Interleukin 12: A Potent Vaccine Adjuvant for Promoting Cellular Immunity and Modulating Humoral Immunity
Thomas F. Kresina in Immune Modulating Agents, 2020
Interleukin 12 (IL-12) is a unique cytokine produced by antigen presenting cells. As discussed in more detail in several recent reviews [1–3], among the activities of IL-12 are several which bear on its potential as a vaccine adjuvant for both promoting cellular immune responses and modulating and enhancing humoral responses. One of the most potent activities of IL-12 is induction of 7-interferon (IFN-7) from T and natural killer (NK) cells. Enhancement of antigen presentation and suppression of T helper 2 (Th2) cell development by IFN-7 play key roles in promoting and directing the immune response developed in the presence of IL-12. Interleukin-12 also specifically and uniquely promotes the differentiation of T helper progenitors to be come Th1 cells. In both mice and humans at least two classes of T helper cell subsets that exert specific effects on immune development develop. T helper 1 (Th1) cells express IFN-7 and IL-2 cytokines that promote a cellular immune response by activating macrophage and enhancing development and expansion of CD8+ effector cells. Th2 cells express IL-4 and IL-5 and lack expression of IFN-7 and IL-2. As a consequence, Th2 cells promote the differentiation of B cells to express noncytophilic antibodies (e.g., immunoglobulin G1 [IgG 1] in mice) and IgA and recruit eosinophils. Although IL-12 has only moderate activity in promoting proliferation of primed T cells, costimulation with accessory molecules such as B7.1 has been shown dramatically to enhance proliferation of CD4+ and CD8+ T cells induced by IL-12 [4].
Medical Treatment for Ankylosing Spondylitis: An Overview
Barend J. van Royen, Ben A. C. Dijkmans in Ankylosing Spondylitis Diagnosis and Management, 2006
This drug has an anti-tumor necrosis factor (TNF) α activity by enhancing messenger RNA (mRNA) degradation (23). An inhibition of interleukin-12 has also been reported (24). More recent studies have evidenced that thalidomide increases natural killer cell cytotoxicity and augments T-cell proliferation (25,26). The clinical efficacy of thalidomide might be related to those biological effects. The main goal of the pharmacological industry is now to develop more potent and less toxic drugs, notably without teratogenic effects. Two classes of second generation analogs have been synthesized: immunomodulatory drugs (IMIDs) and selective cytokines inhibitory drugs (SelCIDs). These drugs are much more potent than thalidomide at inhibiting TNFα production in vitro and are currently being assessed in the treatment of cancer patients (27–29). Nevertheless, further applications in chronic inflammatory diseases are expected.
Sjögren Syndrome
Dongyou Liu in Handbook of Tumor Syndromes, 2020
The IL12A (interleukin 12, particularly the promoter region) gene encodes the p35 subunit that interacts with the p40 subunit encoded by IL12B to form the IL-12 heterodimer, which functions as an immunomodulatory cytokine. Secreted by monocytes and dendritic cells, IL-12 is critical for T-helper 1 cell differentiation and for interferon-γ production by T cells and NK cells. Pathogenic variants in the IL12A 5′ end are involved in celiac disease, and those in the IL12A 3′ end are linked to primary biliary cirrhosis. As a component of the IL-12 signaling pathway, IL12A along with STAT4-dependent signaling demonstrates a clear association with non-Hodgkin lymphoma, SLE, EBV infection, dry eye syndrome, and Sjögren syndrome [5].
Oral administration of Bifidobacterium breve promotes antitumor efficacy via dendritic cells-derived interleukin 12
Published in OncoImmunology, 2021
Qingxiang Li, Yuke Li, Yifei Wang, Le Xu, Yuxing Guo, Yixiang Wang, Lin Wang, Chuanbin Guo
Since the association between gut microbiota and cancer immunotherapy gradually uncovered, some important cytokines and immune cells have been noticed. Interleukin 12 (IL-12), produced by inflammatory myeloid cells, is a kind of heterodimeric cytokines with proinflammatory properties.16 IL-12 polarizes naive helper T cells (Th) to Th1 type and stimulates CD8+ T cells and NKT cells.17 Clinical studies based on IL-12 achieved well response, which mainly focused on local gene therapy.18 Current studies indicated that IL-12 promoted the curative effect of CTLA-4 or PD-1 blockade17,19,20 and adoptive cell therapy.21 Dendritic cells (DCs) are important source of endogenous IL-12. It was reported that effective anti-PD-1 immunotherapy requires intratumoral DCs-derived IL-12.19 And conventional type 1 DCs-derived IL-12 was necessary to the priming of follicular helper T cells, which was vitally important for the efficacy of chemotherapy for proximal colon cancer.22 All these evidence suggest the crucial role of IL-12 in immunotherapy against solid tumor.
Intratumoral delivery and therapeutic efficacy of nanoparticle-encapsulated anti-tumor siRNA following intrapulmonary administration for potential treatment of lung cancer
Published in Pharmaceutical Development and Technology, 2019
Yukimune Kanehira, Kohei Togami, Kiyomi Ishizawa, Shingo Sato, Hitoshi Tada, Sumio Chono
The intrapulmonary and intravenous administration of nanoparticles containing antitumor siRNA against MDM2, c-Myc, and VEGF (MDM2:c-Myc:VEGF = 1:1:1, molar ratio) did not induce significant production of interleukin-6 and -12 as proinflammatory cytokines (Figure 7). Interleukin-6 is secreted by monocytes, macrophages, and endothelial cells in systemic inflammation. Interleukin-6 causes the proliferation and activation of T cells and the differentiation of B cells and controls the acute-phase response (Musolino et al. 2017). Interleukin-12 stimulates innate and adaptive immunity; further, it induces cytotoxicity of T helper type 1 cells, macrophages, and natural killer cells (Armstead and Li 2016; Musolino et al. 2017). Therefore, these cytokines are used for the evaluation of siRNA immunotoxicity (Hu-Lieskovan et al. 2005; Li et al. 2008; Woods et al. 2015). These findings suggest that the siRNA-containing nanoparticles do not induce systemic toxicity after both intrapulmonary and intravenous administration. Thus, the nanoparticles exhibited tumor-cell specificity and delivery efficiency, effectively silencing the oncogenes in lung metastasis without any significant systemic toxicity.
MUC16 mutations improve patients’ prognosis by enhancing the infiltration and antitumor immunity of cytotoxic T lymphocytes in the endometrial cancer microenvironment
Published in OncoImmunology, 2018
Jing Hu, Jing Sun
Interleukin-12 (IL-12) promotes cell mediated immunity by activating the cytotoxic activity of both T cell and NK cell and inducing Th1 cell differentiation which is believed to represent an important link between innate and adaptive immunity.43 In our analysis, we observed that two IL-12 mediated pathways in T cells and NK cells were upregulated in tumor samples with MUC16 mutations (Figure 4E). Studies reported that chimeric antigen receptors expressing T cells (CAR T cells), which secrete IL-12 and target retained MUC16 ectodomain, exhibited enhanced antitumor efficacy in recurrent ovarian cancer.44,45 The combination use of MUC16 and IL-12 provided novel and promising approachs for cancer immunotherapy. And, more researches are needed to explore appropriate protocols, the safety and efficacy of these methods in clinical application.
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