CN115166250B - Application of T cells as biomarkers in monitoring or predicting the efficacy of anti-HBV treatment or predicting the risk of relapse - Google Patents
Application of T cells as biomarkers in monitoring or predicting the efficacy of anti-HBV treatment or predicting the risk of relapse Download PDFInfo
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Abstract
本发明公开了T细胞作为生物标志物在制备用于监测或预测抗HBV治疗的疗效的产品中的应用，所述T细胞包括Treg细胞、CD4+T细胞、CD8+T细胞；还公开了T细胞作为生物标志物在制备用于预测抗HBV治疗中达到临床功能性治愈后复发风险的产品中的应用，所述T细胞包括CD8+亚群CXCR5+CD8+T细胞和CD4+亚群CXCR5+CD4+T细胞。本发明可应用于指导慢性乙型肝炎干扰素抗病毒治疗，为探索慢乙肝抗病毒治疗提供新的免疫靶点，提高治愈率，减少复发率。
The present invention discloses the application of T cells as biomarkers in the preparation of products for monitoring or predicting the efficacy of anti-HBV treatment, wherein the T cells include Treg cells, CD4+T cells, and CD8+T cells; and also discloses the application of T cells as biomarkers in the preparation of products for predicting the risk of relapse after achieving clinical functional cure in anti-HBV treatment, wherein the T cells include CD8+ subgroup CXCR5+CD8+T cells and CD4+ subgroup CXCR5+CD4+T cells. The present invention can be applied to guide interferon antiviral treatment of chronic hepatitis B, provide new immune targets for exploring antiviral treatment of chronic hepatitis B, improve cure rate, and reduce relapse rate.
Description
Technical Field
The invention relates to the technical field of biomedicine, in particular to application of T cells as biomarkers in monitoring or predicting curative effect of anti-HBV treatment or predicting recurrence risk.
Background
Chronic Hepatitis B (CHB) is a type of infectious disease caused by the Hepatitis B Virus (HBV) and severely jeopardizes public life safety. The treatment of chronic hepatitis B aims at reducing the occurrence of liver cirrhosis, liver failure and HCC, improving the life quality of patients and prolonging survival time. The "actual functional cure" is the goal currently pursued by medical workers, and is distinguished from the "inactive HBV carrier after drug withdrawal", which means HBsAg negative, anti-HBs negative or positive, HBeAg negative, serum HBVDNA below the lower detection limit, the risk of HCC also decreasing with time, and the distinction is that the intrahepatic cccDNA is still in a detectable state but inactive, which is distinguished from the "complete cure". As the first-line medicine polyethylene glycol interferon (PEGYLATED INTERFERON, peg-IFN) for achieving clinical cure, the anti-virus and immunoregulation dual action mechanism is provided, the HBsAg loss rate of patients with chronic hepatitis B can be obviously improved, on the aspect of the anti-virus action, the formation of core particles can be blocked, cccDNA epigenetic is regulated, ISGs mediated anti-virus defense in infected cells and non-infected cells is regulated, thereby reducing HBVDNA and HBV antigen (HBsAg, HBcAg, HBeAg) expression, on the aspect of immunoregulation, NK cell TRAIL expression can be increased, CD56brihgtNK cells are activated, CD8+ T cell response is slightly increased, and CD4+ T cell response is regulated, so that the direct anti-virus IFN-gamma production is enhanced, T cell response is promoted, and finally the clinical cure effect is achieved. The WuD et al study considers that the combined immune modulation of multi-target intervention based on continuous virus control, and the remodelling of the antiviral immune efficacy of the organism is the future of patients with chronic hepatitis B. In recent years, reports on immunoregulation research are increasingly paid attention by scholars. XiaY et al believe that IFN-gamma and TNF-alpha produced by T cells can reduce HBVcccDNA by inducing deamination and subsequent cccDNA decay, wang et al believe that Foxp3 (a surface marker for Treg) and the interaction mechanism of IL-17/IL-23 can be new breakthrough points for HBV clearance, and that Foxp3 is positively correlated with HBVDNA and HBsAg.
In CHB, however, there is a significant correlation between activation of CXCL13 and IL-21 axes and the occurrence of functional cure. Shen Z et al demonstrated by animal models that IL-21 and IL-33 are closely related to HBV clearance. C-X-C chemokine receptor5 (C-X-C chemokinereceptor, CXCR 5) and its cognate receptor CXCL13 are members of the CXC subtype of the chemokine superfamily, which chemotactic mature B cells and T follicular helper cells migrate to B cell follicles and the center of development, secreting memory B cells and plasma cells. The subset cxcr5+cd8+ T cell follicular cytotoxic T cells of cd8+ T cells plays an important role in controlling chronic viral infections. Any Red Sect of Lamaism study on the teaching subject group shows that the gamma delta T cell proportion is positively correlated with HBV replication, is negatively correlated with liver inflammation degree, and has better therapeutic effect of treating CHB by combining Peg-IFN alpha-2 a with TDF as the proportion of the effector memory subgroup is lower.
In summary, a plurality of researches prove the importance of enhancing the immune function of a host in Peg-IFN combined TDF anti-HBV treatment to one of key factors for improving the clinical cure rate of chronic hepatitis B. However, after achieving a clinically functional cure, some about 9.6% of patients have developed a relapse, i.e., positive for hepatitis B surface antigen or positive for HBV-DNA. Therefore, the method for researching the difference between relapse and non-relapse has important significance for guiding the chronic hepatitis B interferon antiviral treatment, providing a new immune target for exploring the chronic hepatitis B antiviral treatment, improving the cure rate and reducing the relapse rate.
Disclosure of Invention
It is an object of the present invention to provide the use of T cells, including Treg cells, cd4+ T cells, cd8+ T cells, as biomarkers in the manufacture of a product for monitoring or predicting the efficacy of anti-HBV treatment.
In the above technical scheme, the change of CD4+ T cell content, treg cell content and CD4/CD8 ratio is used for predicting or monitoring the curative effect of anti-HBV treatment, compared with a reference, the CD4+ T cell content of a subject is obviously reduced, the CD4/CD8 ratio shows obviously reduced trend, the Treg cell content is obviously reduced, the curative effect is demonstrated, and the other way around, preferably, the reference is the cell content of a normal human group and/or a subject before the use.
It is another object of the present invention to provide the use of T cells, including cd8+ subset cxcr5+ cd8+ T cells and cd4+ subset cxcr5+ cd4+ T cells, as biomarkers in the manufacture of a product for predicting the risk of recurrence after achieving a clinically functional cure in anti-HBV therapy.
In the above-described protocol, a significant decrease in cxcr5+cd8+ T cells and cxcr5+cd4+ T cells in the subject as compared to a reference in the non-relapsed group is indicative of a high risk of HBsAg re-yang, whereas a high level of cxcr5+cd8+ T cells and cxcr5+cd4+ T cells in T cells is indicative of no or low risk of re-yang.
It is a further object of the present invention to provide the use of a substance for detecting the amount of Treg cells, cd4+ T cells, cd8+ T cells in the preparation of a product for monitoring or predicting the efficacy of anti-HBV treatment.
In the technical scheme, the change of the CD4+ T cell content, the Treg cell content and the CD4/CD8 ratio is used for predicting or monitoring the curative effect of anti-HBV treatment, compared with a reference, the CD4+ T cell content of a subject is obviously reduced, the CD4/CD8 ratio shows a obviously reduced trend, the Treg cell content is obviously reduced, and the curative effect of the medicament is indicated.
It is a further object of the present invention to provide the use of a substance for detecting the amount of cxcr5+cd8+ T cells and cxcr5+cd4+ T cells of the cd8+ subset for the preparation of a product for predicting the risk of recurrence after a clinically functional cure in anti-HBV therapy.
In the above-described protocol, a significant decrease in cxcr5+cd8+ T cells and cxcr5+cd4+ T cells in the subject as compared to a reference in the non-relapsed group is indicative of a high risk of HBsAg re-yang, whereas a high level of cxcr5+cd8+ T cells and cxcr5+cd4+ T cells in T cells is indicative of no or low risk of re-yang.
In the application technical scheme, the T cells refer to T cells in peripheral blood, and the anti-HBV treatment refers to Peg-IFN treatment, preferably Peg-IFN and tenofovir combined treatment.
The substance is selected from antibodies and chips.
The beneficial effects of the invention are as follows:
After the Peg-IFN alpha combined TDF is analyzed to treat chronic hepatitis B to achieve clinical functional cure, the influence of various immune cell functions on clinical recurrence and the difference between recurrence and non-recurrence are analyzed, and the expression condition of various immune cells in whole blood specimens after the interferon treatment achieves functional cure is observed. Through the research results, the chronic hepatitis B interferon antiviral treatment is guided, a new immune target is provided for exploring the chronic hepatitis B antiviral treatment, the cure rate is improved, and the recurrence rate is reduced.
According to the invention, through research results and clinical data analysis, the distribution and dynamic change of peripheral blood T lymphocytes after HBV is clinically cured are obvious, wherein the total ratio of CD4+ T cells to Treg cells is in a decreasing trend, the total ratio of CD8+ T cells is not obviously changed, the change of the ratio of CD4+ T cells to Treg cells to CD4/CD8 can be used for monitoring and predicting the curative effect of Peg-IFN alpha-2 b combined with tenofovir in HBV treatment, CXCR5 plays an important role in the process of clinical Cure and relapse after HBV is clinically cured by Peg-IFN combined with tenofovir, the total ratio of Tfh to Tfc is higher than that of Re group, and the total ratio of Tfh to Tfc is lower than that of CL group and HC group, so that when surface antigen clearance is achieved, tfh and Tfc are maintained at a higher concentration, and the rapid decrease of the ratio of Tfh to Tfc is likely to indicate the positive restoration of HBg, the ratio is maintained at a higher level, and the clinical Cure is beneficial to the clinical Cure.
Drawings
Figure 1 is a graph of flow analysis of CD3, CD4, CD8 and Treg cells in PBMCs.
FIG. 2 is a distribution of CD4+ T cells in each group.
FIG. 3 is a distribution of CD8+ T cells in each group.
FIG. 4 is a distribution of CD4+ T cell to CD8+ T cell ratios in each group.
Figure 5 is the distribution of Treg cells in each group.
FIG. 6 is a flow chart of Tfh cells and Tfc cells in PMBC.
Figure 7 is the distribution of cxcr5+cd4+ T cells in each group.
Figure 8 is the distribution of cxcr5+cd8+ T cells in each group.
Detailed Description
The invention is further illustrated, but is not limited, by the following examples.
The experimental methods in the following examples are all conventional methods unless otherwise specified, and the reagents used are all conventional reagents in the art unless otherwise specified and are all commercially available.
Example 1
1 Materials and methods
1.1 Study object
35 CHB patients from 2019.10 to 2021.10 with a visit at the university of Chongqing medical science were included as subjects.
The standard was included for ① adult (age >18 years) chronic hepatitis B patients, but less than 60 years of age, ② agrees to treatment with Peg-IFN alpha-2 b in combination with Tenofovir (TDF) and to adhere to follow-up visits at the clinic, ③ has knowledge of the risk of the study and treatment, and signed informed consent.
The exclusion criteria were ① combined with other viral infections such as hepatitis A, hepatitis C, hepatitis E and HIV infection, ② IFN treatment contraindications such as severe infections, schizophrenia, severe end-stage liver disease, pregnant women, etc., ③ combined with severe chronic diseases such as coronary heart disease, alcoholic liver disease, end-stage renal disease and severe lupus erythematosus, etc., ④ using Peg-IFN alpha-2 b in combination with TDF showed some severe adverse reactions.
Drug withdrawal criteria were normal liver function, HBsAg <0.04IU/mL (undetectable), HBV DNA <100IU/mL.
The personal information and clinical information of the patients in the group are recorded, wherein the personal information and clinical information comprise age, sex, treatment period and the like, and follow-up conditions of the patients in the treatment period are adhered to, and the follow-up conditions comprise indexes such as blood convention, liver function, hepatitis B two halves, HBV DNA content, AFP and the like. The study has been approved by the first hospital ethics committee affiliated with the university of Chongqing medical science (2020-409).
1.2 Experimental reagents and instruments
1.2.1 Main Experimental reagent
1.2.2 Major laboratory instruments and apparatus
1.3 Experimental methods
1.3.1 Sample collection
The peripheral blood of healthy volunteers and patients who included the study was collected at an outpatient site at 10ml, and blood collection was performed with a vacuum blood collection tube. And specimen processing was performed within two hours.
1.3.2PBMC extraction
(1) Centrifugal blood sample of 1200r/min 10min
(2) Draw 1ml serum to 1.5mlEP tube
(3) The remaining plasma was added to a 15ml centrifuge tube containing 4ml PBS and mixed well
(4) Slowly add 4ml of shower (45℃inclined slowly add)
(5) Slowly lifting and lowering the mixture in a centrifuge 400G for 40min
(6) The serum is put into a centrifuge 12000r for 10min for centrifugation and then is sucked into a new EP tube
(7) Suction of PBMC suspended in a centrifuge tube with a capillary
(8) Centrifuging in centrifuge 300G for 8min
(9) Sucking out the upper layer liquid
(10) Cell count
(11) Centrifuge 300G 5min
(12) Sucking out the upper layer liquid
(13) RPMI 1640 (800 ul or 1.2 ml) was added to the centrifuge tube
(14) Slowly dripping equivalent cell freezing solution
(15) After mixing, separating into 1.5ml frozen storage tube (2 tubes or three tubes)
(16) After gradient freezing, the freezing tube is put into liquid nitrogen for preservation
1.3.3 Cell resuscitation
(1) Preparation of RPMI1640+10% FBS about 5ml as a culture medium
(2) Taking out the PBMC from the liquid nitrogen tank, putting the PBMC into a 37 ℃ water bath kettle, and transferring the PBMC into a culture medium when ice cubes are dissolved almost;
(3) Centrifuging at 300g for 5min at room temperature, and discarding the supernatant;
(4) Counting by PBS, sucking 20ul PBMC, placing into a cell counter, and ensuring the number not lower than 2×10 6 under a mirror;
(5) Centrifuge 300g,5min, room temperature, discard supernatant, divide them into three 50. Mu.l 3 tubes, tube1 blank, tube2 sample, tube3 isotype control.
1.3.4 Flow cytometry analysis of Peripheral Blood Mononuclear Cells (PBMC)
(1) Fc blocking, namely adding 2.5 mu l of blocking agent into 50 mu l of cell system, and avoiding light for 8min without washing;
(2) Antibodies were added to each tube:
Tube 1 (blank) no
Tube 2 (sample Tube):
PE MouseAnti-Human CD3:0.5μl
FITC MouseAnti-Human CD8:2μl
PerCP-Cy5.5 MouseAnti-Human CD4:1μl
BV650 MouseAnti-Human CD25:1μl
BV421 Rat Anti-Human CXCR5(CD185):0.5μl
Alexa 647Mouse Anti-Human CD127:2μl
Tube 3 (isotype control):
PE Mouse Anti-Human CD3:0.5μl
FITC Mouse Anti-Human CD8:2μl
PerCP-Cy5.5 Mouse Anti-Human CD4:1μl
BV650 Mouse IgG1,κIsotype Control:0.5μl
Alexa 647Mouse IgG1,κIsotype Control:0.5μl
BV421 Mouse IgG2b,κIsotype Control:0.5ul
(3) After adding 1ml PBS and standing in dark for 20min.
(4) Centrifuging at 300g for 5min at room temperature, and discarding the supernatant;
(5) 300g of 400ul PBS at room temperature was added again and resuspended by 5min centrifugation;
(6) Moving the flow tube through the filter membrane;
(7) Preparation Shan Yangguan BD TM CompBeads Anti-Mouse Ig, kappa and BD TM CompBeads
Positive Control 1:1 was mixed into 6 tubes, 50ul each, and added separately to each tube PE MouseAnti-Human CD3、FITC MouseAnti-Human CD8、PerCP-Cy5.5 MouseAnti-Human CD4、BV650 Mouse IgG1,κIsotype Control、Alexa 647Mouse IgG1, kappa Isotype Control, BV421 Mouse IgG2b, kappa Isotype Control.
(6) Repeating the operations of (3) and (6);
(7) And (5) debugging an instrument and detecting on-line.
(8) Data analysis was performed by FlowJo.
1.4 Statistical analysis
Mapping and analysis were performed using GraphPadPrism 8.0. In the measurement data, t test is adopted for meeting normalization and variance uniformity, welch's correction t test is adopted for variance uniformity, and Mann-Whitney rank sum test is not adopted for normalization. The count data was accurately examined using Fisher's. When P <0.05, the differences between groups are statistically significant.
2 Results
2.1 Achieving obvious distribution and dynamic change of peripheral blood T lymphocytes after clinical cure through Peg-IFN combined with TDF anti-HBV
Some groups of PBMC were performed, namely a healthy control group (Healthy control, HC, n=10), an HBsAg clearance group (CLEARANCE GROUP, CL, n=10), a Cure group (Cure, n=10), a relapse group (Recrudescence, RE, n=15), wherein the healthy control group is a specimen of healthy people who are negative for HBsAg and positive for HBsAb, the HBsAg clearance group is a specimen of a patient who achieves the negative for HBsAg after the first detection after the Peg-IFN combined TDF treatment, the Cure group is a specimen of a patient who is negative for HBsAg after the Peg-IFN combined TDF treatment and maintains for half a year or more, and the relapse group is a specimen of a patient who is returned to negative after the follow-up visit after the HBsAg is converted to negative after the Peg-IFN combined TDF treatment. Flow analyses were performed on CD3, CD4, CD8 and Treg cells in their PMBC (fig. 1).
2.1.1CD4+T cell distribution
The difference in the percentage of cd4+ T cells to T cells (abbreviated as cd4+ T total ratio) was statistically significant in both Re and HC groups, re and CL groups, HC group higher than Re group (p=0.0029), CL group higher than Re group (P < 0.001), and the difference between Re and Cure groups was not statistically significant (P > 0.05), see fig. 2.
2.1.2CD8+ T cell distribution
The difference in the T cell percentage of cd8+ T cells (abbreviated as cd8+ T total) in the flow analysis was not statistically significant (P > 0.05) in the Re group and HC group, re group and Cure group, and Re group and CL group, as shown in fig. 3.
2.1.3CD4+ to CD8+ T cell ratio
The difference in the ratio of cd4+ T cells to cd8+ T cells (abbreviated as CD4/CD8 ratio) was statistically significant in the Re group and CL group, which was higher than the Re group (p=0.010), and the difference between the Re group and HC group, re group and Cure group was not statistically significant (P > 0.05), see fig. 4.
2.1.4Treg cell distribution
The ratio of Treg cells in T cells (abbreviated Treg ratio) is statistically significant for differences in Re versus CL, re and HC groups, CL being higher than Re (p=0.003), HC being higher than Re (p=0.03), the differences between Re and Cure groups not being statistically significant (P > 0.05), see fig. 5.
In conclusion, it can be found that the distribution of CD4+ and Treg cells of peripheral blood PBMC is obviously different after hepatitis B surface antigen clearance, clinical cure and relapse are achieved in patients treated with CHB by Peg-IFN alpha-2 b combined with TDF. It is also shown that the dynamic changes of these immune cells are related to Peg-IFN alpha-2 b, wherein the changes of CD4+ T cells are most obvious, the CD4+ T cells all show a decreasing trend from the hepatitis B surface antigen clearing period to clinical Cure or recurrence, the change trend of CD8+ T cells is not obvious compared with the CD4/CD8 ratio, and the CD4/CD8 ratio shows a decreasing trend from the CL phase to the Re phase and the CD4/CD8 ratio from the CL phase to the Cure phase is not obvious. Changes in CD4+ T cells, treg cells and CD4/CD8 ratio can be used to predict or monitor the therapeutic effect of Peg-IFN alpha-2 b in combination with TDF.
2.2CXCR5 plays an important role in achieving whether relapse occurs or not after clinical cure through Peg-IFN alpha-2 b combined with TDF anti-HBV treatment
Similarly, we performed a flow assay on two subpopulations of CXCR5 follicular helper T cells (cxcr5+cd4+ T cells) and follicular cytotoxic T cells (cxcr5+cd8+ T cells) (fig. 6) to investigate their differences between HBsAg-Cleared (CL), cure (Cure), relapse (Re) and Healthy Control (HC).
2.2.1CXCR5+CD4+T cell distribution
The ratio of cxcr5+cd4+t in T cells (abbreviated TFH ratio) is statistically significant for differences in Re and CL groups, re and HC groups, re and Cure groups, CL being higher than Re (P < 0.001), HC being higher than Re (p=0.0097), cure being higher than Re (p=0.031), see fig. 7.
2.2.2CXCR5+CD8+T cell distribution
The ratio of cxcr5+cd8+t in T cells (abbreviated TFC ratio) is statistically significant for differences in Re and CL groups, re and HC groups, re and Cure groups, CL being higher than Re group (p=0.0006), HC being higher than Re group (p=0.0021), cure being higher than Re group (p=0.023), see fig. 8.
Through the results of flow experiments, the patient treated with the Peg-IFN alpha-2 b combined with TDF for CHB has obvious differences in the distribution of TFH cells and TFC cells after hepatitis B surface antigen clearance, clinical cure and recurrence. In the period from the time of hepatitis B surface antigen elimination to clinical cure or recurrence, TFH cells and TFC cells all show a descending trend, in the early stage of hepatitis B surface antigen elimination, TFH cells and TFC cells in peripheral blood of a patient are in a state of high expression higher than that of a healthy group, in the progress of treatment, after the patient reaches functional cure, the Tfh cells and TFc cells all show a descending trend lower than that of the healthy group, and in the recurrence group, the Tfh cells and the TFc cells of the patient show an expression trend lower than that of the cure group, so that the depletion of the Tfh cells and the TFc cells has a close relation with the therapeutic effect of the Peg-IFN alpha-2 b combined TDF, and the anti-HBV therapeutic effect of the Peg-IFN alpha-2 b combined TDF can be predicted by detecting the subcellular group or a new immune target is searched for to reduce the recurrence rate, and the cure rate is improved.
3 Analysis and conclusion
Our studies found that the total percentage of CD4+ T cells in both the Cure and Re groups was lower than in the HC and CL groups, whereas our previous studies found that the total percentage of CD4+ T cells in the CHB patients was higher than in the HC group, and that the total percentage of CD8+ T cells was lower than in the HC group, and that the degree of T cell dysfunction and depletion in the Cure and Re groups was restored compared to the CHB patients, and that CD8+ T cells were characterized by the large number of expanded and differentiated into cytotoxic effector cells to clear off or resist invasion by foreign factors. Depletion of cd8+ T cells is associated with progressive impairment of their function, especially in terms of expansion capacity, secretion of cytokines, antigen elimination, etc. The clinical data collected by the inventor show that compared with the CHB patients, HBV-DNA of the Cure group and the Re group are lower than the detection limit, although HBV-DNA of the Re group is increased along with the time, the Re group is obviously lower than the HC group and the CL group in the aspect of the distribution of Treg cells, the Treg cells are a subgroup of CD4+ T cells, have the effect of immunonegative regulation, can inhibit the auxiliary effect of the CD4+ T cells on the CD8+ T cells, and can non-specifically inhibit the activation and proliferation of the CD4+ T cells and the CD8+ T cells through secretion of inhibitory cytokines. Treg cells are more active in Re than in Cure, and can be reflected by a negative feedback mechanism that Re is less cleared of HBsAg than Cure. Therefore, treg cells and CD8+ T cells are good monitoring indexes for realizing the curative effect of whether functional cure recurs or not, and the detection of other indexes such as HBV DNA, AST, ALT and the like should be analyzed together at the same time, so that the curative effect can be predicted better only by controlling the dynamic change of each index.
Two subpopulations of follicular helper T cells (Follicular HELPER T CELLS, tfh, cxcr5+cd4+ T cells), follicular cytotoxic T cells (Follicular cytotoxic T cell, tfc, cxcr5+cd8+ T cells) have received increasing attention and attention from expert scholars in the treatment of CHB in recent years. The molecule CXCR5 and its ligand CXCL13 are also included in extensive research on their marker surface.
The harmonization of Tfh cell subsets in humoral immunity for adaptive immune response, as well as the ancillary effects of the generation of various antibodies, are the directions of our major research. Mature Tfh cells are located in follicles of secondary lymphoid organs (Secondary lymphoid organs, SLO) and differentiate towards memory B cells and plasma cells and produce corresponding mature antibodies by assisting in activating B cells located therein in germinal centers (GERMINAL CENTER, GC). Furthermore, tfh cells play a very important role in the prevention and treatment of cancer, in the prevention of microbial pathogen infection, and in the prevention of autoimmune hyperpathia, as a reservoir for HIV. Of course, the Tfh cell subpopulation is no exception in anti-HBV. In the present study it was found that the Tfh total duty cycle was lower in both the Re and Cure groups than in the CL and HC groups, and the Re group was also lower than in the Cure group. This demonstrates that the Tfh overall ratio is directly related to HBsAg clearance and has great immunological value for predicting the efficacy of Peg-IFN- α combined TDF treatment.
Cxcr5+cd8+ T cells, a specific class of cd8+ subpopulations, were cell subpopulations that were discovered and studied only in recent years. Detailed characterization studies of this subset of cells at the transcriptome level were performed by Im Se Jin et al, which found this subset to be a class of adaptive responses that deplete PD-1+cd8+t cells. Has similar stem cell characteristics during chronic infection of chronic hepatitis B, namely, can differentiate into end-stage CXCR5+ CD8+ T cells to exert antiviral efficacy while self-renewing. The transcription factor TCF1 is critical for the production of this subpopulation, whereas the blockade of PD-1 can cause a sharp amplification and differentiation of this subpopulation towards the terminal stage. Cxcr5+cd8+ T cells play a key role in controlling viral replication, these cxcr5+cd8+ T cells, which are affected by CXCL13 chemotaxis, migrate into B cell follicles with fewer inhibitory receptors and exhibit greater cytotoxicity than a subset of CXCR5-, and also exhibit greater therapeutic potential in HIV. The research shows that TFC total ratio is lower than that of CL group and HC group in Re and Cure group, and Re group is lower than that of Cure group, so that TFC cells can show better antiviral effect in the initial stage of CL, in Re group, HBsAg Re-cation is caused by depletion of CD8+T cells, while Tfc total ratio in Cure group is higher than Re group, so that Tfc plays a critical role in controlling replication of HBV virus, and CXC5+CD8+T cells can be used as a breakthrough point for improving Cure rate and reducing recurrence rate of anti-HBV treatment.
In conclusion, according to experimental results and clinical data analysis, the invention can be used for obviously distributing and dynamically changing peripheral blood T lymphocytes after the anti-HBV is clinically cured by Peg-IFN combined with TDF, wherein the total ratio of CD4+ T cells to Treg cells is in a decreasing trend, the total ratio of CD8+ T cells is not obviously changed, and the change of the ratio of CD4+ T cells, treg cells and CD4/CD8 can be used for monitoring and predicting the curative effect of Peg-IFN alpha-2 b combined with tenofovir in anti-HBV treatment.
CXCR5 plays an important role in the clinical cure achieved by anti-HBV treatment and in the recurrent process through Peg-IFN alpha-2 b combined with tenofovir. The total ratio of Tfh and Tfc is higher in the Cure group than in the Re group, and similarly, the Re group is lower than in the CL group and the HC group, so that when surface antigen clearance is achieved, tfh and Tfc are maintained at a higher concentration, and their rapid decline is likely to be indicative of the Re-positive of HBsAg, and the maintenance of a high ratio is more beneficial to HBsAg clearance and clinical functional Cure. CXCR5/CXCR13 is expected to become a new immune target for achieving functional cure.
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