Cytokines as adjuvants for vaccines: antigen-specific responses differ from polyclonal responses

Taylor, Christopher E.

doi:10.1128/iai.63.9.3241-3244.1995

Cited by 35 publications

(17 citation statements)

References 50 publications

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“…In conclusion, we found a relationship between the humoral immune response to LPS of A. actinomycetemcomitans serotype b and production of type 2 cytokines by splenocytes. Furthermore in order to con¢rm this, we are planning to investigate the e¡ects of using IL-4 and IL-5 in the administration of immunogens as adjuvants [26] on low-IgM responders to A. actinomycetemcomitans serotype b.…”

Section: Discussionmentioning

confidence: 99%

Heterogeneity in the immune response to serotype b LPS of Actinobacillus actinomycetemcomitans in inbred strains of mice

Kato¹

2000

FEMS Immunology and Medical Microbiology

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We investigated the heterogeneity of the humoral immune responses to whole cells and lipopolysaccharide (LPS) of Actinobacillus actinomycetemcomitans serotype b and production of cytokines in inbred strains of mice. Nine such strains were tested:, DBA/1 (H-2 q ) and B10.S (H-2 s ). Mice were immunized intraperitoneally with whole cells of A. actinomycetemcomitans ATCC 43718 (serotype b) in phosphate buffered saline (PBS; pH 7.2) emulsified with an equal volume of Freund's incomplete adjuvant. Serum immunoglobulin G (IgG), immunoglobulin A (IgA) and immunoglobulin M (IgM) levels against A. actinomycetemcomitans were measured by an ELISA system. ELISA analysis, using LPS fractions from serotype a, b or c strains of A. actinomycetemcomitans as the coating antigens, revealed that mice strains C3H/He, C3H/HeJ, B10.BR and B10.S had an extremely high-IgM response against serotype b LPS. High-IgM titer sera contain also elevated levels of IgA antibodies to the antigen. To compare the cytokine production among inbred mice, the amounts of interleukin-4 (IL-4), interleukin-5 (IL-5), and interleukin-6 (IL-6) released from mouse splenocytes were measured using ELISA systems specific for these cytokines. A. actinomycetemcomitans serotype b LPS stimulation induced IL-6 release from murine splenocytes of all tested strains. However, IL-4 and IL-5 were detected only in high-IgM/IgA responders to A. actinomycetemcomitans serotype b LPS, not in low-IgM/IgA responders. Thus, we found a relationship between the humoral immune response to LPS of A. actinomycetemcomitans serotype b and production of type 2 cytokines by splenocytes. ß

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Section: Discussionmentioning

confidence: 99%

Heterogeneity in the immune response to serotype b LPS of Actinobacillus actinomycetemcomitans in inbred strains of mice

Kato¹

2000

FEMS Immunology and Medical Microbiology

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“…Since CMI is induced, and regulated, by cytokines, we have now studied the profiles of the major cytokines constitutively expressed or elicited by in vitro PBMC restimulation with B. pertussis antigens. We were particularly interested in assessing the balance between representative type 1 (IFN-␥ and IL-2) and type 2 (IL-4 and IL-5) cytokines because of the current awareness of the critical importance of this balance for protection against infections (18,24,32). Evidence from murine models suggests that control of B. pertussis respiratory infection can be better achieved by immunization schedules favoring type 1 cytokine production (20,28,30).…”

Section: Discussionmentioning

confidence: 99%

Vaccine- and antigen-dependent type 1 and type 2 cytokine induction after primary vaccination of infants with whole-cell or acellular pertussis vaccines

et al. 1997

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Cytokine profiles were examined 1 month after primary vaccination of infants with a whole-cell pertussis vaccine (wP) (Connaught) or either of two acellular pertussis vaccines, aP-Chiron Biocine (aP-CB) or aP-SmithKline Beecham (aP-SB), each combined with diphtheria-tetanus toxoids (DT), in Bordetella pertussis antigen-stimulated or unstimulated peripheral blood mononuclear cells (PBMC). Pertussis toxin (PT), filamentous hemagglutinin (FHA), and pertactin (PRN) were used as antigens, and the children were defined as responsive when their PBMC proliferated in response to these antigens. The controls were either children who received only DT or children who received pertussis vaccine but whose PBMC did not proliferate upon stimulation with B. pertussis antigens (unresponsive children). Antigen-stimulated PBMC of responsive wP recipients were characterized by an elevated production of T-helper-cell type 1 cytokines gamma interferon (IFN-␥) and interleukin 2 (IL-2), low to minimal production of IL-5, and no production of IL-4. The PBMC of aP vaccine-responsive recipients showed, in addition to the elevated IFN-␥ production, a consistent, antigendependent production of type 2 cytokines (IL-4 and IL-5), with PRN being the most and PT being the least effective antigen. Type 2 cytokine induction was more pronounced in aP-SB than in aP-CB recipients, as shown by the presence of IL-4 mRNA transcripts and higher IL-5 production in the former (161.6 ؎ 36 and 47.9 ؎ 44 pg/ml [mean ؎ standard error for five subjects each], respectively, after PRN stimulation). Appreciable, antigen-unstimulated (constitutive) IFN-␥ production was also detected in PBMC cultures of all vaccinees. However, this spontaneous IFN-␥ production was, in most vaccinees, significantly lower than the antigendriven cytokine production. In contrast, no constitutive type 2 cytokine production was ever observed in any vaccine group. PBMC from the two control groups (either DT or pertussis vaccine recipients) did not show any type 2 cytokine production, while IFN-␥ production was comparable in both antigen-stimulated and unstimulated conditions. Absence of type 2 cytokines and low levels of constitutive IFN-␥ production were also seen in prevaccination children. Thus, pertussis vaccines induce in infants a basically type 1 cytokine profile, which is, however, accompanied by some production of type 2 cytokines. The latter are more expressed by aP-SB than by aP-CB recipients, and with PRN than with other antigens, and they are minimally expressed in wP recipients and with PT as antigen. Our data also highlight a constitutive IFN-␥ production in infancy, which might reflect natural immunization and/or the burden of concomitant vaccinations and which may have an impact on T-helper-cell cytokine pattern polarization consequent to pertussis vaccination.

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“…On the other hand, Th2 cells secrete IL-4, IL-5, IL-6, and IL-10 (22) and have been shown to contribute to resistance to intestinal nematode infections (7,8). Both Th1 and Th2 cells are capable of providing help to antibody-producing B cells, and the cytokines they secrete dictate the isotypes which are generated (27,39). Furthermore, IFN-␥, IL-12, and transforming growth factor ␤ induce the differentiation of Th1 cells, while IL-4 encourages the differentiation of Th2 cells and inhibits the development of Th1 cells (36,38).…”

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confidence: 99%

Interleukin-4 causes delayed virus clearance in influenza virus-infected mice

Moran

Isobe

Fernández-Sesma

et al. 1996

J Virol

130

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Two different subsets of T cells, Th1 and Th2 cells, have been demonstrated to secrete different profiles of cytokines and to influence various infections in different ways. Whereas cytokines secreted by Th1 cells, particularly gamma interferon, promote the generation of cell-mediated immunity, Th2 cells and their cytokines (interleukin-4 [IL-4], IL-5, IL-10, and IL-13) have been shown to function in recovery from parasitic infections and in antibody responses. In this study, we analyzed the effects of the dominant Th2 cytokine, IL-4, on immunity to virus infection. We assessed the effects of IL-4 on both secondary immune responses by an adoptive transfer assay and primary immune responses by in vivo treatment of influenza virus-infected mice with IL-4. The results demonstrated that IL-4 can function to inhibit antiviral immunity at both stages. We found that IL-4 treatment of sensitized cells during secondary stimulation in vitro had little effect on their ability to lyse virus-infected target cells in a 51 Cr release assay. Nevertheless, the clearance of influenza A/PR/8/34 (H1N1) virus from the lungs of infected BALB/c mice was significantly delayed after the transfer of virus-specific T cells secondarily stimulated in the presence of IL-4 in comparison to virus clearance in recipients of cells stimulated in the absence of IL-4. In contrast to the adoptive transfer results, the treatment of PR8 virus-infected mice with IL-4 during primary infection greatly suppressed the generation of cytotoxic T-cell precursors, as assessed by secondary stimulation in vitro.In addition, culture supernatants of secondarily stimulated spleen cells from IL-4-treated mice contained significantly less gamma interferon and more IL-4 than did spleen cells from controls. More importantly, the treatment of mice with IL-4 resulted in an extremely significant delay in virus clearance. Thus, IL-4 can inhibit both primary and secondary antiviral immune responses.

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Cytokines as adjuvants for vaccines: antigen-specific responses differ from polyclonal responses

Cited by 35 publications

References 50 publications

Heterogeneity in the immune response to serotype b LPS of Actinobacillus actinomycetemcomitans in inbred strains of mice

Heterogeneity in the immune response to serotype b LPS of Actinobacillus actinomycetemcomitans in inbred strains of mice

Vaccine- and antigen-dependent type 1 and type 2 cytokine induction after primary vaccination of infants with whole-cell or acellular pertussis vaccines

Interleukin-4 causes delayed virus clearance in influenza virus-infected mice

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