GM-CSF-loaded chitosan hydrogel as an immunoadjuvant enhances antigen-specific immune responses with reduced toxicity

There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

Abstract

Background

The application of vaccine adjuvants has been vigorously studied for a diverse range of diseases in order to improve immune responses and reduce toxicity. However, most adjuvants have limited uses in clinical practice due to their toxicity.

Methods

Therefore, to reduce health risks associated with the use of such adjuvants, we developed an advanced non-toxic adjuvant utilizing biodegradable chitosan hydrogel (CH-HG) containing ovalbumin (OVA) and granulocyte-macrophage colony-stimulating factor (GM-CSF) as a local antigen delivery system.

Results

After subcutaneous injection into mice, OVA/GM-CSF-loaded CH-HG demonstrated improved safety and enhanced OVA-specific antibody production compared to oil-based adjuvants such as Complete Freund’s adjuvant (CFA) or Incomplete Freund’s adjuvant (IFA). Moreover, CH-HG system-mediated immune responses was characterized by increased number of OVA-specific CD4 ⁺ and CD8 ⁺ INF-γ ⁺ T cells, leading to enhanced humoral and cellular immunity.

Conclusions

In this study, the improved safety and enhanced immune response characteristics of our novel adjuvant system suggest the possibility of the extended use of adjuvants in clinical practice with reduced apprehension about toxic side effects.

Electronic supplementary material

The online version of this article (doi:10.1186/s12865-014-0048-x) contains supplementary material, which is available to authorized users.

Related collections

Most cited references 18

Record: found
Abstract: found
Article: not found

The adjuvant MF59 induces ATP release from muscle that potentiates response to vaccination.

Marilena Gallotta, Maria Vono, M Pallaoro … (2013)

Vaccines are the most effective agents to control infections. In addition to the pathogen antigens, vaccines contain adjuvants that are used to enhance protective immune responses. However, the molecular mechanism of action of most adjuvants is ill-known, and a better understanding of adjuvanticity is needed to develop improved adjuvants based on molecular targets that further enhance vaccine efficacy. This is particularly important for tuberculosis, malaria, AIDS, and other diseases for which protective vaccines do not exist. Release of endogenous danger signals has been linked to adjuvanticity; however, the role of extracellular ATP during vaccination has never been explored. Here, we tested whether ATP release is involved in the immune boosting effect of four common adjuvants: aluminum hydroxide, calcium phosphate, incomplete Freund's adjuvant, and the oil-in-water emulsion MF59. We found that intramuscular injection is always associated with a weak transient release of ATP, which was greatly enhanced by the presence of MF59 but not by all other adjuvants tested. Local injection of apyrase, an ATP-hydrolyzing enzyme, inhibited cell recruitment in the muscle induced by MF59 but not by alum or incomplete Freund's adjuvant. In addition, apyrase strongly inhibited influenza-specific T-cell responses and hemagglutination inhibition titers in response to an MF59-adjuvanted trivalent influenza vaccine. These data demonstrate that a transient ATP release is required for innate and adaptive immune responses induced by MF59 and link extracellular ATP with an enhanced response to vaccination.

0 comments Cited 62 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

CD8+ CTL priming by exact peptide epitopes in incomplete Freund's adjuvant induces a vanishing CTL response, whereas long peptides induce sustained CTL reactivity.

Michel Hof, Rienk Offringa, Else M. Bijker … (2007)

Therapeutic vaccination trials, in which patients with cancer were vaccinated with minimal CTL peptide in oil-in-water formulations, have met with limited success. Many of these studies were based on the promising data of mice studies, showing that vaccination with a short synthetic peptide in IFA results in protective CD8(+) T cell immunity. By use of the highly immunogenic OVA CTL peptide in IFA as a model peptide-based vaccine, we investigated why minimal CTL peptide vaccines in IFA performed so inadequately to allow full optimization of peptide vaccination. Injection of the minimal MHC class I-binding OVA(257-264) peptide in IFA transiently activated CD8(+) effector T cells, which eventually failed to undergo secondary expansion or to kill target cells, as a result of a sustained and systemic presentation of the CTL peptides gradually leaking out of the IFA depot without systemic danger signals. Complementation of this vaccine with the MHC class II-binding Th peptide (OVA(323-339)) restored both secondary expansion and in vivo effector functions of CD8(+) T cells. Simply extending the CTL peptide to a length of 30 aa also preserved these CD8(+) T cell functions, independent of T cell help, because the longer CTL peptide was predominantly presented in the locally inflamed draining lymph node. Importantly, these functional differences were reproduced in two additional model Ag systems. Our data clearly show why priming of CTL with minimal peptide epitopes in IFA is suboptimal, and demonstrate that the use of longer versions of these CTL peptide epitopes ensures the induction of sustained effector CD8(+) T cell reactivity in vivo.

0 comments Cited 46 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Granulocyte-macrophage colony-stimulating factor: an effective adjuvant for protein and peptide-based vaccines.

Martin A Cheever, Bruce Gillis, H Bernhard … (1996)

The current studies evaluate granulocyte-macrophage colony-stimulating factor (GM-CSF) as a vaccine adjuvant. An important issue for developing vaccine therapy for human malignancy is identifying adjuvants that can elicit T-cell responses to proteins and peptides derived from "self" tumor antigens. GM-CSF, in vitro, stimulates the growth of antigen-presenting cells such as dendritic cells and macrophages. Initial experiments examined whether GM-CSF injected into the skin of rats could affect the number or character of antigen presenting cells, measured as class II major histocompatability complex expressing cells, in lymph nodes draining the injection site. Intradermal (id) inoculation of GM-CSF every 24 hours for a total of five inoculations resulted in an increase of class II+ fluorescing cells that peaked at the fourth inoculation. Subcutaneous (sq) inoculation resulted in an increase of class II+ fluorescing cells that peaked following the second inoculation, then decreased over time. Using this schema for "conditioning" the inoculation site, GM-CSF was administered id or sq for five injections and a foreign antigen, tetanus toxoid (tt), was given at the beginning or the end of the immunization cycle. Id immunization was more effective than sq at eliciting tt specific immunity. In addition, GM-CSF id, administered as a single dose with antigen, compared favorably with complete Freund's adjuvant (CFA) and alum in eliciting tt specific antibody and cellular immunity. We have shown that immunity to rat neu (c-erbB-2) protein, an oncogenic self protein, can be generated in rats by immunization with peptides derived from the normal rat neu sequence plus CFA. The current study demonstrates that rat neu peptides inoculated with GM-CSF could elicit a strong delayed type hypersensitivity reaction (DTH) response, whereas peptides alone were non-immunogenic. GM-CSF was as effective as CFA in generating rat neu specific DTH responses after immunization with a neu peptide based vaccine. Soluble GM-CSF is a potent adjuvant for the generation of immune responses to foreign proteins as well as peptides derived from a self tumor antigen.

0 comments Cited 31 times – based on 0 reviews      Review now

Bookmark

All references

Author and article information

Contributors

Kyung Hee Noh: trollius@hanmail.net

Yeong Min Park: immun3023@kku.ac.kr

Hyuk Soon Kim: imperial9@naver.com

Tae Heung Kang: kangiron@kku.ac.kr

Kwon-Ho Song: kwonho@live.co.kr

Young-Ho Lee: zerotiger0919@gmail.com

Yeongseon Byeon: tarsakh@naver.com

Hat Nim Jeon: thdtkfldhk@naver.com

In Duk Jung: jungid@kku.ac.kr

Byung Cheol Shin: bcshin@krict.re.kr

Kyung-Mi Lee: kml60637@gmail.com

Seung-Yong Seong: seongsy@snu.ac.kr

Hee Dong Han: hanhd@kku.ac.kr

Tae Woo Kim: twkim0421@korea.ac.kr

Journal

Journal ID (nlm-ta): BMC Immunol

Journal ID (iso-abbrev): BMC Immunol

Title: BMC Immunology

Publisher: BioMed Central (London )

ISSN (Electronic): 1471-2172

Publication date (Electronic): 18 October 2014

Publication date PMC-release: 18 October 2014

Publication date Collection: 2014

Volume: 15

Issue: 1

Electronic Location Identifier: 48

Affiliations

[ ]Laboratory of Infection and Immunology, Graduate School of Medicine, Korea University, Gojan-1 Dong, Ansan-Si, Gyeonggi-Do 425-707 South Korea

[ ]Department of Biochemistry, College of Medicine, Korea University, Seoul, Korea

[ ]Department of Immunology, School of Medicine, Konkuk University, 268 Chungwondaero, Chungju-Si, Chungcheongbuk-Do 380-701 South Korea

[ ]Department of Immunology and Physiology and Functional Genomics Institute, College of Medicine, Konkuk University, 268 Chungwondaero, Chungju-Si, Chungcheongbuk-Do 380-701 South Korea

[ ]Research Center for Medicinal Chemistry, Division of Drug Discovery Research, Korea Research Institute of Chemical Technology, 141 Gajeong-ro, Yuseong-gu Daejeon, 305-600 South Korea

[ ]Department of Microbiology and Immunology, College of Medicine, Seoul National University, 28 Yongon-dong, Jongno-gu Seoul, 110-799 Republic of Korea

[ ]Department of Biomedical Sciences, College of Medicine, Seoul National University, 28 Yongon-dong, Jongno-gu Seoul, 110-799 Republic of Korea

Article

Publisher ID: 48

DOI: 10.1186/s12865-014-0048-x

PMC ID: 4201920

PubMed ID: 25323934

SO-VID: cd8aea40-896a-4fb0-a7f1-9ffc61aa714a

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 19 May 2014

Date accepted : 10 October 2014

Custom metadata

ScienceOpen disciplines: Immunology

Keywords: adjuvant,chitosan,hydrogel,immune response

Data availability:

ScienceOpen disciplines: Immunology

Keywords: adjuvant, chitosan, hydrogel, immune response

Comments

Comment on this article

scite_

Cited by 12

See all cited by

Most referenced authors 294

See all reference authors

GM-CSF-loaded chitosan hydrogel as an immunoadjuvant enhances antigen-specific immune responses with reduced toxicity

Read this article at

Abstract

Background

Methods

Results

Conclusions

Electronic supplementary material

Related collections

HLA-G and immune tolerance in pregnancy

Most cited references 18

The adjuvant MF59 induces ATP release from muscle that potentiates response to vaccination.

CD8+ CTL priming by exact peptide epitopes in incomplete Freund's adjuvant induces a vanishing CTL response, whereas long peptides induce sustained CTL reactivity.

Granulocyte-macrophage colony-stimulating factor: an effective adjuvant for protein and peptide-based vaccines.

Author and article information

Contributors

Journal

Affiliations

Article

History

Categories

Custom metadata

Comments

Comment on this article

Similar content 146

Cited by 12

Most referenced authors 294