CN103880961A - Construction of immune tolerance inducing fusion peptide - Google Patents
Construction of immune tolerance inducing fusion peptide Download PDFInfo
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- CN103880961A CN103880961A CN201210555471.XA CN201210555471A CN103880961A CN 103880961 A CN103880961 A CN 103880961A CN 201210555471 A CN201210555471 A CN 201210555471A CN 103880961 A CN103880961 A CN 103880961A
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Abstract
The present invention belongs to the technical fields of autoimmune diseases and organ transplantation immune tolerance induction treatment, and particularly relates to an antigen peptide, proteolytic cleavage function gene selection, gene recombination, and a fusion protein construction method. According to the present invention, the gene coding sequence of a TAT protein core amino acid sequence, a CLPP1 domain coding gene sequence and a specific antigen peptide coding gene sequence are connected by adopting a gene synthesis method, wherein the three substances are connected through specific restriction site coding gene sequences. The immune tolerance inducing fusion peptide can be used for individualized treatments of autoimmune diseases and organ transplantation immunologic rejection.
Description
Technical field: the invention belongs to autoimmune disorder, organ transplantation inducing immune tolerance treatment technology field, be specifically related to antigen peptide, the selection of proteolytic cleavage functional gene, gene recombination, fusion protein construction method.
Background technology: how inducing host immune tolerance is that the immunological rejection (organ-graft refection) that treatment immunoregulatory abnormality disease (as inflammatory bowel) and isoantigen cause is focus and the difficult problem of current field of immunology.There is following problem in research inducing immune tolerance at present: 1, and acceptor, accepting, after antigen of donor stimulation, to be produced as nature adjusting T cell and B cell, contacts antigen propagation and immunoregulation capability limited again.2, antigen of donor is absorbed by dendritic cell (DC) by antigen presenting cell (APC), the beta induced Treg of DC emiocytosis specificity T GF-produces, but research shows at present, why do not induce a considerable amount of Treg and produce, be due to the TGF-β that DC cell produces be connected with a peptide section (Latent TGF-β) cannot bring into play function.Previously there is people to study and use proteolytic enzyme to cut off this peptide section, indefinite at present but which kind of proteolytic enzyme can cut off this peptide section; New albumen if not acceptor this existence, cause again DC cell produce immune response.
Enteron aisle is as second largest immune organ, absorbs every day can be absorbed from a large amount of various albumen of external source and do not produce rejection, and this phenomenon is called oral tolerance (oral tolerance is a whole body tolerance response).Find that by early-stage Study enteron aisle fungal component acts on obviously in oral tolerance, and oral tolerance mechanism may cut off peptide section in Latent TGF-β for enteron aisle fungal component can secrete a kind of Special Proteins enzyme, make it to become the beta induced immunological tolerance of functional TGF-.This laboratory is by repeated screening, find that bifidobacterium infantis can induce Treg to produce, by sequence alignment and bioinformatic analysis, find that the proteolytic enzyme of this bacterium CLPP1 genetic expression has the function of the peptide section of cutting off in vitro in LatentTGF-β.Therefore this patent couples together CLPP1 gene and specific antigens (allo-MHC peptide) by engineered method, forms new fusion rotein, regulates T cell and B cell to produce, inducing immune tolerance by the induction of inducing specific.
The protein function district of TAT in human immunodeficiency virus HIV-1 (Trans-activatortranscription) albumen, be referred to as PTD section (Protein transductiondomain), effectively leader peptide or protein enter cell, have albumen transmitting function.The core sequence of TAT albumen PTD is made up of 11 amino acid, its sequence is YGRKKRRQRRR, 11 amino acid transduction sequences of TAT are the shortest sequences of TAT PTD of finding so far, its transduction ability is unlike total length TAT sequence transduction ability, be characterized in that transduction speed is fast, efficiency is high.
CLPP1 gene be in intestinal bifidobacteria (bifidobacterium infantis) can according to this experiment be research can expressing protein peptide section in the external cut-out of enzyme Latent TGF-β, making it to become has function TGF-β, thereby induction regulatory T cells and B cell produce and inducing immune tolerance.
Summary of the invention:
The present invention is directed to above-mentioned background, a kind of structure of inducing immune tolerance fusogenic peptide is provided.Its technical scheme is as follows:
By the gene coded sequence of TAT protein core aminoacid sequence, CLPP1 structural domain coding gene sequence and specific antigens DNA encoding peptide sequence, the method synthetic by gene links together, between three, be connected by specificity restriction enzyme site coding gene sequence, gene synthetic product is inserted in expression vector pET32a, and expression, purifying fusogenic peptide regulatory T cells and B cell have keying action at inducing immune tolerance.After antigen presenting cell contact specific antigens, can produce killer T cell and regulatory T cells and the B cell of antigen-specific.Antigen by DC cellular uptake after, offer antigen peptide to cd4 cell, secrete cytokines TGF-β 1 simultaneously, INF-γ, TNF-α, when cd4 cell must obtain antigen, obtain when cytokine stimulates simultaneously and could breed, in immunology, make immunity stimulate altogether phenomenon, for example cd4 cell obtains antigen to be stimulated and will produce Th1 cell by INF-γ simultaneously, stimulated and will produce Th2 cell by TNF-α, these two kinds of cells mainly mediate rejection, if stimulated and just become Tregs inducing immune tolerance by TGF-β 1, TGF-β 1 suppresses INF-γ in addition simultaneously, the effect of TNF-α.But DC emiocytosis TGF-β 1 is out immature LTBP, prematurity TGF-β 1 hypofunction causes Tregs output very low.CLPP1 gene be in intestinal bifidobacteria (bifidobacterium infantis) can according to this experiment be research can expressing protein peptide section in the external cut-out of enzyme Latent TGF-β, making it to become has function TGF-β, thereby induction regulatory T cells and B cell produce and inducing immune tolerance.TGF-β 1 causes the generation of FOXP3 by a series of signal approach, thereby produce FOXP3+CD4+T cell, FOXP3+CD4+T cell moves to lymphoglandula and reaches maturity and become the cell of FOXP3+CD4+CD25+T after generation, if next time is at identification antigen, the breeding of will increasing in a large number, performance immunoloregulation function.
Beneficial effect:
Fusogenic peptide can be identified by antigen-antibody with antigen presenting cell after entering in body, and the proteolytic enzyme that CLPP1 expresses cuts off the peptide section in Latent TGF-β, inducing antigen-specific regulatory T cells and B cell produce, thus the immunological tolerance of inducing specific antigen to host.Can be used for carrying out autoimmune disorder and organ transplantation immunological rejection individualized treatment.
Accompanying drawing explanation:
Fig. 1 is that inducing immune tolerance fusogenic peptide of the present invention builds;
Fig. 2 is that inducing immune tolerance fusogenic peptide of the present invention causes SRDC cell expressing IL-10 and mature T GF-β to increase (flow cytometer showed data);
Fig. 3 is that inducing immune tolerance fusogenic peptide of the present invention causes SRDC cell expressing IL-10 and mature T GF-β to increase (Western-blot data);
Label in Fig. 1 is explained: 1, TAT coding gene sequence, 2, gene catenation sequence, 3, antigen encoding gene sequence, 4, DC cellular enzymes cuts gene order, 5, CLPP1 structural domain coding gene sequence.
Specific embodiments:
Below in conjunction with accompanying drawing, the enforcement of technical scheme is described in further detail:
As shown in Figure 1, Figure 2 and Figure 3: inducing immune tolerance fusogenic peptide builds and comprises that TAT coding gene sequence 1, gene catenation sequence 2, antigen encoding gene sequence 3, DC cellular enzymes cut gene order 4, CLPP1 structural domain coding gene sequence 5; Cell-based assay: by synthetic protein purification, cross after post, survey concentration, to in SRDC and 6 orifice plates, cultivate, every hole 5x105 cell, every hole adds albumen 50 micrograms/ML, do not add as blank, add protein transfort after inhibit24 hour, leach protein.Be FACS and add for first 3 hours, dye on ice TGF-beta and IL-10 30 minutes, flow cytometer detects the expression of TGF-beta and IL-10, and western blot detects expressing quantity.
The undeclared part relating in the present invention is same as the prior art.
Claims (2)
1. an inducing immune tolerance fusogenic peptide builds, TAT pilot protein, CLPP1 genetic expression proteolytic enzyme structural domain (cutting off TGF-β 1 (LTBP) the peptide section of non-activity) are connected with antigen specific antigen peptide three, construction of fusion protein, is characterized in that TGF-β 1 (LTBP) the peptide section of TAT pilot protein, CLPP1 proteolytic cleavage cut-out non-activity is connected with antigen specific antigen peptide.
2. inducing immune tolerance fusogenic peptide builds according to claim 1, it is characterized in that TAT pilot protein, CP1 genetic expression proteolytic enzyme structural domain are connected with antigen specific antigen peptide three, in the middle of three, can insert specific cell endoproteinase restriction enzyme site.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1533284A (en) * | 2001-07-26 | 2004-09-29 | ��������ͨ���о�Ժ | Use of biologically active HIV-1 Tat, fragments or derivatives thereof for preventing or therapeutic vaccination and/or treating other diseases |
| CN101117635A (en) * | 2006-07-31 | 2008-02-06 | 中国人民解放军军事医学科学院毒物药物研究所 | Fusion expression of PTD,HIF ODD and tumour inhibitory gene and uses thereof |
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- 2012-12-19 CN CN201210555471.XA patent/CN103880961A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1533284A (en) * | 2001-07-26 | 2004-09-29 | ��������ͨ���о�Ժ | Use of biologically active HIV-1 Tat, fragments or derivatives thereof for preventing or therapeutic vaccination and/or treating other diseases |
| CN101117635A (en) * | 2006-07-31 | 2008-02-06 | 中国人民解放军军事医学科学院毒物药物研究所 | Fusion expression of PTD,HIF ODD and tumour inhibitory gene and uses thereof |
Non-Patent Citations (1)
| Title |
|---|
| 田雨香: "PTD-hFOXP3融合蛋白的表达、纯化、鉴定及生物学功能的初步研究", 《江苏大学硕士学位论文》 * |
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Application publication date: 20140625 |