Distinct TLR adjuvants differentially stimulate systemic and local innate immune responses in nonhuman primates

Kwissa, Marcin; Nakaya, Hidehiko; Oluoch, Herold; Pulendran, Bali

doi:10.1182/blood-2011-10-388579

Cited by 123 publications

(128 citation statements)

References 51 publications

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“…The differences between ITP patients and healthy controls may be the result of an increase in activation state of this monocyte subset in ITP patients. As such, stimulation through TLR-7, which is preferentially expressed on CD16 ϩ monocytes at least in nonhuman primates, 33 was associated with increased IL-12 secretion in ITP patients, but not in healthy controls, indicating that patients' cells are at a heightened activation state. 34 Although our study has focused on the role of CD16 ϩ monocyte subset, a few studies have also explored the role of CD14 ϩ monocytes in modulation of Th17 development in the setting of autoimmunity.…”

Section: Discussionmentioning

confidence: 99%

CD16+ monocytes control T-cell subset development in immune thrombocytopenia

Zhong

Bao

et al. 2012

Blood

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IntroductionClassic differentiation of naive CD4 ϩ T cells into different T helper (Th) subsets, including Th1, Th2, and Th17, occurs in lymphoid tissues after contact with antigen-presenting cells that produce polarizing cytokines. These Th subsets in turn orchestrate diverse immune responses also mediated by production of distinct cytokines. Because aberrant Th1 or Th17 activities have the potential to trigger chronic inflammatory and autoimmune diseases, 1,2 effector Th responses in healthy persons are under tight regulation mediated in part by CD4 ϩ regulatory T cells (Tregs) that are thymic-derived or naive T cell-inducible. 3 Understanding how Th1/Th17/Treg differentiation and expansion are controlled is likely to provide an explanation of how inflammation may be sustained in pathologic environments.More recently, human monocytes were shown to trigger and polarize Th responses 4,5 as well as to both stimulate and suppress T-cell responses during infection and in autoimmune diseases. 5,6 Monocytes, which are generally regarded as precursors of tissue macrophages and dendritic cells, 7 can be phenotypically divided based on surface expression of CD14 (lipopolysaccharide receptor) and CD16 (low affinity Fc␥ receptor III) expression into subsets, each with distinct functional activities. The major monocyte subpopulation characterized by high CD14 but no CD16 expression (CD14 hi CD16 Ϫ ), also referred to as classic monocytes, have higher phagocytic activity. 8 The minor CD16 ϩ cells produce higher TNF after stimulation and expand under infectious or inflammatory conditions. 9,10 With regards to the control of Th differentiation and reactivation, the specific role of the monocyte subsets has not been fully characterized.Immune thrombocytopenia (ITP) is an autoimmune bleeding disease resulting from decreased platelet production as well as accelerated platelet destruction mediated in part by autoantibody-based destruction mechanisms. 11 ITP patients harbor activated platelet-autoreactive T cells with increasing cytokine imbalance toward IL-2 and IFN-␥ 12-14 as well as altered Treg numbers and function. [15][16][17][18][19][20] A shift toward stimulatory monocytes with enhanced Fc␥R-mediated phagocytic capacity further supports a generalized immune dysregulation in ITP. 21 More recently, studies reported increased Th17 cells or IL-17 cytokine in ITP patients, 22-24 implicating a possible role for Th17 cells in ITP immunopathology, although 2 reports did not detect any difference. 25,26 Among the treatment options available to ITP patients, the recently licensed thrombopoietic agents, by increasing platelet production, have yielded overall durable responses in patients with persistent, chronic, and/or refractory ITP while on treatment. 27 Interestingly, improved Treg function in ITP patients was associated with increased platelet counts after the use of these agents, 28 despite apparent lack of immunomodulatory activity associated with such agents. Similarly, improved Treg compartment was reported in ITP patients w...

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Section: Discussionmentioning

confidence: 99%

CD16+ monocytes control T-cell subset development in immune thrombocytopenia

Zhong

Bao

et al. 2012

Blood

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“…Rhesus macaques (which reliably mirror the response of humans to TLR agonists) were used to evaluate the activity of PAM3 in vivo. [39][40][41] PAM3 treatment induced a 20-fold increase in the frequency of circulating CD163 1 macrophages and the local production of IL-10 but had no significant effect on CD163…”

Section: Discussionmentioning

confidence: 99%

“…[39][40][41] Rhesus macaques were therefore treated with 2 mg of PAM3, and the effect of subcutaneous treatment on circulating macrophages was monitored for 72 hours. Consistent with in vitro results derived from studies of purified human monocytes, the frequency of CD68…”

Section: In Vivo Activity Of Pam3mentioning

confidence: 99%

Regulation of the maturation of human monocytes into immunosuppressive macrophages

et al. 2017

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“…The majority of clinical trials involving DC-based vaccination uses a cocktail of proinflammatory cytokines, including TNF, IL1b, IL6, and PGE 2 (45). Moreover, other authors explored the use of CD40L (46) and Toll-like receptor agonists that differentially stimulate systemic and local innate immune responses (47). Taken together, our previous (15,16) and current findings propose the emergence of T3 as an adjuvant alternative that educates DCs for stimulating antigen-specific effective T-cell responses in cancer settings.…”

Section: Discussionmentioning

confidence: 99%

Antitumor Responses Stimulated by Dendritic Cells Are Improved by Triiodothyronine Binding to the Thyroid Hormone Receptor β

et al. 2015

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Bidirectional cross-talk between the neuroendocrine and immune systems orchestrates immune responses in both physiologic and pathologic settings. In this study, we provide in vivo evidence of a critical role for the thyroid hormone triiodothyronine (T3) in controlling the maturation and antitumor functions of dendritic cells (DC). We used a thyroid hormone receptor (TR) b mutant mouse (TRbPV) to establish the relevance of the T3-TRb system in vivo. In this model, TRb signaling endowed DCs with the ability to stimulate antigen-specific cytotoxic T-cell responses during tumor development. T3 binding to TRb increased DC viability and augmented DC migration to lymph nodes. Moreover, T3 stimulated the ability of DCs to cross-present antigens and to stimulate cytotoxic T-cell responses. In a B16-OVA mouse model of melanoma, vaccination with T3-stimulated DCs inhibited tumor growth and prolonged host survival, in part by promoting the generation of IFNg-producing CD8 þ T cells.Overall, our results establish an adjuvant effect of T3-TRb signaling in DCs, suggesting an immediately translatable method to empower DC vaccination approaches for cancer immunotherapy. Cancer Res; 75(7); 1265-74. Ó2015 AACR.

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Distinct TLR adjuvants differentially stimulate systemic and local innate immune responses in nonhuman primates

Abstract: TLR ligands (TLR-Ls

Cited by 123 publications

References 51 publications

CD16+ monocytes control T-cell subset development in immune thrombocytopenia

CD16+ monocytes control T-cell subset development in immune thrombocytopenia

Regulation of the maturation of human monocytes into immunosuppressive macrophages

Antitumor Responses Stimulated by Dendritic Cells Are Improved by Triiodothyronine Binding to the Thyroid Hormone Receptor β

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