Single nucleotide polymorphisms (SNP) and association with resistance to immune tolerance induction

a single nucleotide polymorphism and immune tolerance technology, applied in the field of single nucleotide polymorphisms and association with resistance to immune tolerance induction, can solve the problems of heterogeneous patient response to treatment with pharmaceuticals, both beneficial and detrimental, and achieve the effect of facilitating tolerance induction

Inactive Publication Date: 2012-05-31
UNIV OF TENNESSEE RES FOUND
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0009]The present invention relates to correlating the presence or absence of certain nucleic acid sequences within a population with the ability to create immune tolerance in that same population. This correlation may be used to assist with induction of immune tolerance. In some embodiments, the invention concerns tolerance induced by repeated administration of very large doses of antigen, or of small doses that are below the threshold required for stimulation of an immune response. In some embodiments, tolerance is most readily induced by soluble antigens administered either intravenously or sublingually. Furthermore, it's contemplated that immunosuppression also facilitates the induction of tolerance. Based on the correlation of the presence or absence of certain nucleic acid sequences associated with specific diseases or disorders, the present invention also provides for methods of detecting variants. In one specific embodiment, the nucleic acid sequences of interest are SNPs. In addition embodiments of the invention address the use or avoidance of non streroidal anti inflammatory drugs in therapy.

Problems solved by technology

Additionally, the effects of a variant form may be both beneficial and detrimental, depending on the circumstances.
For example, a heterozygous sickle cell mutation confers resistance to malaria, but a homozygous sickle cell mutation is usually lethal.
Clinical trials have shown that patient response to treatment with pharmaceuticals is often heterogeneous.
Today genomics is still not used to refine our medical management, despite the large quantities of research into the genome and SNPs.
As such, there are few reliable wide-scale assays, kits and methods that examine an individual's genome to find inherited susceptibility, gene expression, and predicted pharmacogenomic response.

Method used

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  • Single nucleotide polymorphisms (SNP) and association with resistance to immune tolerance induction
  • Single nucleotide polymorphisms (SNP) and association with resistance to immune tolerance induction
  • Single nucleotide polymorphisms (SNP) and association with resistance to immune tolerance induction

Examples

Experimental program
Comparison scheme
Effect test

example 1

Rheumatoid Arthritis (RA) Patients

[0182]120 RA patients on maintenance conventional therapies for their RA were tested for the ability of their peripheral blood mononuclear cells (PBMC) to produce IFNγ when cultured for six days with the autoantigen, purified bovine α1 chain of Collagen II (CII) or α1(II) at 50 μg / u. Culture supernatants were harvested and IFNγ levels determined by ELISA.

IFNγα1(II)S.I.=IFNγα1(II)-IFNγPBSIFNγPBS-100.

As shown below (Table I), 76 patients had increased by two-fold over their unstimulated or (PBS) cultured PBMC, or a prevalence of 63% RA patients with an immune responses to CII (termed “Responders”). Although there is a high prevalence of RA patients with CII autoimmunity, it is one of several possible antigens apparent during the disease.

TABLE IPERCENTAGE of RA PATIENTS WITH IMMUNE RESPONSE byCULTURED PBMC to CII*PatientN%Mean IFNγα1(II) SI ± SEMResponders E76631494 ± 313Non-Responders443720.6 ± 6.5Total120100p = **Mann-Whitney Rank Sum Test

example 2

Low Dose Collagen II Induces Tolerance in DBA / 1 Lac Mice

[0183]Groups of 12 mice were fed oral CII at the doses indicated 8 times over 2 weeks and immunized with 100 μg bovine CII in CFA. After 4 days rest, the mice were then immunized at the base of the tail with 100 μg CII emulsified with complete Freund's adjuvant. The degree of arthritis was assessed by a blinded observer for 8 weeks.

[0184]As can be seen in FIG. 6, 10 μg / day oral dose of CII was most effective in reducing the incidence of arthritis with 500 μg / day being also, but less, effective. The percent of mice with grade 3 or 4 arthritis is indicated on the Y-axis. The biphasis response is due to induction of different tolerance mechanisms by low dose vs high dose CII. Low dose CII (10 μg) induces regulatory T cells while high dose (500 μg) induces anergy or clonal deletion.

example 3

NSAID Inhibition of Induction of Immune Tolerance to Collagen II in DBA / 1 Mice

[0185]To determine whether tolerance induction to orally fed bovine CII in DBA / 1 mice would be abrogated by orally fed NSAID, 3 groups of 20-22 DBA / 1 mice were fed (by gavage) eight doses (Monday, Tuesday, Thursday, and Friday for 2 weeks) of the following: Placebo (saline) in the a.m. and Placebo (0.1 M HAc) in the p.m.; Placebo (saline) in the a.m. and 10 μg native bovine CII in the p.m.; or piroxicam (2.4 μg / gm) in the a.m. and native bovine CII (10 μg) in the p.m. After 1 week, all mice were immunized (intradermally at the base of tail) with 100 μg of bovine CII emulsified in complete Freund's adjuvant. Animals were placed in coded cages and were scored by a blinded observer twice weekly for the number of arthritic joints (joints swollen, red, and / or deformed).

[0186]As shown in FIG. 7, compared to Placebo+Placebo fed controls, the percent of arthritic joints was less over the observation period in the ...

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Abstract

This application discloses methods, systems and kits for correlating the presence or absence of certain nucleic acid sequences within a population with the ability to create immune tolerance in that same population. Tolerance can be induced by solo or repeated administration of antigen, including soluble antigens administered either intravenously or sublingually. This application also discloses methods for detecting variants. In addition the application addresses the use or avoidance of non steroidal anti inflammatory drugs in therapy.

Description

FIELD OF THE INVENTION[0001]The present invention is in the field of the immune system and therapy. In particular, the present invention relates to specific nucleic acid sequences in the human genome, and their association with diseases and pathologies as well as immune tolerance induction. Based on differences in allele frequencies in the patient population relative to normal individuals, the naturally-occurring nucleic acid sequences disclosed herein can be used as targets for the design of diagnostic reagents and the development of therapeutic agents, as well as for disease association and linkage analysis. In particular, the nucleic acid sequences of the present invention are useful for identifying an individual (e.g., patient) who is at an increased or decreased risk of developing a disease or pathology and for early detection of the disease or pathology, for providing clinically important information for the prevention and / or treatment of disease or pathology, and for screenin...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K39/00A61P37/02C40B20/00C12Q1/68G01N21/64
CPCC12Q1/6883C12Q2600/106A61K39/00C12Q2600/158C12Q2600/156A61K38/39A61P37/02C12Q2600/118
Inventor POSTLETHWAITE, ARNOLD E.GU, WEIKUAN
Owner UNIV OF TENNESSEE RES FOUND
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