Co-stimulatory agonists as immunological adjuvants

Barr, Tom A.; Carlring, Jennifer; Heath, Andrew W.

doi:10.1016/j.vaccine.2006.02.022

Cited by 55 publications

(35 citation statements)

References 54 publications

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“…20,21 Identification of CD40L as an important signaling molecule led to the development of a soluble form of recombinant CD40 ligand (rCD40L) that could be used in various clinical situations. 22,23 This trimeric form of human rCD40L was generated using an isoleucine zipper that is capable of activating the CD40 receptor (Amgen). We first conducted preclinical studies in a murine model of XHM in which the CD40 ligand was disrupted through genetic engineering revealed that administration of CD40 agonists or recombinant murine CD40L trimer reversed the core immunologic abnormalities.…”

Section: X-linked Hyper Igm Syndrome (Xhm) Is a Combined Immune Deficmentioning

confidence: 99%

Partial immune reconstitution of X-linked hyper IgM syndrome with recombinant CD40 ligand

Jain

Kovacs

Nelson

et al. 2011

Blood

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X-linked hyper IgM syndrome (XHM) is a combined immune deficiency disorder caused by genetic alterations in CD40ligand. The purpose of this study was to investigate the safety and efficacy of recombinant CD40 ligand (rCD40L) in the treatment of the disease. Three children were administered rCD40L subcutaneously 3 times per week at 0.03 mg/kg for 22 weeks, and after a 12-week drug-free interval, the dose was increased to 0.05 mg/kg for an additional 22 weeks of treatment. Although specific antibody responses to T cell-dependent antigens was lacking, administration of rCD40 resulted in acquisition of the capacity to mount cutaneous delayed type hypersensitivity reactions that disappeared during the drug-free interval as well as the postbiologic follow-up period. [1][2][3] The cognate interaction between CD40L expressed on activated CD4 ϩ T cells and CD40 expressed constitutively on B cells leads to B-cell proliferation, somatic hypermutation in the immunoglobulin variable region, and immunoglobulin class switch recombination from IgM to IgG, IgA, and IgE. [4][5][6] Humans with mutations in the genes encoding CD40L have skewed IgM antibody responses and a markedly diminished or absent IgG response to protein antigens. 7-9 CD40 engagement on the surface of dendritic cells also influences dendritic cell maturation and activation. 8,10 It thus promotes the expression of factors that promote T-cell priming such as costimulatory molecules B7.1 (CD80) and B7.2 (CD86), IL-12 secretion, and the release of chemokines. 10,11 Indeed, humans and mice with CD40L deficiency exhibit defective T-cell function that manifests by a marked predisposition to develop opportunistic infections with Pneumocystis jerovici, Toxoplasma gondii, and Cryptosporidium species as well as an increased tendency to develop malignancies. [12][13][14][15] The IgG/IgA deficiency and associated humoral immune abnormalities in patients with XHM is effectively controlled by ␥ globulin replacement therapy (intravenous immunoglobulin [IVIG] therapy). 13,16 However, despite such treatment, the majority of patients die in the second decade of life as a consequence of impaired T-cell function. 13,17 Bone marrow transplantation is an effective treatment for patients with XHM, especially if performed early in life before the onset of secondary opportunistic infection, 18,19 although the need for matched related donors and the associated morbidity and mortality of the transplant impact on its clinical application. 20,21 Identification of CD40L as an important signaling molecule led to the development of a soluble form of recombinant CD40 ligand (rCD40L) that could be used in various clinical situations. 22,23 This trimeric form of human rCD40L was generated using an isoleucine zipper that is capable of activating the CD40 receptor (Amgen). We first conducted preclinical studies in a murine model of XHM in which the CD40 ligand was disrupted through genetic engineering revealed that administration of CD40 agonists or recombinant murine CD40L trimer reversed the c...

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Section: X-linked Hyper Igm Syndrome (Xhm) Is a Combined Immune Deficmentioning

confidence: 99%

Partial immune reconstitution of X-linked hyper IgM syndrome with recombinant CD40 ligand

Jain

Kovacs

Nelson

et al. 2011

Blood

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“…Nowadays, traditional vaccines developed from live attenuated or inactivated pathogens (Singh and O'hagan 2002) coexist with a new generation of vaccines produced from synthetic peptides and recombinant proteins (Barr et al 2006). However, despite the great technological advance of vaccinology in the last decades, many soluble proteins, purified and of low molecular mass antigens are of low immunogenic potential, necessitating to be associated with adjuvants (Leclerc 2003).…”

Section: Introductionmentioning

confidence: 99%

Recombinant Escherichia coli heat-labile enterotoxin B subunit humoral adjuvant effect depends on dose and administration route

Fischer

Conceição

Moraes

et al. 2009

World J Microbiol Biotechnol

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Information on the use of Escherichia coli heatlabile enterotoxin B subunit (LTB) as a parenteral adjuvant is scarce. We evaluate the adjuvant effect of different concentrations of recombinant LTB (rLTB), as well as the influence of administration route (intramuscular and subcutaneous) on mice immune response. The use of 10 lg/ dose of rLTB as adjuvant of an inactivated vaccine composed by Suid herpesvirus type 1 (SuHV-1), used to immunize mice intramuscularly, induced the highest average titers of anti-SuHV-1 antibodies (P \ 0.05). The same vaccines used subcutaneously induced lower titers of antibodies. The lower the anti-rLTB humoral response determined by ELISA, the higher was its adjuvant activity. In the challenge experiment with SuHV-1, 56% (14/25) (P \ 0.05) of the animals inoculated intramuscularly and 32% (8/25) inoculated subcutaneously survived, highlighting the influence of the concentration and the route of administration of rLTB on its performance as an adjuvant. Therefore, rLTB can significantly help in the induction of immunity against SuHV-1 in mice, especially if used intramuscularly in the concentration of 10 lg/dose, representing the best cost-benefit ratio.

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“…In fact, previous studies showed that CD40 stimulation alone could substitute CD4 + T cells in generating CD8 + T cell responses [20][21][22][23]. Stimulation of CD40, mainly through agonistic anti-CD40 antibody, has been used experimentally to enhance immune responses elicited by antigens from bacteria, viruses, and tumors (see reference [24] for review).…”

Section: Introductionmentioning

confidence: 99%

CD40L expressed from the canarypox vector, ALVAC, can boost immunogenicity of HIV-1 canarypox vaccine in mice and enhance the in vitro expansion of viral specific CD8+ T cell memory responses from HIV-1-infected and HIV-1-uninfected individuals

Liu

Stone

et al. 2008

Vaccine

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SummaryHuman immunodeficiency virus-1 (HIV-1) canarypox vaccines are safe but poorly immunogenic. CD40 ligand (CD40L), a member of the tumor necrosis factor superfamily (TNFSF), is a pivotal co-stimulatory molecule for immune responses. To explore whether CD40L can be used as an adjuvant for HIV-1 canarypox vaccine, we constructed recombinant canarypox viruses expressing CD40L. Co-immunization of mice with CD40L expressing canarypox and the canarypox vaccine expressing HIV-1 proteins, vCP1452, augmented HIV-1 specific cytotoxic T lymphocyte (CTL) responses in terms of frequency, polyfunctionality and interleukin (IL)-7 receptor α chain (IL-7Rα, CD127) expression. In addition, CD40L expressed from canarypox virus could significantly augment CD4 + T cell responses against HIV-1 in mice. CD40L expressed from canarypox virus matured human monocyte-derived dendritic cells (MDDCs) in a tumor necrosis factor α (TNF-α) independent manner, which underwent less apoptosis, and could expand ex vivo Epstein-Barr virus (EBV)-specific CTL responses from healthy human individuals and ex vivo HIV-1-specific CTL responses from HIV-1-infected individuals in the presence or absence of CD4 + T cells. Taken together, our results suggest that CD40L incorporation into poxvirus vectors could be used as a strategy to enhance their immunogenicity.

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Co-stimulatory agonists as immunological adjuvants

Cited by 55 publications

References 54 publications

Partial immune reconstitution of X-linked hyper IgM syndrome with recombinant CD40 ligand

Partial immune reconstitution of X-linked hyper IgM syndrome with recombinant CD40 ligand

Recombinant Escherichia coli heat-labile enterotoxin B subunit humoral adjuvant effect depends on dose and administration route

CD40L expressed from the canarypox vector, ALVAC, can boost immunogenicity of HIV-1 canarypox vaccine in mice and enhance the in vitro expansion of viral specific CD8+ T cell memory responses from HIV-1-infected and HIV-1-uninfected individuals

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