Direct reversal of the suppressive function of cd4+ regulatory t cells via toll-like receptor 8 signaling

A cell and cell activity technology, applied in allergic diseases, recombinant DNA technology, microbial measurement/inspection, etc., can solve the problems of inhibition, non-response, stimulation, etc.

Inactive Publication Date: 2008-05-21
BAYLOR COLLEGE OF MEDICINE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

It has been reported that stimulation of mouse DCs with TLR ligands (such as lipopolysaccharide (LPS) and CpG DNA) induces DCs to secrete lymphokines such as IL-6 and CD4 + Effector cells do not respond to Treg cell-mediated suppression

Method used

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  • Direct reversal of the suppressive function of cd4+ regulatory t cells via toll-like receptor 8 signaling
  • Direct reversal of the suppressive function of cd4+ regulatory t cells via toll-like receptor 8 signaling
  • Direct reversal of the suppressive function of cd4+ regulatory t cells via toll-like receptor 8 signaling

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Experimental program
Comparison scheme
Effect test

Embodiment

[0046] Establishment of Treg cell lines and purification of native CD4 + CD25 + Treg cells

[0047] Using methods well known in the art, from CD4 + Tumor infiltrating lymphocytes (TIL102 and TIL164) established CD4 + Treg clones were maintained in RPMI 1640 medium containing 10% human AB serum and recombinant IL-2 (300 IU / ml) (see, eg, H.Y. Wang et al., Immunity 20, 107-118 (2004)). The Treg clones obtained from TIL102 cells or TIL164 cells were combined and named as Treg102 or Treg164. CD4 was isolated by sorting from fresh PBMC after anti-CD4 antibody and anti-CD25 antibody staining + T cell populations that acquire naturally occurring CD4 + CD25 + Treg cells. For optimal amplification, OKT3 amplification was performed using methods well known in the art (see, eg, H.Y. Wang et al., Immunity 20, 107-118 (2004)). T cell clones were maintained at low concentrations of IL-2 (300 IU / ml). The melanoma cell lines and EBV-transformed B cell lines used in this study we...

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Abstract

CD4<+> regulatory T (Treg) cells profoundly suppress host immune responses and thus protect against autoimmune disease while restricting desired immune responses such as antitumor immunity. Synthetic phosphorothioate-protected, guanosine-containing oligonucleotides can directly reverse the suppressive activity of Treg cells without involving dendritic cells. This effect appears to be transduced by signaling through Toll-like receptor (TLR) 8 and engagement of the MyD88 and IRAK4 molecules in Treg cells. Stimulation of Treg cells with natural ligands for human TLR8 recapitulated the effect of the synthetic guanosine-containing oligonucleotides .

Description

[0001] Cross References to Related Applications [0002] [001] This application claims the benefit of US Provisional Application 60 / 660,028, the contents of which are incorporated herein by reference. [0003] statement regarding federally funded research or development [0004] [002] This invention was made with government support in part under grant numbers R01CA90327, R01CA101795, P50CA58204, P50CA093459, and PO1CA94237 from the National Institutes of Health. The US Government has certain rights in this invention. Background of the invention [0005] [003] Natural CD4 + CD25 + Regulatory T cells (Treg cells) and antigen-induced Treg cells can induce self-tolerance by suppressing host immune responses, and thus play an important role in the prevention of many autoimmune diseases. However, Treg cells have a detrimental effect on immunotherapy for cancer or other diseases because they potentially suppress immune responses elicited by vaccination or other systemic antigen s...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12Q1/68C07H21/02C12N15/113C12N15/117
CPCC12N15/113C12N2310/14C12N15/117C12N15/1138C12N2310/315C12N2310/17C12N2310/111A61P31/00A61P35/00A61P37/04A61P43/00
Inventor R·-F·王G·彭Y·王
Owner BAYLOR COLLEGE OF MEDICINE
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