Taking a Toll on human disease: Toll-like receptor 4 agonists as vaccine adjuvants and monotherapeutic agents

Baldridge, Jory R.; McGowan, Patrick O.; Evans, John K.; Cluff, C W; Mossman, Sally; Johnson, David A.; Persing, David H.

doi:10.1517/14712598.4.7.1129

Cited by 236 publications

(157 citation statements)

References 38 publications

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“…LPS is a potent adjuvant for systemically administered experimental vaccines, although the extreme inflammatory toxicity of LPS precludes it from being clinically useful as an adjuvant in humans (3). Efforts to reduce the toxicity of LPS, while retaining its potent adjuvant properties, have led to the development of monophosphoryl lipid A (MPLA), 3 an LPS derivative capable of generating potent immune responses to coadministered Ags with minimal toxicity (4,5). Like LPS, the adjuvant properties of MPLA appear to be TLR4 dependent (4 -6).…”

Section: Tlr-induced Localmentioning

confidence: 99%

TLR-Induced Local Metabolism of Vitamin D3 Plays an Important Role in the Diversification of Adaptive Immune Responses

Enioutina

Bareyan

Daynes

2009

The Journal of Immunology

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The addition of monophosphoryl lipid A, a minimally toxic derivative of LPS, to nonmucosally administered vaccines induced both systemic and mucosal immune responses to coadministered Ags. This was dependent on an up-regulated expression of 1α-hydroxylase (CYP27B1, 1αOHase), the enzyme that converts 25-hydroxycholecalciferol, a circulating inactive metabolite of vitamin D3, into 1,25(OH)2D3 (calcitriol). In response to locally produced calcitriol, myeloid dendritic cells (DCs) migrated from cutaneous vaccination sites into multiple secondary lymphoid organs, including classical inductive sites of mucosal immunity, where they effectively stimulated B and T cell immune responses. The endogenous production of calcitriol by monophosphoryl lipid A-stimulated DCs appeared to be Toll-IL-1R domain-containing adapter-inducing IFN-β-dependent, mediated through a type 1 IFN-induced expression of 1αOHase. Responsiveness to calcitriol was essential to promote the trafficking of mobilized DCs to nondraining lymphoid organs. Collectively, these studies help to expand our understanding of the physiologically important roles played by locally metabolized vitamin D3 in the initiation and diversification of adaptive immune responses. The influences of locally produced calcitriol on the migration of activated DCs from sites of vaccination/infection into both draining and nondraining lymphoid organs create a condition whereby Ag-responsive B and T cells residing in multiple lymphoid organs are able to simultaneously engage in the induction of adaptive immune responses to peripherally administered Ags as if they were responding to an infection of peripheral or mucosal tissues they were designed to protect.

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Section: Tlr-induced Localmentioning

confidence: 99%

TLR-Induced Local Metabolism of Vitamin D3 Plays an Important Role in the Diversification of Adaptive Immune Responses

Enioutina

Bareyan

Daynes

2009

The Journal of Immunology

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“…The TLR7 agonist imiquimod, for example, has been used to treat superficial basal cell carcinoma (Stockfleth et al, 2003), while theTLR9 agonist CpG-ODN B type is being evaluated in clinical trials in patients with melanoma and lymphoma (Speiser et al, 2005;Jahrsdorfer et al, 2005a). TLR4 agonists, including monophosphoryl lipid, have been used as adjuvant for vaccines against HBV and other pathogens (Baldridge et al, 2004). Several mechanisms have been proposed to explain the apparent adjuvant effects of TLR agonists on antitumor immunity.…”

Section: Targeting Tlrs For Cancer Therapymentioning

confidence: 99%

Toll-like receptors and immune regulation: implications for cancer therapy

2008

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“…Although review of the field of vaccine adjuvant development is outside the scope of this review, it is critical to note that rapid advances in the field of dendritic cell biology, B cell immunoregulation and Toll-like receptor signaling have provided important new insights that the HIV-1 vaccine field needs to access for design of optimal HIV-1 vaccines [195][196][197][198][199][200][201][202][203].…”

Section: Adjuvant Design For Hiv-1 Vaccinesmentioning

confidence: 99%

Aiming to induce broadly reactive neutralizing antibody responses with HIV-1 vaccine candidates

Haynes¹,

Montefiori²

2006

Expert Review of Vaccines

103

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Neutralizing antibody induction is a key feature of many effective vaccines and is the only immune response that has proven to be capable of completely blocking AIDS virus infection in animal models. Unfortunately, the extensive genetic variability and complex immune-evasion strategies of HIV-1 have thwarted all attempts to date at eliciting an effective neutralizing antibody response with candidate HIV-1 vaccine immunogens. Recent advances in our understanding of how these evasion strategies operate, coupled with growing progress in unravelling the structure and immunobiology of the viral envelope glycoproteins, are contributing to novel immunogen designs to overcome the many barriers to inducing protective antibodies against HIV-1. Keywordsantiretroviral therapy; HIV-1; host cell fusion; immunogen; neutralizing antibody induction Development of a safe, practical and effective HIV-1 vaccine is one of the highest priorities of the global scientific community [1,2]. Although antiretroviral therapy (ART) has dramatically prolonged the lives of HIV-1 infected patients, ART is not yet routinely available in developing countries, and the global rate of spread of HIV-1 continues unabated. If no effective AIDS vaccine is developed by 2010, the number of people infected world-wide with HIV-1 could exceed 60 million [3].In spite of more than 20 years of research, the types of immune responses needed to protect an immunized individual from HIV-1 infection are not known. Its is known that CD8 + cytotoxic T-cell responses can control HIV-1 replication to varying degrees in acute HIV-1 infection (AHI) [4,5], and when induced by immunogens, can control viral set point after simian immunodeficiancy virus (SIV) or simian HIV (SHIV) challenges in non-human primates [4]. Strong proliferative CD4 + T-cell responses to HIV-1 proteins have been demonstrated to correlate well with immune control of HIV-1 viral load [5]. Therefore, it is highly desirable for an HIV-1 vaccine co induce robust CD4 + and CD8 + T-cell responses in order to control virus replication and reduce the likelihood of subsequent transmission [4][5][6][7]. The potential for complete ('sterilizing') immunity from HIV-1 infection may depend on the presence of pre-existing neutralizing antibodies. We know that neutralizing antibodies can prevent the acquisition of AIDS virus infection after intravenous, vaginal, rectal and oral virus challenge in nonhuman primates [8][9][10][11][12]. This level of protection is highly attractive for a vaccine against a virus, such as HIV-1, which integrates genetically and forms latent viral reservoirs soon after infection. However, the diversity of transmitted HIV-1 genetic variants and the relative resistance of the majority of HIV-1 primary isolates to most types of inducible neutralizing antibodies have posed major hurdles to current vaccine efforts. Furthermore, the few rare broadly reactive neutralizing monoclonal antibodies (mAbs) that have been isolated from HIV-1 infected patients represent species of antibodies that...

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Taking a Toll on human disease: Toll-like receptor 4 agonists as vaccine adjuvants and monotherapeutic agents

Cited by 236 publications

References 38 publications

TLR-Induced Local Metabolism of Vitamin D3 Plays an Important Role in the Diversification of Adaptive Immune Responses

TLR-Induced Local Metabolism of Vitamin D3 Plays an Important Role in the Diversification of Adaptive Immune Responses

Toll-like receptors and immune regulation: implications for cancer therapy

Aiming to induce broadly reactive neutralizing antibody responses with HIV-1 vaccine candidates

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