IFN-
-independent IgG2a production in mice infected with viruses and parasites
Dominique Markine-Goriaynoff,
Jos T.M. van der Logt3,
Carine Truyens2,
Trung D. Nguyen1,
Frans W. A. Heessen3,
Geoffroy Bigaignon1,
Yves Carlier2 and
Jean-Paul Coutelier
Unit of Experimental Medicine, Christian de Duve Institute of Cellular Pathology and
1 Microbiology Unit, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, 1200 Brussels, Belgium
2 Laboratory of Parasitology, Faculty of Medicine, University of Brussels, 1000 Brussels, Belgium
3 Department of Medical Microbiology, University of Nijmegen, 6500 HB Nijmegen, The Netherlands
Correspondence to:
J.-P. Coutelier
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Abstract
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After infection with some viruses and intracellular parasites, antibody production is restricted to IgG2a. We first observed that, whereas live viruses such as lactate dehydrogenase-elevating virus (LDV) or mouse adenovirus induced mostly an IgG2a response, a large proportion of antibodies produced against killed viruses were IgG1. This IgG1 antiviral response was suppressed when live virions were added to inactivated viral particles. These results indicate that the IgG2a preponderance is related to the infectious process itself rather than to the type of antigen involved. Since IFN-
is known to stimulate IgG2a production by activated B lymphocytes and to be secreted after infection, we examined the role of this cytokine in the antibody isotypic distribution caused by LDV. Most IgG2a responses were relatively unaffected in mice deficient for the IFN-
receptor or treated with anti-IFN-
antibody. A similar IFN-
-independent IgG2a secretion was observed after infection with the parasites Toxoplasma gondii and Trypanosoma cruzi. However, the IFN-
-independent IgG2a production triggered by infection still required the presence of functional Th lymphocytes. Therefore, signal(s) other than IFN-
secretion may explain the Th-dependent isotypic bias in antibody secretion triggered by viruses and parasites.
Keywords: cytokine, antibody isotype, lactate dehydrogenase-elevating virus, adenovirus, Toxoplasma gondii, Trypanosoma cruzi
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Introduction
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In contrast to anti-soluble protein or anti-carbohydrate antibodies, which are generally restricted to the IgG1 and IgG3 isotypes respectively (1,2), most antiviral antibodies elicited by infection with RNA and DNA viruses belong to the IgG2a subclass (3). Quite a few exceptions to this general rule have been reported. A strong production of IgG1 antiviral antibodies was found in animals infected with herpes simplex virus (4) and in C3H mice carrier for, but not acutely infected with lymphocytic choriomeningitis virus (5). Large proportions of IgG1 were observed in C57BL/6, but not in BALB/c mice, infected with cold-adapted influenza virus (6). IgG1 antiviral antibodies were also abundantly produced by H-2d animals inoculated intradermally, but not orally, with reovirus (7) and by resistant, but not by susceptible mice to Theiler's murine encephalomyelitis virus infection (8). The functional properties of Ig are closely related to their isotype. For instance, IgG2a antibodies activate the complement system more readily than do IgG1 antibodies (9); they bind to specific Fc receptors that are expressed on murine macrophages and are involved in phagocytosis (10); and they are quite efficient mediators of antibody-dependent cell-mediated cytotoxicity (11). With such properties, the IgG2a restriction observed in antiviral antibodies could provide a more suitable defense against virus infection, by triggering easier elimination of viral particles as well as of infected cellular targets. It may be postulated that this isotypic bias in antiviral responses either follows the cascade of immune events triggered by an active infectious process or relies on the mere presence of viral antigens, since these antigens have some particular biochemical characteristics such as the repetition of identical determinants. In this paper, using lactate dehydrogenase (LDH)-elevating virus (LDV), a murine, single-stranded positive-sense RNA, enveloped virus in the arterivirus family, and mouse adenovirus (MAV), a medium-size, non-enveloped virus containing a linear double-stranded DNA, we report that infection with a live virus is required to induce a preponderance of the IgG2a isotype in antibody responses.
In addition to this isotypic restriction of antiviral responses, mouse infection with several viruses, including LDV, MAV, lymphocytic choriomeningitis virus and mouse hepatitis virus, is followed by B lymphocyte polyclonal activation, IgG2a restriction of antibodies directed against non-viral antigens and inhibition of Th2 cytokine expression (3,1218). Similar changes have been observed after infection with parasites such as Toxoplasma gondii and Trypanosoma cruzi (1921). Because most of the total, as well as the specific, antiviral antibody responses following infection are T-dependent (13,22,23), and because the Th1 cytokine IFN-
has been shown to stimulate IgG2a secretion by activated B lymphocytes (24) and the differentiation of Th1 cells (reviewed in 25), it may be postulated that the antibody isotypic restriction triggered by viruses and parasites is mediated by this cytokine. However, our results indicate that IFN-
is not required for the IgG2a bias in the secretion of most antibodies in the course of viral or parasitic infection.
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Methods
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Mice
Specific pathogen-free, female, CBA/Ht and isolator-reared, 129/Sv mice were bred by Dr G. Warnier at the Ludwig Institute for Cancer Research (Brussels, Belgium), and were used at the age of 68 weeks. Their microbiological status has been described previously (26). IFN-
receptor-deficient mice (G129), received by courtesy of Dr F. Brombacher (Max Planck Institute for Immunobiology, Freiburg, Germany) and then reared in the same manner as the 129/Sv animals, were initially derived on a 129/Sv background by S. Huang and M. Aguet (27). BALB/c mice were purchased from Bantin and Kingman Universal (Hull, UK).
Viruses, parasites and antigens
Mice were infected by i.p. injection of ~2x107 ID50 of LDV (Riley strain; ATCC, Rockville, MD) or by i.p. injection of ~105 ID50 of MAV (FL strain).
UV-inactivated LDV and MAV were prepared by irradiating the viruses with a 30 or 40 W UV source (Philips) for 90180 min at a distance of 15 cm. The effectiveness of the inactivation was tested by assaying plasma LDH 45 days after LDV inoculation (28) and by a plaque assay on L929 cells for MAV (29). Protein concentration of inactivated viruses was determined by the Lowry method (30). Mice were immunized s.c. in the legs or footpads with 50 µg UV-inactivated LDV or with 10 µg UV-inactivated MAV in 200 µl saline (NaCl, 9 g/l) containing 50% complete Freund's adjuvant.
Mice were infected with the weakly virulent Beverley strain of T. gondii by i.p. inoculation with five cyst parasites, as described previously (19).
T. cruzi-infected mice were obtained after i.p. inoculation of 100 parasites, as described previously (31). Two months later, i.e. during the chronic phase of infection, they received neutralizing anti-murine IFN-
or a control mAb injected as ascite fluids twice a week by i.p. route.
Immunization with keyhole limpet hemocyanin (KLH; Calbiochem, San Diego, CA) was performed by i.p. injection of 100 µg antigen in 500 µl saline.
Antibodies
XMG-1.2 anti-IFN-
mAb was kindly provided by Dr T. Mosmann (DNAX, Palo Alto, CA) (32). This mAb was used in vivo at a dose (1 mg) that has previously been shown to efficiently inhibit Brucella abortus-induced IgG2a production (33). Anti-CD4 mAb GK1.5 was made available by Dr F. W. Fitch (Chicago) and obtained through the courtesy of Dr H. R. MacDonald (Epalinges sur Lausanne, Switzerland) (34). F3 anti-murine IFN-
mAb, a rat IgG2a, was kindly donated by Dr H. Heremans (Rega Institute for Medical Research, Leuven, Belgium). Its neutralizing capacity has been described previously (35). An irrelevant rat IgG2a mAb (IR418, a gift from Professor H. Bazin, Brussels, Belgium) was used as a control.
Spleen cell cultures
As described previously (22), 25x106 spleen cells were cultured in Iscove's medium containing 10% FCS and supplemented with 0.24 mM L-asparagine, 0.55 mM L-arginine, 1.5 mM L-glutamine and 0.05 mM 2-mercaptoethanol. Supernatants were collected 24 h after initiation of cultures.
Antibody determination
Specific antibody IgG subclasses were assayed by ELISA as previously described (36). Briefly, polystyrene plates were coated overnight with pelleted virus, BSA or DNP-BSA (a gift from Dr G. V. Gulaf, Brussels, Belgium) (10 µg/ml) and incubated with serial dilutions of sera or cell supernatants for 3 h at 37°C. Binding of antibodies was measured after incubation for 3 h at 37°C with rabbit antisera specific for mouse IgG subclasses (a gift from Dr J. Van Snick, Brussels, Belgium) followed by peroxidase-conjugated donkey anti-rabbit IgG antibodies (Amersham Belgium, Gent, Belgium; reference NA934, 1/3000 dilution). Results were calculated on standard curves of selected anti-DNP mAb. Non-specific binding, including that of rabbit antibodies to virus-coated plates, and that of wells coated with BSA was subtracted. As published previously (36), a minimal cross-reactivity (usually <3%) was observed between the different isotypes.
Total IgG1 and IgG2a subclasses were determined by direct ELISA, as described previously (13). The binding of IgG subclasses to insolubilized mouse IgG isotype-specific rabbit antibody was measured with peroxidase-labeled anti-mouse Ig donkey antibody (Jackson ImmunoResearch, West Grove, PA). Standards were mAb of the appropriate isotype.
Specific anti-T. cruzi antibody and total Ig isotypes were assayed by ELISA, as previously described (21).
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Results
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Requirement of live virus for the modulation of IgG isotypes in antibody responses
Antiviral antibody isotypic distribution was analyzed after 129/Sv mice were inoculated with live and UV-inactivated LDV and MAV. Because infection with LDV, but not administration of inactivated virus, triggers a large increase in plasma LDH levels, the use of this virus facilitates the assessment of the efficacy of LDV inactivation. Here, the LDH plasma level of a mouse that had received an injection of UV-inactivated LDV was 79 U/l, which corresponds to the level found in uninfected mice, while infected animals had plasma LDH ranging between 630 and 2775 U/l. Whereas live LDV has previously been shown to induce mostly an IgG2a antiviral response (36), a large proportion of antibodies produced against killed virus were IgG1 (Fig. 1
). These data suggest that the isotypic distribution of antiviral antibodies elicited by live and inactivated virus differs, and therefore that the infectious process is responsible for the IgG2a preponderance observed after infection. The necessity of the infectious process to the antibody isotypic restriction was further analyzed by addition of live virus to inactivated viral particles. This led to a dramatic suppression of the IgG1 antiviral antibody production elicited by these killed virions, while other subclasses were not affected (Fig. 1
).

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Fig. 1. Effect of infection on the isotypic distribution of antiviral antibodies elicited by immunization with inactivated LDV. Serum anti-LDV antibody isotypes were measured by ELISA 3 weeks after immunization with UV-inactivated virus of uninfected 129/Sv mice (&z.sqh;) or of animals that received simultaneously live virus ( ). Results are shown as means ± SE for groups of four mice.
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As shown in Table 1
, similar results were obtained using another virus, MAV. Indeed, a large proportion of IgG1 antiviral antibodies, similar to that elicited by inoculation of UV-inactivated LDV, was also produced after immunization with UV-inactivated MAV. Similar results were obtained in three different experiments. In addition, in some experiments, high levels of antibodies that did not react with viral antigens and that could be the result of B cell polyclonal activation were detected in mice receiving killed MAV, with the same IgG1 preponderance as antiviral antibodies (not shown).
IFN-
independence of the IgG2a bias of antibodies with antiviral and non-antiviral specificity produced after infection
IFN-
, a cytokine produced in the course of infection with diverse viruses, is a potent inducer of in vitro IgG2a secretion by activated B lymphocytes (24), including B cells stimulated after viral infection (13). We therefore analyzed the role of this molecule in the IgG2a restriction observed in vivo after viral infection. When analyzing the specific anti-LDV antibody response elicited by infection, a lower response was observed in animals deficient for the IFN-
receptor (Table 2
). However, although it was variable from one experiment to another, this suppression of antiviral antibodies affected both IgG1 and IgG2a, and the latter isotype usually remained preponderant even in the absence of IFN-
function.
Basal levels of total serum IgG2a were slightly decreased in uninfected mice deficient for the IFN-
receptor when compared to normal counterparts (Fig. 2
). However, after LDV infection, a similar increase in total IgG2a was observed in the two groups of animals. Similar results were obtained at 7 and 14 days after infection (data not shown). Total IgG1 secretion, which was not enhanced by the infection, was similar in mice with and without functional IFN-
receptors. These results were confirmed by analysis of the ex vivo production of total IgG2a by spleen cells obtained 7 days after LDV infection. Indeed, when compared to normal counterparts, we observed no statistically significant decrease in IgG2a produced in response to infection by spleen cells from both IFN-
receptor-deficient mice and CBA/Ht animals treated in vivo with an anti-IFN-
mAb (Table 3
, MannWhitney test, P
0.1).
It has been reported previously that some viral infections can modulate the isotypic distribution of Th-dependent antibodies elicited concomitantly with the infection against non-viral antigens. This subclass-selective adjuvant effect results in a preponderance of IgG2a and can be observed even in subsequent secondary immunizations (12,15). The role of IFN-
in this IgG2a production was analyzed by immunizing mice deficient for the IFN-
receptor with KLH simultaneously with LDV infection. The increase in IgG2a anti-KLH antibodies triggered by the virus was similar in these animals and in normal 129/Sv mice, after primary as well as secondary immunizations (shown in Fig. 3
for a secondary immunization). In contrast, while IgG1 anti-KLH antibodies were usually moderately decreased by the infection in normal mice, their production was also increased in infected animals deficient for the IFN-
receptor.
Previous work has demonstrated that IgG2a production in virally infected normal mice is mostly a Th lymphocyte-dependent phenomenon (13). To determine if these T cells were also required for the virally induced IFN-
-independent IgG2a secretion observed here, we treated IFN-
receptor-deficient animals with an anti-CD4 antibody able to inhibit Th-dependent responses in vivo (37). As shown in Fig. 4
for a typical experiment, the inhibition of IgG2a production by anti-CD4 treatment, although not complete, was similar in mice with and without functional IFN-
receptors.

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Fig. 4. CD4-dependence of IgG2a production in IFN- receptor-deficient mice. Total IgG2a was measured by ELISA in the serum of 129/Sv (IFN R +/+) and G129 (IFN R /) mice (four mice per group) obtained 1 week after LDV infection. Anti-CD4 mAb (1 mg) was administered i.p. 1 day before infection. Control mice were not infected. Results are shown in µg/ml (means ± SE).
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IFN-
-independent IgG2a production after parasitic infection
T. gondii induces an IgG2a restriction similar to that triggered by viruses both in antiparasite responses and in the production of antibodies directed against non-parasitic antigens (19). Because IFN-
receptor-deficient mice quickly succumb to T. gondii infection, we could only analyze the role of this cytokine in early IgG2a-restricted polyclonal antibody responses induced by the parasite. Accordingly, spleen cell supernatants were prepared from uninfected control and IFN-
receptor-deficient mice, and from animals that had been infected for 7 days with T. gondii. Assays for total IgG1 and IgG2a in these supernatants indicated that the sharp polyclonal IgG2a production triggered by the infection was totally IFN-
independent (Fig. 5
). IgG1 levels were low and not modified in IFN-
receptor-deficient mice (not shown). Analysis of serum IgG, performed at the same time as that as supernatant IgG, showed high levels of IgG2a in infected IFN-
receptor-deficient animals, although not as high as in mice with functional receptors (not shown).

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Fig. 5. IFN- independence of total IgG2a produced after T. gondii infection. Total IgG2a was measured by ELISA in the supernatants of spleen cells obtained 7 days after administration of PBS (control) or T. gondii to groups of five 129/Sv (IFN R +/+) and G129 (IFN R /) mice. Results are shown in ng/ml (means ± SE).
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In addition, confirming and extending previous results obtained during acute infection with T. cruzi (35), in vivo treatment with an anti-IFN-
antibody did not modify the isotypic distribution of both total and specific anti-parasite antibodies produced during chronic infection with the parasite (shown in Fig. 6
for mice receiving 5 µg mAb/g mouse weight per injection). Similar results were obtained in two other similar experiments where 10 and 20 µg mAb/g mouse weight were administered (data not shown).
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Discussion
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We have previously shown that antiviral antibodies elicited in mice by infection with a large variety of common viruses are largely restricted to the IgG2a isotype (3). This isotypic bias contrasts sharply with the subclass distribution of antibodies produced after immunization with soluble protein antigens (1) and could be explained either by some repetitive or other biochemical properties of viral antigens, or by immune mechanisms triggered by the infectious process itself. Previous observations that immunization with many viral proteins or peptides, combined with diverse adjuvants, leads to a strong IgG1 antibody response (6,3845), much like other common protein antigens, suggest that there is no basic difference between these molecules in terms of antigenicity. However, when inactivated viruses have been used for immunization, widely divergent results have been obtained. Administration of inactivated herpes simplex and influenza viruses has been shown to trigger predominantly IgG2a antiviral antibody responses similar to those following infections (38,41,46). In contrast, other reports, using Theiler's murine encephalomyelitis and influenza viruses, have indicated that immunization with killed virus may induce as much IgG1 as IgG2a antiviral antibodies (8,47). Interestingly, differences in the isotypic distribution of antiviral IgG antibodies produced in response to immunization with inactivated viruses have been related to the mouse strain or the adjuvant used for these experiments (8,48). However, it may also be possible that some divergent results observed previously were partly due either to differences in the microbiological status of the animals used in these studies or to the presence of remaining live virus particles in preparations of inactivated viruses. By using LDV, we could easily test for the presence of live virus in our inactivated preparation, since infection with this virus, but not administration of inactivated virions, quickly leads to a strong enhancement of LDH levels in the plasma of inoculated mice. Our results with both LDV and MAV, two very different viruses, clearly indicated that immunization with inactivated viral particles triggers as much IgG1 as IgG2a antiviral antibodies. Since previous reports have shown that immunizations in the presence of complete Freund's adjuvant can trigger strong IgG2a responses (8,48), the difference that we observed in the isotypic distribution of antiviral antibodies elicited by infection and by immunization with inactivated virus could not be related to the use of this adjuvant. In addition, although it has been shown by others that LDV inactivation by formalin may reveal epitopes not recognized after infection (49), UV inactivation is less likely to modify the antigenicity of viral particles similarly. Finally, previous analysis by Western blots of the fine antigenic specificity of anti-LDV isotypes, separated from sera of infected mice by sequential elution from Protein ASepharose, showed the same reactivity pattern for the different subclasses (36). Together, these observations indicate that the IgG2a restriction of antiviral antibodies produced after infection is not related to particular antigenic properties of viral particles.
We have also previously observed that viral infections could modulate the isotypic distribution of concomitant antibody responses directed against non-viral antigens (12,15). Our results obtained with concomitant administration to mice of live and inactivated viruses clearly confirm that live viruses can actively decrease IgG1 responses triggered by other stimuli (here, UV-inactivated virions). Therefore, they strengthen the hypothesis that the IgG2a restriction of antiviral antibodies, as well as of antibodies with unrelated specificity, occurring after viral infections (12,13,15,18,50), involves immune events triggered by the infectious process itself rather than special properties of viral antigens. The effect of an added infection to immunization with inactivated viral particles was more a sharp inhibition of IgG1 responses than an enhancement of IgG2a antibodies. This suggests that the IgG2a restriction of antiviral antibodies observed after most infections results mainly from an inhibition of Th2-mediated responses. Previous results showing a virally-driven decrease in IL-4 and IL-9 expression induced by immunization with non-viral antigens (1618) also support this hypothesis. Interestingly, adenovirus has recently been shown to induce a decrease of experimental Th2-dependent allergic responses, such as airway inflammation, although in this model, IgE antibodies directed against non-viral antigens were not modified by the infection (51).
Since the initial report showing that IFN-
could induce IgG2a production by activated B lymphocytes (24), numerous observations have confirmed the primordial role of this cytokine in both in vitro and in vivo IgG2a responses, including after viral and parasitic infections (13,27,33,5256). Our results, showing a strong decrease in anti-LDV IgG raised after infection of animals deficient for the IFN-
receptor, confirm the role of this cytokine in antiviral antibody responses. However, the IgG2a preponderance in this antiviral antibody production, as well as other IgG2a responses, such as polyclonal IgG2a secretion and specific responses against non-infectious antigens, were hardly reduced in LDV- and Toxoplasma-infected IFN-
receptor-deficient animals. Similarly, anti-IFN-
treatment was not able to significantly suppress total IgG2a production after LDV infection or after Trypanosoma inoculation. These data clearly indicate that at least some of the in vivo secretion of IgG2a is an IFN-
-independent phenomenon. Interestingly, some other reports have also shown a partial IFN-
independence of specific or total IgG2a responses (46,53,5759). However, at this point, it is difficult to determine which type of IgG2a responses depend on IFN-
. Nguyen et al. (46) found that the administration of an anti-IFN-
antibody had no effect on specific anti-herpes virus IgG2a, but greatly reduced the total IgG2a secretion triggered by this virus. Others have reported the secretion of at least partially IFN-
-dependent IgG2a that developed in the absence of CD4+ T cells or of
ß T lymphocytes after infection with murine cytomegalovirus (60) or vesicular stomatitis virus (56). These observations suggest that different pathways may lead to the secretion of the IgG2a isotype in the course of infections. It may thus be speculated that, while IFN-
alone is able to trigger IgG2a secretion by B lymphocytes, other cytokines or cocktails of cytokines can in some circumstances lead to the same result. IFN-
, which is also largely produced after viral infection, has for instance also been shown to trigger IgG2a production (58,61) and has been suggested to explain the IFN-
-independent secretion of this isotype. However, since the IgG2a production that we observed after LDV infection requires the presence of functional CD4+ T cells, additional signals are probably needed. For the same reason, IL-12, which is also expressed after viral infection (62) and increases IgG2a secretion (63,64), cannot be responsible alone for the effect of LDV on antibody isotypic distribution. Interestingly, a Th2-like T cell line that secreted no IFN-
, derived from mice infected with T. cruzi, has been reported to induce in vivo B lymphocyte polyclonal activation and IgG2a secretion (65). From these observations, it is therefore possible to postulate that other signals than IFN-
can be generated by Th lymphocytes after viral or parasite infections and trigger IgG2a restriction of antibody responses, alone or in conjunction with cytokines produced by other cell types.
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Acknowledgments
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F. Brombacher, T. Mosmann, F. W. Fitch, H. R. MacDonald, H. Heremans, H. Bazin, J. Van Snick and G. V. Gulaf are thanked for their gift of valuable reagents. The authors are indebted to J. Van Snick, P. L. Masson and S. Mapp for critical reading of this manuscript, and to T. Briet, M.-D. Gonzales, N. Havaux and K. Victoire for help in performing the experiments. This work was supported by the Fonds National de la Recherche Scientifique (FNRS), Fonds de la Recherche Scientifique Médicale (FRSM), Loterie Nationale, Fonds de Développement Scientifique (UCL) and the State-Prime Minister's Office (SSTC). (interuniversity attraction poles, grant no. 44) and the French Community (concerted actions, grant no. 99/04-239), the Ministry of Scientific Policy (Belgium), and the Université Libre de Bruxelles, Belgium. D. M. is a research assistant and J.-P. C. a research director with the FNRS.
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Abbreviations
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KLH keyhole limpet hemocyanin |
LDH lactate dehydrogenase |
LDV lactate dehydrogenase-elevating virus |
MAV mouse adenovirus |
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Notes
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Transmitting editor: A. Radbruch
Received 12 April 1999,
accepted 27 October 1999.
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