidney renin have been characterised. Their binding affinity, inhibition of renin activity, epitope distribution, crossreactivity with related enzymes and finally in vivo pharmacological effects were analysed. All antibodies were found to be specific for primate renin recognising 6 independent antigenic structures on the renin molecule. They expressed different effects on renin activity namely (1) no inhibition, (2) only partial, or (3) complete inhibition. Partially inhibiting antibodies demonstrated specific degrees of inhibition (30, 60 or 80%). One antibody, R-36-16, demonstrated an IC 50 of 1.3 X 10(-11) M/L and, when injected into marmosets, induced complete inhibition of plasma renin activity and reduction of blood pressure. Using a selected pair of antibodies a radioimmunoassay has been established providing a fast and highly reproducible determination of human and marmoset immunoreactive renin, detecting both active and inactive renin down to concentrations of 10 pg/ml (1.25 X 10(-17) moles of renin per 50 microliter sample).

Regulation of a memory IgE antibody response may be different from the induction of a primary response and may, therefore, be more relevant to the study of allergic diseases and the therapeutic manipulation of IgE antibody formation. In this paper a murine hapten-specific in vitro memory IgE antibody response to benzylpenicilloyl(BPO)-KLH is described. The response was analyzed by determining the number of antibody-producing cells (APC) in an ELISA spot assay. Of the total number of BPO-specific APC (10,000 APC/ 10⁶ cultured spleen cells), about 1 % were IgE-producing cells (100/10⁶ cultured cells), as detected on day 6 of culture. The level of the antibody response is antigen dose-dependent, and the detected APC are BPO specific. The memory IgE response is not inhibited by the addition of anti-IL-4 antibody (11B11), even at a high excess. In the presence of the mitogen lipopolysaccharide, it has been shown that switch of B cells to IgE is induced by IL-4, a process which can be inhibited by anti-IL-4 antibody. Because the antigen-induced IgE response cannot be inhibited by anti-IL-4 antibody, in vitro responding cells derived from BPO-KLH-preimmunized mice may, therefore, have already switched in vivo to IgE. On the other hand, B cells switching to IgE in a situation of cognate T-B cell interaction might receive IL-4 in a transsynaptical way from T cells which might not be accessible to inhibition by anti-IL-4 antibody. The identification of the two possibilities in situations of established allergic disorders will be decisive for determining whether pharmacological inhibition of IL-4 (or IL-4-induced switch) – e.g., by putative low molecular weight compounds – will ever be a meaningful approach to suppress allergic diseases.