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Effect of alpha 2b interferon on inducement of mIL-2R and treatment of HCV in PBMC from patients with chronic viral hepatitis C
Jian Wang, Gui-Ju Xiang, Bing-Xiang Liu
Jian Wang,
Department of Aetiology and Immunology, Anhui University of Science and
Technology, Huainan 232001, Anhui Province, China
Gui-Ju Xiang,
Department of Infectious Diseases, the Second Miner Hospital of Huainan, Huainan
232001, Anhui Province, China
Bing-Xiang Liu,
Department of Infectious Diseases, Shibei Hospital of Shanghai, Shanghai 200435,
China
Supported by the
grants from Science Foundation of the Ministry of Coal Industry of China, No.
96-072
Correspondence to: Jian
Wang, Department of Aetiology and Immunology, Anhui University of Science and
Technology, Huainan 232001, Anhui Province, China. wangjian8237@sina.com
Telephone:
+86-0554-6659942
Received:
2002-07-31 Accepted: 2002-08-23
Abstract
AIM: To study the level of membrane
interleukin-2 receptor (mIL-2R) on surface of peripheral blood mononuclear cells
(PBMC) and the therapeutic efficacy of alpha 2b interferon on the treatment of
HCV-RNA in PBMC of patients with chronic hepatitis C and to compare the negative
rates of HCV-RNA in PBMC, HCV-RNA and anti-HCV in serum.
METHODS: Before
and after treatment of alpha 2b interferon, the level of mIL-2R of patients with
chronic hepatitis C was detected by biotin-streptavidin (BSA). The therapeutic
group (26 cases) was treated with alpha 2b interferon (3 MU/d) and control
therapeutic group (22 cases) was treated with routine drugs (VitC, aspartic
acid). The total course of treatment with alpha 2b interferon and routine drug
was six months and per course of the treatment was three months. The levels of
HCV-RNA in PBMC, HCV-RNA and anti-HCV in serum were detected before and after a
course of the treatment.
RESULTS: Before
and after treatment of alpha 2b interferon and routine drugs, the levels of
mIL-2R in silence stage were (3.44±0.77) % and (2.95±0.72) %, the levels of mIL-2R in inducement stage were (33.62±3.95) % and (30.04±3.73) %. There was a significant difference between two groups (P<0.01-P<0.05).
After treatment of alpha 2b interferon with 3 MU/d for two courses of the
treatment, the total negative rates of HCV-RNA in the PBMC and HCV-RNA, anti-HCV
in serum were 42.31 % (11/26), 57.69 % (15/26), 65.38 %(17/26) respectively.
After the treatment of routine drug, the negative rates of HCV-RNA in PBMC and
HCV-RNA, anti-HCV in serum were 13.64 % (3/22), 22.73 % (5/22), 27.27 % (6/22)
respectively. There was high significant difference in the group treated with
alpha 2b interferon and the group treated with routine drugs (P<0.01-P<0.05).
CONCLUSION: The
mIL-2R can be induced by alpha 2b interferon during the treatment. The alpha 2b
interferon has a definite effect on the treatment of HCV-RNA in PBMC. The
curative effect of alpha 2b interferon is better than that of the routine drugs.
Wang J, Xiang GJ, Liu BX. Effect of alpha 2b
interferon on inducement of mIL-2R and treatment of HCV in PBMC from patients
with chronic viral hepatitis C. World J Gastroenterol 2003; 9(4): 751-754
http://www.wjgnet.com/1007-9327/9/751.htm
INTRODUCTION
Treatment of interferon on the chronic viral
hepatitis C has been shown to have a good curative effect on inhibition of HCV
replication, reduction in transmission level in serum and liver cells[1-8],
but the improvement in clinical condition was not obvious and its effective rate
was only 50 %[9-17]. The curative effect of interferon was based on
virostatic replication of HCV in serum and some improvement of liver function.
The literatures show that the peripheral blood mononuclear cells (PBMC) have
large different active immune cells and membrane interleukin-2 receptor (mIL-2R)
is an important symbol of active T cells, and the immune function of PBMC will
be inhibited after being infected by HCV and the scavenging effect limited[18,19].
In order to study the effect of interferon on treatment of HCV in PBMC and the
effect of interferon on inducement to mIL-2R, forty-eight patients with typical
chronic hepatitis C were observed.
MATERIALS AND METHODS
Clinical data
Forty-eight patients with chronic viral
hepatitis C were selected from the Second Miner Hospital of Huainan and our
teaching hospital during 1997/03-2000/05. The total number of patients was 48
(male 27, female 21) and range of age was from 18 to 57 years old (average
37.3). The clinical diagnosis was based on the modified diagnosis criterion
being affirmed on the Chinese viral hepatitis conference in Xian (2000). The
patients all needed the following qualifications: (1) The positivity of anti-HCV
in serum for more than six months. (2) The HCV-RNA in peripheral blood
mononuclear cells and serum were positive. (3) The patients had been eliminated
the infection of hepatitis A, B, D, E and G viruses. (4) There were no any
systemic treatment of antiviral medicine, immunomodulator, cortical hormone for
the patients. The normal control was 20 healthy students (male 12, female 8)
with range age from 20 to 23 years old (average 22.5).
Treatment medicine
The alpha 2b interferon was produced by High
Science and Technology of Anke Biology in Anhui Province.
Treatment methods
The patients with chronic hepatitis C were
divided into two groups with treatment of alpha 2b interferon 3MU (26 cases) and
routine medicine (22 cases) respectively. The total course of treatment lasted
sixty months, and per course was three months. Alpha 2b interferon was given
intramuscularly injection (im) qd for two weeks and then alt dieb for two
courses of treatment. The routine treatment group (22 cases) was given with Vit
C, aspactic acid, etc for six months.
Reagents
The diagnostic reagent of anti-HCV was
purchased from Huamei Bioengineering Company of Shanghai, No:980811. The
diagnostic reagent of HCV-RNA with RT-PCR was purchased from Shanghai Zhongya
Gene Institute, No: 980805. The diagnostic reagent of mIL-2R was purchased from
Immunology Institute of Shanghai. The lymphocytes separation medium was
purchased from the Second Reagent Factory of Shanghai, No:970505. The reagent of
PRMI 1640 culture was produced by Sigma (USA).
Instruments
The analysis instrument of Spector-I was made
in USA; MDF-135 CO2 incubator was made in Japan; The instrument for
gene amplification (Hema-8000) was made in Hema Company of China.
Methods
The total volume of 5 ml peripheral venous
blood from patients with hepatitis C before breakfast was taken before and after
treatment, and distributed a sterile Eppendorf tube and an anticoagulant tube
(heparin) respectively. For detection of anti-HCV, the process was performed
strictly according to the direction, and with two blank, two negative and two
positive pores as controls in each test. The average titer was examined by the
analyser Spector-I. The average OD titer of test sample ≥2.1 times of average
OD titer in negative control was considered to be positive. Detection of HCV-RNA
in PBMC with RT-nested-PCR: After the heparin anticoagulant blood mixed with the
equal volume Hank's liquid without Ca2+
and Mg2+, lymphocytes separation medium was used to separate the PBMC.
The cells were washed twice with Hank's liquid
without Ca2+, Mg2+ and diluted to (1-3)×106/ml before detection of HCV-RNA. A positive and a
negative control were set up at the same time for comparison in each test. The
RT-nested-PCR was made by reverse transcription and primer selected from
non-coded region and part of C region of HCV. The specific amplificated fragment
length was 248 bp. The synthesis parameters for cDNA were 94 ℃
40 s, 55 ℃
40 s, 72 ℃
1 min, for 30 circles. The amplification parameters for cDNA were 94 ℃
50 s, 55 ℃
40 s and 72 ℃
90 s, 35 circles, including initial denaturation for 4 min at 94 ℃
and last extension for 5 min at 72 ℃.
The amplification product was run for electrophoresis on gel with 2 % EB. The
result that was uniform to the positive control was considered to be positive.
The detection of mIL-2R in silence and inducement stages: 10 ml
suspension of the PBMC was smeared on the slide and left dry naturally and fixed
with acetone for fifteen minutes or twenty minutes. The 10 ml
anti-Tac antibody was mixed with the membrane of smears. The cells were grown in
continuous culture (37 ℃,
50 ml.l-1 CO2 in atmosphere)
for thirty minutes. The immune sheet glass pores were measured after staining
with the color-developing agent and several washings with Tris Buffer Solution
(TBS). Of the PBMC suspension, 0.5 ml was mixed with RPMI 1640 culture liquid,
which had PHA 200 mg.l-1. The cells were
grown in continuous culture (37 ℃,50
ml.l-1 CO2 in atmosphere) 72 h
and its mIL-2R induced by PHA could be measured by the antibodies against
membrane of T cells. The Tac with biotin and SA-HRP were smeared on different
sheet glasses. The immune sheet glass pores were measured after staining with
the color-developing agent and several washings with TBS. The total number of
200 PBMC was counted and its positive cells were statistically analyzed with the
help of high power lens. The positive criterion was that the color of cytoplasm
or cell membrane was brown.
Statistical analysis
Statistical analysis included analysis of
Chi-square (x2) and t test.
RESULTS
The forty-eight patients with chronic hepatitis C
were divided into two groups and treated with alpha 2b interferon (26 cases) and
routine drugs (22 cases) respectively. The results had been shown that the high
negative rates of anti-HCV and HCV-RNA in serum were in the group with treatment
of alpha 2b interferon. There was very significant difference before and after
treatment of alpha 2b interferon (P<0.01-P<0.05, Table 1).
The negative rate of HCV-RNA between in PBMC and in serum was similar (P>0.05,
Table 2). The level of mIL-2R in situation of silence and inducement stages
after treatment with alpha 2b interferon was higher than that after treatment
with routine drugs (P<0.05, Table 3).
Table 1 The
detective results of HCV-RNA in serum and PBMC after treatment with alpha 2b
interferon (n, %)
| Group | n | HCV-RNA in PBMC | HCV-RNA in serum | Anti-HCV | |||
| Negative | Negative rate | Negative | Negative rate | Negative | Negative rate | ||
| Interferon treatment | 26 | 11 | 42.31a | 15 | 57.69a | 17 | 65.38b |
| Routin treatment | 22 | 3 | 13.64 | 5 | 22.73 | 6 | 27.27 |
aP<0.05, bP<0.01
vs interferon treatment.
Table 2
The results of negative rate of HCV-RNA in serum and PBMC
| HCV-RNA in serum | HCV-RNA in PBMC | Total | x2 | P | |
| + | - | ||||
| + | 7 | 4 | 11 | ||
| - | 8 | 7 | 15 | 0.75 | >0.05 |
| Total | 15 | 11 | 26 | ||
Table 3 The level of mIL-2R before and after treatment of interferon (n, x±s, %)
| Group | n | mIL-2R (in silence) | mIL-2R (inducement) | ||
| Before treatment | After treatment | Before treatment | After treatment | ||
| Interferon treatment | 26 | 2.63±0.70 | 3.44±0.77bcd | 30.34±3.55 | 33.62±3.95cd |
| Routin treatment | 22 | 2.43±0.78 | 2.95±0.72ad | 30.07±3.87 | 30.04±3.73d |
| Normal control | 20 | 4.54±1.48 | 37.42±4.10 | ||
aP<0.05, bP<0.01
vs before and after treatment, cP<0.05, dP<0.01
vs interferon treatment.
DISCUSSION
There are three kinds of interferon, a, b, g.
Interferon alpha is the most active one. Alpha 2b interferon can not enter into
the host cells and kill the virus directly, but can induce the production of
protein kinase (2', 5'AS) in the infected cells. The
protein kinase and 2', 5'AS can be produced after
being infected by virus in cells. The degradation of virus-RNA can be made by
endogenous ednonuclease induced with activated 2', 5'AS
so that the necessary enzyme activity for synthesis of ribose is killed, the
synthetic protein of virus can be decreased, the growth of hepatitis virus C is
inhibited[20-30].
The reports have
been shown that interferon has definite curative effect of the treatment of
chronic hepatitis C and elimination of HCV-RNA, anti-HCV in serum. Therefore,
HCV-RNA is an important index to evaluate condition of the patient's[4].
HCV-RNA in PBMC is a direct evidence of the existence of extrahepatic or latent
infection, and is one of important reasons causing the chronicity of viral
hepatitis C[28-31]. The results of Table 1 had shown that the rate of
change HCV-RNA into negative in PBMC and serum after treatment of alpha 2b
interferon was similar between two groups (P>0.05). The curative
effect was higher in the treatment group with alpha 2b interferon than that with
routine treatment (P<0.05-P<0.01). This result had showed
that the inducing capability of alpha 2b interferon in lymphocytes of the
patients was strong, and the high effect against HCV would be taken by activated
lymphocytes obviously. Although the negative rate of HCV-RNA in PBMC was lower
than that in serum, there was no significant difference (P>0.05). The
results had shown that alpha 2b interferon had high effect on HCV-RNA both in
PBMC and in serum. There were four cases of chronic hepatitis C with negative in
serum and positive in PBMC. It indicated that with the T lymphocytes activation,
multiple cell factors were released, that inhibited the replication of free HCV-RNA
in serum, but not the HCV-RNA in PBMC. The cellular immune function was disorder
in different extent in patients with chronic hepatitis C and so was their
response to interferon and anti-HCV[32-37]. Otherwise, the low level
of membrane interleukin-2 receptor (mIL-2R) on the surface of PBMC decreased the
activity in chronic hepatitis C, which limited the inducement of protein kinase
and the activity of 2', 5'AS to eliminate HCV-RNA[38].
Anti-HCV is an
important index for the diagnosis of HCV and is one of the evidences for
evaluating the curative effect on the treatment of hepatitis C. The anti-HCV
diagnostic kits of the second generation were used in our laboratory testing for
core antigen, NS3, NS4 and had high specificity and sensitivity[39,40].
The rate of negative change of HCV-RNA was higher in alpha 2b interferon
treatment group than that in routine treatment group (P<0.01). Among
the twenty-six cases, there were six cases with anti-HCV(-) in serum and HCV-RNA(+)
in PBMC, two cases with anti-HCV(-) in serum and HCV-RNA(+) in serum. This
result showed that even the anti-HCV in serum became negative, HCV-RNA not
stopping replication completely, some HCV-RNA could still be detected in some
patients[6]. The probable reasons were: (1) After being treatment of
alpha 2b interferon, the level of anti-HCV in serum decreased obviously and
could not be detected by routine test. (2) The degree of variation of HCV is
high, the hydrophilic peptid chain on core protein is subjective to escape the
attack of CTL and keep the infection persist in chronic state. (3) The variant
antigen of HCV can not match the antibody produced.
mIL-2R is an
important symbol of active T cells and plays key role on biologic effect of IL-2
and its level can reflect the course of activity of T cells and immune state[38-41].
The levels of mIL-2R in silence stage detected by BSA were lower in patients
with hepatitis C than those in normal controls (P<0.01). The probable
reasons are: (1) The mIL-2R on surface of some T cells can be restrained by HCV.
(2) The degree of variation of HCV is high, the hydrophilic peptid chain on core
protein is subjective to escape the attack of CTL and keep the infection persist
in chronic state. (3) The variant antigen of HCV can not match the antibody
produced. A lot of soluble interleukin-2 receptor (sIL-2R) can be released after
replication of HCV-RNA in PBMC so that the expression of mIL-2R was restrained.
It is not only a kind of manifestation of disorder and low cellular immune to
HCV but also one of reasons of chronic hepatitis C. Some T cells receptor (TCR)
on surface of some Tc cells can combine with the complement (HCV-MHC-I) and some
perforation proteins can be released so that many liver cells will be injured.
The sIL-2R, a kind of restrained factor, as well as mIL-2R all can combine with
IL-2 competitively and induce infection of HCV from activity to chronicity. With
the inducement of PHA, the level of mIL-2R in silence and inducement stages was
obviously increased. This result showed that the mIL-2R could be induced by PHA
and had strong compete ability against sIL-2R in serum.
After inducement
of PHA, the level of mIL-2R of patients in inducement stage was higher than that
in silence stage, and lower than that in normal controls (P<0.01). The
results of our study showed that the effect of PHA was infirm for patients with
hepatitis C and was similar to the reports published. The level of mIL-2R in
silence and inducement stages were higher after treatment of alpha 2b interferon
than that before treatment of alpha 2b interferon (P<0.01). The active
T cells and high level of mIL-2R can be induced by alpha 2b interferon during
the treatment. The results showed that alpha 2b interferon not only can induce
the protein kinase and 2', 5'AS but also stimulate T
cells and induce the effect of Tc cells against infected cells.
In conclusion,
some active T cells and mIL-2R can be induced during the treatment of alpha 2b
interferon. The patients with viremia are sensitive to treatment of alpha 2b
interferon that have good effect on negative change of HCV-RNA in PBMC and serum
and anti-HCV in serum. If the treatment time of alpha 2b interferon prolongs,
the negative rate of anti-HCV and HCV-RNA will increase simultaneously. In
treatment of HCV with alpha 2b interferon, the value of negative change of HCV-RNA
in serum alone is limited. In well equipped hospital both HCV-RNA in serum and
PBMC can be examined at the same time.
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