| 1 BackgroundHighly active antiretroviral therapy(HAART)is recognized as the most effective treatment,which has greatly reduced the incidence and mortality of AIDS.However,even though HAART treatment ensures good compliance,plasma viral load is controlled at undetectable levels for a long time,and CD4+T lymphocyte counts in about 30%of patients are still below normal.AIDS patients with this immune-non-responsive status have higher rates of mortality,morbidity,and opportunistic infection than those with good immunological response.Studies have found long-term complication rates and mortality rates in immunoreactive non-responders.It is 10 times higher than the immune response.Therefore,the research on the mechanism of immune non-response and the intervention have become the research hotspots in the post-HAART era.From the current situation of TCM intervention in immune non-response studies,most of the studies only stayed in the study of CD4+T cell count changes,pure and memory T lymphocyte changes before and after TCM intervention.Significant influence mechanisms:There are few studies on indicators of abnormal activation of the innate immune system and the acquired immune system."Immune abnormal activation" has been considered as one of the important mechanisms of immune non-response in recent years.At present,some studies have been carried out abroad to apply immunosuppressive agents to treat immune function reconstruction in patients with immune non-response.Traditional Chinese medicine treatment emphasizes the overall adjustment of the body and adjusts the state of yin and yang deficiency.Moderate adjustment of the state of inhibition and activation of the body's immune system is an important manifestation of the regulation of yin and yang in the body's immune regulation.Therefore,whether Chinese medicine can interfere with the abnormal activation of immune non-responders through multi-target action,two-way regulation,promote immune reconstitution,and improve the efficacy of HAART is worthy of research and exploration.To study the mechanism of abnormal immune activation,it is of great significance to clarify the mechanism of TCM intervention in immune non-response state,and opportunities and challenges coexist.Some foreign studies have applied the detection of T lymphocyte activation subgroups as indicators for evaluating the efficacy of HAART treatments and the recovery of immune function in patients.CD4+T lymphocytes are still used as gold indicators in China,and T cell activation subgroups are reported less.In clinical work,we often find that some patients have a serious opportunistic infection with a CD4+T cell count of more than 350/mm3,while some patients have a CD4+T cell count of less than 350/mm3.However,the status is good,even among individuals with no significant differences in laboratory indicators,the speed of disease progression and clinical manifestations vary.These conditions indicate that there is a deficiency in the efficacy of the therapeutic drug and the recovery of immune function of the body using only the CD4+T cell count as the sole gold indicator.The combination of plasma viral load determination may solve the above problems,but the method also has technical(high experimental conditions required,long detection time)detection and economic(expensive,thousands of dollars or more)difficulties.Therefore,in addition to the indicators of CD4+T count,it is necessary to carry out evaluation studies on the mechanism of action and intervention effect of TCM from abnormal immune activation subpopulations and regulatory T cellsThis research paper relies on the National Natural Science Foundation of China to explore the mechanism of improving the immune function of AIDS in the middle and late stages of AIDS by energy metabolism.Kunming Hospital of Traditional Chinese Medicine and Shenyang Sixth People's Hospital participated in clinical implementation.The ethics committee of the Sixth People's Hospital of Shenyang passed the ethical review,and the approval number is 2016-05-001-02.The effect of Wenshen Jianpi Granule on immune activation of T cells and NK cells in patients with immune response after HAART,Kunming Hospital of Traditional Chinese Medicine and Shenyang the Sixth People's Hospital participated in the clinical implementation.I completed the design,daily management,patient follow-up,clinical monitoring and other work in the research project,and wrote a technical summary report.The clinical data of 60 subjects randomized to double blind enrollment were analyzed and preliminary conclusions were drawn.2 ObjectiveIn this study,Wenshu Jianpi Recipe combined with HAART therapy was performed in a randomized,double-blind,placebo-controlled study of 60 patients with non-responders.The CD4+T lymphocyte counts,pure and memory T cell counts in peripheral blood were compared before and after intervention to check if it can improve the immune response status of patients.At the same time,the intervention mechanism was studied in depth,mainly to observe whether it can inhibit the T cell immune activation level in the experimental group,whether it can promote the immune reconstitution by inhibiting the activation of NK cells,and whether the immune regulation can be achieved by affecting the proportion of regulatory T cells.3 MethodRandomized,double-blind,placebo-controlled clinical study design,statisticians used statistical software to generate random number tables,and the randomized process was implemented by the Clinical Evaluation Center of China Academy of Chinese Medical Sciences.Subjects who met the inclusion criteria obtained random numbers through a central randomized system(That is the drug number)was randomly divided into a treatment group and a placebo control group according to a 1:1 ratio.4 Results4.1 General InformationA total of 56 patients were enrolled,including 28 in the treatment group and 28 in the control group.The study group was divided into 55 subjects who underwent at least one efficacy evaluation and entered the SS group,56 subjects entered the FAS group,28 in the two groups,52 subjects Entering the PPS group,24 patients in the treatment group,28 patients in the control group,and 4 patients in the control group.73.21%of the subjects were sexually transmitted,of which 46.42%were heterosexual,26.79%were male and male,5.36%were intravenous drug users,and no blood was found in the blood supply.Other unexplained infections accounted for 21.43%.The subjects in this study were mainly menstrual transmission;the mean baseline of CD4+cell count in the treatment group was 207.41±66.4,and the mean value of the control group was 228.28±60.05.In the interval of 200-350/mm3,all were incompletely immune.No combined HBV or HCV infection was found4.2 Changes of CD4+T lymphocyte count,pure and memory T cell count in peripheral blood of two groups of patientsThe treatment group was more effective than the placebo control group in increasing the peripheral blood CD4+T cell count.This increase was more and more significant with the treatment time,and it appeared statistically significant at the 24th week of treatment.At the same time,the CD8+T cell count in the treatment group also increased significantly compared with the control group,with statistical differences.The increase in CD4+T lymphocyte counts is mainly due to the growth of pure CD4+T lymphocytes.4.3 Changes of T lymphocyte activation subpopulation HLADR+CD38+/HLADR+CD38-/HLADR-CD38+in CD4+T cells and CD8+T cells in two groups1)The proportion of HLADR+CD38+T cell activation subpopulations in CD4+T cells:The ratio of the treatment group decreased significantly at the 12th week,and the control group was basically flat,the difference was statistically significant(P<0.05).At the 24th week,the control group decreased significantly from the baseline level,and the treatment group rebounded to the baseline level.The two groups were statistically significant(P=0.01).2)The proportion of HLADR+CD38-T cell activation subpopulations in CD4+T cells:The ratio of the treatment group decreased significantly at the 12th week,and the ratio of the control group increased significantly.The difference between the two groups was statistically significant(P=0.034).At 24 weeks,the ratio of the control group decreased,while the treatment group increased significantly,and the two groups were statistically significant(P=0.036).3)The proportion of HLADR+CD38+T cell activation subpopulations in CD8+T cells:The ratio of the treatment group decreased significantly at the 12th week,and the ratio of the control group increased significantly.The difference between the two groups was statistically significant(P=0.002).At 24 weeks,the ratio of the control group decreased,while the treatment group increased significantly.There was no statistically significant difference between the two groups(P>0.05).4)The proportion of HLADR+CD38-T cell activation subpopulations in CD8+T cells:The ratio of the two groups increased at the 12th week,and the increase of the control group was significantly greater than that of the treatment group.The difference between the two groups was statistically significant(P=0.010).At 24 weeks,the ratio of the control group decreased significantly,and the treatment group continued to rise.There was a statistically significant difference between the two groups(P=0.001).5)The proportion of HLADR-CD38+T cell activation subpopulations in CD4+T and CD8+T cells:No significant difference was found between the two groups at the 12th week and the 24th week(P>0.05).4.4 Correlation between the proportion of each T lymphocyte activation subpopulation and CD4+T cell countHLADR+CD38+/CD4+ratio and HLADR-CD38+/CD4+ratio were positively correlated with CD4+T cell count(P<0.05),while other T cell activation subpopulations were nonlinearly correlated with CD4+T cell count(P>0.05).4.5 Changes of NK cell activation subpopulations CD56bri,CD56neg,CD56dim in two groups of patients1)There was a statistically significant difference between the two groups in the 12 weeks between CD56bri and baseline(P<0.01).The CD56bri of the treatment group was decreased by-0.92±3.17 compared with the baseline,and the CD56bri of the control group was increased by 3.26±5.72 compared with the baseline.The CD56bri in the treatment group was 1.5±3.26 higher than the baseline,and the CD56bri in the control group was 3.35±4.2 higher than the baseline.There was no statistically significant difference between the two groups(P>0.05).2)There was significant difference in the difference between CD56neg and baseline in the 12th week(P<0.01).The CD56neg in the treatment group was decreased by 24.92±97.96 compared with the baseline,and the CD56neg in the control group was increased by 93.52±69.08 from the baseline.The group was 24.92±53.03 higher than the baseline,and the control group was 90.00±110.00 higher than the baseline.The difference between the two groups was significantly statistically significant(P<0.05).3)The CD56dim of the two groups increased at baseline in the 12th week,but the difference was not statistically significant(P>0.05).In the 24th week,the treatment group increased by 0.75±73.20 compared with the baseline,and the control group increased by 89.04.±128.98,the difference between the two groups and the baseline was statistically significant(P<0.01)4.6 Correlation between NK cell activation subpopulation and CD4+T cell countThere was a significant positive correlation between CD56bri and CD4+T cell counts(P<0.01),while CD56neg and CD56dim NK cell subsets were nonlinearly correlated with CD4+T cell counts(P>0.05).4.7 Changes in regulatory T cells(Treg)CD4CD25+T lymphocytes in both groupsAt week 12,the absolute values of CD4CD25+T lymphocytes in the two groups were lower than those in the baseline,but the difference was not statistically significant(P>0.05).In the 24th week,the treatment group was 26.81 ±43.13 higher than the baseline.The decrease was 106.64± 137,52,and the difference between the two groups was significantly statistically significant(P<0.01).Correlation analysis showed that there was a significant linear correlation between CD4CD25+T lymphocytes and CD4+T cell counts(P<0.05).5 Conclusion5.1 Wenshen Jianpi Decoction combined with HAART therapy can effectively increase the peripheral blood CD4+T cell count in patients compared with placebo control group.This increase is more and more obvious with the treatment time,and appears at the 24th week of treatment.Statistically significant.The increase in CD4+T lymphocyte counts is mainly due to the growth of pure CD4+T lymphocytes,which promotes the generation of CD4+T lymphocyte counts rather than reducing their destruction5.2 The two-way regulation of the immune activation level associated with Wenshen Jianpi Recipe was mainly related to HLADR+CD38+and HLADR+CD38-CD4+T and CD8+T cells,and no statistically significant difference was found with HLADR-CD38+.The overall immune activation level did not show significant inhibition or down-regulation;the increase in HLADR+CD38-T cell activation subpopulation was more pronounced than in other subpopulations.It is further explained that the mechanism of action of Wenshen Jianpi Recipe is to promote the generation of CD4+T lymphocyte count,rather than reduce its destruction.The increase of CD4+T cell count is not through the simple inhibition of T lymphocyte immune activation.5.3 Wenshen Jianpi Recipe can better down-regulate the levels of CD56bri and CD56neg,although there is a rebound in the 24th week,the level of continuous up-regulation is significantly different from the placebo group;the inhibition of CD56dim is inhibited.The effect was in stark contrast to the level of sustained up-regulation in the placebo group,with a difference of up to 88.29.It is indicated that the increase of CD4+T cell count by Wenshen Jianpi Recipe may be through down-regulating or inhibiting the up-regulation of NK cell activation subpopulation.5.4 There was a significant linear correlation between regulatory T cell Treg CD4CD25+T lymphocytes and CD4+T cell counts(P<0.05).The basic support for Treg is a protective factor for immune function reconstruction that controls the disease process to down-regulate immune activation.It can be concluded that the mechanism of Wenshen Jianpi Recipe to help immune reconstitution is related to the up-regulation of the proportion of Treg subpopulations.It is speculated that the role of the Chinese herbal compound in this study is achieved by affecting the Treg pathway,and the literature shows that Tripterygium wilfordii inhibits immune activation.This route.This may become a breakthrough in the study of the mechanism of warming the kidney and strengthening the spleen and strengthening the body of the traditional Chinese medicine,which is different from the immune inhibitor of Tripterygium wilfordii.Due to the small number of cases and short observation time,the long-term effect is still doubtful,and further research is needed for deeper research. |
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