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A unique role of the cholera toxin A1-DD adjuvant for long-term plasma and memory B cell development

Bemark, Mats LU orcid ; Bergqvist, Peter ; Stensson, Anneli ; Holmberg, Anna ; Mattsson, Johan and Lycke, Nils Y. (2011) In Journal of Immunology 186(3). p.1399-1410
Abstract

Adjuvants have traditionally been appreciated for their immunoenhancing effects, whereas their impact on immunological memory has largely been neglected. In this paper, we have compared three mechanistically distinct adjuvants: aluminum salts (Alum), Ribi (monophosphoryl lipid A), and the cholera toxin A1 fusion protein CTA1-DD. Their influence on long-term memory development was dramatically different. Whereas a single immunization i.p. with 4-hydroxy-3-nitrophenyl acetyl (NP)-chicken γ-globulin and adjuvant stimulated serum anti-NP IgG titers that were comparable at 5 wk, CTA1-DD-adjuvanted responses were maintained for >16 mo with a half-life of anti-NP IgG ∼36 wk, but <15 wk after Ribi or Alum. A CTA1-DD dose-dependent... (More)

Adjuvants have traditionally been appreciated for their immunoenhancing effects, whereas their impact on immunological memory has largely been neglected. In this paper, we have compared three mechanistically distinct adjuvants: aluminum salts (Alum), Ribi (monophosphoryl lipid A), and the cholera toxin A1 fusion protein CTA1-DD. Their influence on long-term memory development was dramatically different. Whereas a single immunization i.p. with 4-hydroxy-3-nitrophenyl acetyl (NP)-chicken γ-globulin and adjuvant stimulated serum anti-NP IgG titers that were comparable at 5 wk, CTA1-DD-adjuvanted responses were maintained for >16 mo with a half-life of anti-NP IgG ∼36 wk, but <15 wk after Ribi or Alum. A CTA1-DD dose-dependent increase in germinal center (GC) size and numbers was found, with >60% of splenic B cell follicles hosting GC at an optimal CTA1-DD dose. Roughly 7% of these GC were NP specific. This GC-promoting effect correlated well with the persistence of long-term plasma cells in the bone marrow and memory B cells in the spleen. CTA1-DD also facilitated increased somatic hypermutation and affinity maturation of NP-specific IgG Abs in a dose-dependent fashion, hence arguing that large GC not only promotes higher Ab titers but also high-quality Ab production. Adoptive transfer of splenic CD80+, but not CD80-, B cells, at 1 y after immunization demonstrated functional long-term anti-NP IgG and IgM memory cells. To our knowledge, this is the first report to specifically compare and document that adjuvants can differ considerably in their support of long-term immune responses. Differential effects on the GC reaction appear to be the basis for these differences.

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author
; ; ; ; and
publishing date
type
Contribution to journal
publication status
published
in
Journal of Immunology
volume
186
issue
3
pages
1399 - 1410
publisher
American Association of Immunologists
external identifiers
  • pmid:21199899
  • scopus:79251591958
ISSN
0022-1767
DOI
10.4049/jimmunol.1002881
language
English
LU publication?
no
id
1f14e200-8548-4225-ac9e-b021b896ad3d
date added to LUP
2023-12-06 16:41:06
date last changed
2024-01-04 15:04:57
@article{1f14e200-8548-4225-ac9e-b021b896ad3d,
  abstract     = {{<p>Adjuvants have traditionally been appreciated for their immunoenhancing effects, whereas their impact on immunological memory has largely been neglected. In this paper, we have compared three mechanistically distinct adjuvants: aluminum salts (Alum), Ribi (monophosphoryl lipid A), and the cholera toxin A1 fusion protein CTA1-DD. Their influence on long-term memory development was dramatically different. Whereas a single immunization i.p. with 4-hydroxy-3-nitrophenyl acetyl (NP)-chicken γ-globulin and adjuvant stimulated serum anti-NP IgG titers that were comparable at 5 wk, CTA1-DD-adjuvanted responses were maintained for &gt;16 mo with a half-life of anti-NP IgG ∼36 wk, but &lt;15 wk after Ribi or Alum. A CTA1-DD dose-dependent increase in germinal center (GC) size and numbers was found, with &gt;60% of splenic B cell follicles hosting GC at an optimal CTA1-DD dose. Roughly 7% of these GC were NP specific. This GC-promoting effect correlated well with the persistence of long-term plasma cells in the bone marrow and memory B cells in the spleen. CTA1-DD also facilitated increased somatic hypermutation and affinity maturation of NP-specific IgG Abs in a dose-dependent fashion, hence arguing that large GC not only promotes higher Ab titers but also high-quality Ab production. Adoptive transfer of splenic CD80<sup>+</sup>, but not CD80<sup>-</sup>, B cells, at 1 y after immunization demonstrated functional long-term anti-NP IgG and IgM memory cells. To our knowledge, this is the first report to specifically compare and document that adjuvants can differ considerably in their support of long-term immune responses. Differential effects on the GC reaction appear to be the basis for these differences.</p>}},
  author       = {{Bemark, Mats and Bergqvist, Peter and Stensson, Anneli and Holmberg, Anna and Mattsson, Johan and Lycke, Nils Y.}},
  issn         = {{0022-1767}},
  language     = {{eng}},
  month        = {{02}},
  number       = {{3}},
  pages        = {{1399--1410}},
  publisher    = {{American Association of Immunologists}},
  series       = {{Journal of Immunology}},
  title        = {{A unique role of the cholera toxin A1-DD adjuvant for long-term plasma and memory B cell development}},
  url          = {{http://dx.doi.org/10.4049/jimmunol.1002881}},
  doi          = {{10.4049/jimmunol.1002881}},
  volume       = {{186}},
  year         = {{2011}},
}