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Compositions and methods for modulating an immune response

Inactive Publication Date: 2011-09-22
THE JOHN HOPKINS UNIV SCHOOL OF MEDICINE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0006]In one aspect, the invention generally provides a method for modulating CD4+CD25+ regulatory T cell (Treg) biological function, the method involving contacting the cell with an agent that alters Helios expression, thereby modulating CD4+CD25+ T cell biological function. In one embodiment, the method increases or reduces Treg suppressive activity, for example, by at least about 5%, 10%, 20%, 25%, 50%, 75%, or 100%.
[0056]As used herein, the terms “prevent,”“preventing,”“prevention,”“prophylactic treatment” and the like refer to reducing the probability of developing a disorder or condition in a subject, who does not have, but is at risk of or susceptible to developing a disorder or condition.

Problems solved by technology

However, immunological tolerance against self-antigens may limit an effective antitumor immune response.
In conditions, such as chronic infection and neoplasia, Treg suppressive activity undesirably reduces the efficacy of an immune response capable of fighting the infection or eliminating the neoplasia.
Conversely, in conditions where an immune response is undesirably activity, such as autoimmunity and inflammatory disease, Treg suppressive activity is inadequate to reduce the undesirable immune response.
Conventional methods for modulating an immune response are inadequate for the treatment of such conditions.

Method used

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  • Compositions and methods for modulating an immune response
  • Compositions and methods for modulating an immune response
  • Compositions and methods for modulating an immune response

Examples

Experimental program
Comparison scheme
Effect test

example 1

Helios is Expressed in Human Treg

[0164]To determine whether Helios expression is up-regulated in Treg isolated from the peripheral blood of healthy human donors, Helios expression was evaluated in CD4+CD25+ T cells. As shown in FIG. 1A, qRT-PCR determination of transcript levels from FACS sorted CD4+CD25− or CD4+CD25+ T cells showed that Helios expression is relatively restricted to the CD25+ compartment of human CD4 T cells, which correlates well with FoxP3+ expression. Transient FoxP3 expression is a property of activated human CD4 T cells (Pillai et al., Clin Immunol. 2007; 123:18-29; Wang et al., Eur J. Immunol. 2007; 37:129-138). It was next determined whether up-regulation of Helios precedes FoxP3 up-regulation. As shown in FIG. 1B, Helios message levels reached peak levels 12 hours post-activation, whereas FoxP3 levels appeared to peak approximately 24 hours post-activation. Thus, up-regulation of Helios precedes FoxP3 up-regulation.

example 2

Induced Expression of Helios in CD4 T Cells Induced Apoptosis

[0165]To better elucidate a possible functional relationship between Helios and FoxP3, a series of Helios lentivirus constructs was generated. The viral vectors used were MSCV-IRES GFP vectors. These were used to transduce naïve human CD4 T cells. Initial results suggested poor survival of specifically transduced cells. Therefore, Jurkat T cells were used to specifically test whether Helios affects T cell survival. Cells were transfected with the full-length Helios or a non-DNA binding isoform (as a negative control). Cultures of transfected cells were assayed for apoptosis using 7AAD and Annexin V staining (FIG. 1c) (Zhang et al., Blood 2007; 109:2190-2197). These data showed that ectopic expression of Helios in CD4 T cells induced apoptosis. Taken together these data showed a relative up-regulation of Helios in Treg, but suggested that Helios expression alone was insufficient to generate Treg in vitro.

example 3

Helios is a Transcriptional Regulator of FoxP3

[0166]To explore Helios function in Treg, EL4 thymoma cells were used to determine whether the Helios transcription factor directly interacts with the FoxP3 promoter. EL4 thymoma cells are reported to express multiple isoforms of Helios (Hahm et al., Genes Dev. 1998; 12:782-796). EL4 thymoma cells transcribe FoxP3 upon stimulation with anti-CD3e, anti-CD28, and TGFβ (Tone et al., Nat. Immunol. 2008; 9:194-202). Myc-tagged full-length Helios or insert control were over-expressed in EL4 cells, and the cells were cultured overnight. An anti-Myc antibody was able to precipitate regions of the FoxP3 promoter in a ChIP assay 24 hours after stimulation (FIG. 1D). Two separate but adjacent regions (−1184 to −724 and −692 to −335 from transcriptional start site) on the FoxP3 promoter were specifically immunoprecipitated. These data indicate that the DNA binding isoform of Helios is present at the promoter region during FoxP3 transcription in thes...

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Abstract

The invention generally features compositions and methods for modulating an immune response. In particular embodiments, such compositions and methods modulate regulatory T cell suppressive activity.

Description

CROSS-REFERENCE TO RELATED APPLICATION[0001]This application claims the benefit of the following U.S. Provisional Application No. 61 / 126,882, filed May 8, 2008, the entire contents of which are incorporated herein by reference.STATEMENT OF RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED RESEARCH[0002]This work was supported by the following grants from the National Institutes of Health, Grant No: NCI 1 P50 CA098252. The government has certain rights in the invention.BACKGROUND OF THE INVENTION[0003]Approximately 1 million Americans are diagnosed with neoplasia every year, and about half a million people in the United States die of the disease annually. While improvements in neoplasia detection, diagnosis, and treatment have increased the survival rate for many types of neoplasia, only about 60 percent of people diagnosed with neoplasia are alive five years after treatment, making neoplasia the second leading cause of death in the United States. Cancer vaccines are one promising ...

Claims

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Application Information

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IPC IPC(8): A61K39/00C12N5/02C07H21/04C12N15/63C12Q1/68A61P37/00
CPCC07K14/4702C12N15/113C12Q2600/136G01N33/5011C12Q1/6881C12N2310/14A61P37/00A61K39/0011A61K39/39A61K2039/55561A61K2039/572C12N15/117C12N2310/17C12N2320/31
Inventor DRAKE, CHARLES GEORGEPARDOLL, DREW M.POWELL, JONATHAN DAVIEGETNET, DERESEHIPKISS, EDWARD LUTHERGROSSO, JOSEPH FRANK
Owner THE JOHN HOPKINS UNIV SCHOOL OF MEDICINE