Characterization of Immunoreactive

Ulf Petersson, Anders Borgström
Department of Surgery, Malmö University Hospital, Lund University. Malmö, Sweden
ABSTRACT
Context All work on human trypsinogen
activation peptide (TAP) in acute pancreatitis
has been carried out with the same assay.
Despite the extensive use of this original TAP
assay, there is no characterization of the TAP-
like immunoreactivity measured.
Objective The aims of this study were to
develop an additional TAP assay and to
attempt to characterize the TAP-like
immunoreactivity found in the urine of
patients with acute pancreatitis.
Methods Antibodies against the human TAP
were prepared using the whole octapeptide
APFD4K, conjugated at its N-terminal end.
Characterization of the immunoreactivity
measured with these assays was performed
using gel filtration of human pancreatic juice
before and after activation of trypsinogen
with enterokinase.
Results After activation of the pancreatic
juice, there was a large initial increase in
immunoreactive TAP and a decrease 6-24
hours later. Using our antiserum, we found
low levels of immunoreactive TAP in urine
from patients with acute pancreatitis, although
many of these samples contained high levels
of immunoreactive TAP when tested with the
commercially available TAP kit
®
(Biotrin).
The pentapeptide D4K, used as a standard in
the Biotrin kit, showed much lower
immunoreactivity than the synthetic
octapeptide APFD4K in our assay. The
octapeptide, however, reacted similarly to
D4K in the Biotrin kit assay.
Conclusion Our antibody prepared against
the synthetic octapeptide APFD4K is directed
against the N-terminal part of the octapeptide
and does not recognize the pentapeptide D4K.
Immunoreactive TAP in urine in acute
pancreatitis is mainly composed of the C-
terminal pentapeptide, D4K.
INTRODUCTION
Trypsinogen is one of the most predominant
zymogens in pancreatic juice. Activation of
trypsinogen by enterokinase in the duodenum
[1] is the initial step in the normal activation
of pancreatic digestive enzymes. Premature
activation of the proenzymes within the
pancreas was suggested as the cause of acute
pancreatitis as early as 1896 [2]. Today, the
pathophysiological importance of trypsinogen
activation and trypsin activity in acute
pancreatitis [3, 4, 5, 6, 7, 8, 9, 10] is generally
accepted, even if the initiation and timing of
this activation, as well as its relationship to
other inflammatory reactions, is still under
debate. One explanation for this is that trypsin
activity has been difficult to measure in
biological fluids, as trypsin activated in the
pancreatic tissue or in the circulation is
momentarily bound, and thereby inactivated,

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by protease inhibitors. When trypsinogen is
activated, an N-terminal 8-amino acid long
peptide is split off [11]. An assay for analysis
of this trypsinogen activation peptide (TAP)
was first described in 1988 [12], and is one
way of monitoring trypsinogen activation.
Since then, a limited number of papers on
human acute pancreatitis have been published
[8, 9, 13, 14, 15, 16, 17]. Measurement of
TAP levels in urine has been suggested as a
possible way of predicting the severity of an
attack of acute pancreatitis early in the course
of the disease [8, 9, 14, 16].
The five C-terminal amino acids of TAP are
highly conserved phylogenetically. An assay
with antibodies directed at this part of TAP
can therefore be used in many different
species of experimental animals. A large
number of papers on trypsinogen activation in
different models of experimental acute
pancreatitis have been published using this
method [5, 18, 19].
All the work on TAP in acute pancreatitis has
been carried out with the same assay. No
alternative assay has been available for
confirmation of the results. Despite the
extensive use of the original TAP assay, no
characterization of the TAP-like immuno-
reactivity measured with this method has been
presented. The aims of this study were to
develop an additional TAP assay and to
attempt to characterize the TAP-like
immunoreactivity found in the urine of
patients with acute pancreatitis.
MATERIALS AND METHODS
Peptides
Synthetic human TAP (trypsinogen activation
peptide) APFDDDDK (APFD4K) was
obtained from Euro-Diagnostica (Malmö,
Sweden). This peptide was used as a standard
in our assay. Two other peptides YAPFD4K
(Tyr-TAP) and CAPFD4K (Cys-TAP) were
also purchased from the same source. The
Cys-TAP peptide was used for immunization.
The Tyr-TAP peptide was labelled with I
125
using the chloramine-T method. The mono-
iodinated peptide was purified by HPLC
using a C18 column, and used as a tracer in
the assay.
Porcine enterokinase was obtained from the
Sigma Chemical Company (St. Louis. MI,
USA).
Immunization Procedure
The Cys-TAP peptide was conjugated at its
N-terminus to bovine serum albumin using
maleimidobenzoyl-N-hydroxysuccimide and
rabbits were immunized by multiple
subcutaneous injections of this conjugate in
Freund’s incomplete adjuvant. We obtained
three different polyclonal antisera which
reacted with I
125
Tyr-TAP when diluted more
than 1/1,000. In the following study, only one
of these antibodies was used (designated as
9801).
Activation of Pancreatic Juice
Human pancreatic juice devoid of trypsin
activity was obtained by drainage of the main
pancreatic duct after pancreatic head
resections in 3 patients (2 men and 1 female
aged 45, 67 and 68 years) The juice was kept
at -20°C for up to 12 months before use. For
use, 1.8 mL of pancreatic juice was treated
with 200 µL of enterokinase (1 mg/mL in
0.05 mol/L Tris-HCl buffer, pH 7.4,
containing 0.05 mol/L CaCl2) and incubated
at room temperature. One hundred µL was
withdrawn at time zero and after 1 h, 2 h, 4 h,
6 h, 10 h, 15 h, 24 h and 48 h. These 100 µL
samples were boiled for 15 min and diluted to
1 mL in the buffer described above. The
samples were then stored at 4°C for up to 2
days before analysis.
Gel Chromatography
Gel filtration was performed on a Sephadex
G-50 column, 0.9x60 cm, in the buffer
described above. The column was eluted at 3
mL/h and the eluate was collected in 0.6 mL
fractions.
Radioimmunoassays
The assay buffer used was 0.05 mol/L Tris-
HCl, pH 7.4 containing 0.15 mol/L NaCl,
0.005 mol/L EDTA and 2 g/L bovine serum
albumin. Samples (100 µL) diluted in assay
buffer were incubated for 16 h at 4°C with
200 µL of I
125
Tyr-TAP (about 20,000 cpm) in
assay buffer and 200 µL rabbit anti

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276
octapeptide APFD4K serum (9801) diluted
1/1,500 in assay buffer. Parallel incubation of
synthetic TAP diluted in assay buffer (0.1-10
nmol/L) served as standards. Free and bound
radioactivities were then differentiated by
means of a second antibody precipitation step
using a decanting suspension (with sheep
anti-rabbit IgG antibody) (Pharmacia,
Uppsala, Sweden). After four hours of
incubation, the sample was centrifuged at
2,500 for 15 min, the supernatant was
decanted and the radioactivity of the
precipitate was measured in a gamma-
counter. The sensitivity of the assay was
estimated to be 0.1 nmol/L.
Biotrin TAP Assay
This assay was purchased from Biotrin
International (Dublin, Ireland). It was run
according to the manufacturer’s instructions.
The standard used in this assay is the
pentapeptide D4K. The production and
specificity of the polyclonal antiserum has
been described [12].
Stability of the Octapeptide APFD4K
(TAP) in Serum, Plasma and Urine
Synthetic TAP (APFD4K) was mixed with
either fresh serum, fresh serum boiled for 15
min, fresh EDTA plasma, or fresh urine (all
obtained from one healthy subject), or with
Tris-HCl buffer, pH 7.4, containing 0.05
mol/L CaCl(see above). One sample was
withdrawn immediately from each mixture
and boiled. The mixtures were then incubated
at room temperature and further samples were
withdrawn at different time intervals for up to
48 h and boiled. TAP-like immunoreactivity
was then measured using our assay.
Urine Samples
Urine samples were obtained from 14 patients
with acute pancreatitis. (8 males, 6 females;
mean±SD age: 62±11 years. The samples
were stored at 4°C for up to 18 hours after
sampling and then frozen at -20°C for up to 6
months before analysis. The diagnosis was
based on acute abdominal pain of less than 72
hours duration, with at least a threefold
elevation of the serum amylase level.
ETHICS
The local animal welfare committee (M318-
95) accepted the immunization procedure.
The procedure for drainage of the main
pancreatic duct after pancreatic head
resections was approved by the local ethics
committee (LU Dnr 616/2004); written
consent was obtained from all patients.
Finally, the local ethical committee (LU-00-
47) approved the urine samples obtained from
patients with acute pancreatitis. The study
protocol conforms to the ethical guidelines of
the "World Medical Association Declaration
of Helsinki - Ethical Principles for Medical
Research Involving Human Subjects" adopted
by the 18
th
WMA General Assembly,
Helsinki, Finland, June 1964, as revised in
Tokyo 2004.
STATISTICS
Data are reported as mean±SD. The Wilcoxon
matched-pairs test was applied. A two-tailed
P value less than 0.05 was considered
statistically significant. The SPSS for
Windows (Version 13.0) statistical package
was used to perform the statistical analysis.
Figure 1. TAP radioimmunoassay using the 9801
antibody. Standard dilution curves for the two peptides
APFD4K and D4K.

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RESULTS
Radioimmunoassay for Immunoreactive
Trypsinogen Activation Peptide (irTAP)
Figure 1 shows the pattern of immuno-
reactivity for the synthetic octapeptide
APFD4K and the Biotrin pentapeptide D4K
using the tracer I
125
Tyr-TAP and the
antiserum produced in this study. Our
antibody is very sensitive to the octapeptide
and was found to recognize this intact TAP at
concentrations as low as 0.1-0.2 nmol/L while
reactivity to the pentapeptide was found to be
much lower, the sensitivity for this peptide
being only around 5-10 nmol/L.
Figure 2 shows the corresponding ELISA
results for the Biotrin kit antibody using the
kit. This assay is about twice as sensitive to
the pentapeptide than to the octapeptide. The
sensitivity for the octapeptide in this assay is
in the range 0.5-1.0 nmol/L. Boiling of the
octapeptide did not affect the immuno-
reactivity in either of the assays (data not
shown).
Ir-TAP in Human Pancreatic Juice
The concentrations of ir-TAP in pancreatic
juice before and after activation of
trypsinogen with enterokinase, measured with
both our assay and the Biotrin assay, are
shown in Figure 3. All samples were boiled
before analysis. There are clear differences in
the time curves obtained with the two assays.
Before activation, the Biotrin assay could not
detect any immunoreactivity while our assay
found approximately 0.02 µmol/L of ir-TAP.
Using our assay, maximal immunoreactivity
was seen one hour after activation (about 11
µmol/L) while maximal immunoreactivity
with the Biotrin assay was found after 4 hours
(about 14 µmol/L). After the initial activation,
the immunoreactivity decreased rapidly in our
assay while that measured by the Biotrin
assay was more stable. A reasonable
interpretation of the data would be that the
immunoreactive material measured with our
assay is more labile than that measured using
the Biotrin assay.
Characterization of ir-TAP in Pancreatic
Juice Using Gel Chromatography
Figure 4 shows a characterization of
immunoreactive TAP in pancreatic juice
using gel chromatography and our
radioimmunoassay. Samples were boiled
before gel filtration to avoid autoactivation
during chromatography. No immunoreactivity
was noted before activation with
enterokinase. After activation, a peak of ir-
TAP was found in the vicinity of fractions 56
and 57. Gel chromatography of the synthetic
octapeptide APFD4K showed that this peptide
is eluted in exactly the same volume (results
Figure 2. TAP ELISA (Biotrin kit). Standard dilution
curves for the two peptides APFD4K and D4K.
Figure 3. Immunoreactive TAP in pancreatic juice
before (Time 0) and after activation with enterokinase,
using the 9801 antibody (blue square) and the Biotrin
kit assay (magenta triangle).

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not shown). This experiment was not
performed using the Biotrin assay or the D4K
standard.
Ir-TAP in Urine Obtained from Patients
with Acute Pancreatitis
Urine samples obtained from patients with
acute pancreatitis were found to contain no or
only small amounts of TAP-like
immunoreactivity when measured with our
radioimmunoassay while significantly larger
amounts of immunoreactivity were recorded
using the ELISA assay from Biotrin (Table
1). Only one sample (patient 4) contained
clearly elevated levels of irTAP as measured
with our assay (antiserum 9801).
Characterization of ir-TAP in Urine from
Patients with Acute Pancreatitis Using Gel
Chromatography
Radioimmunoassay
The elution profile after gel chromatography
of the TAP-like immunoreactivity in urine
from patient 4, as measured by our assay, is
shown in Figure 5 (unboiled sample). Most of
the immunoreactivity was recovered in one
peak (peaking in fraction 58) which was
eluted in a volume corresponding to the
elution profile of the activation peptide found
in activated pancreatic juice (Figure 4). A
Figure 4. Elution profiles after gel filtration of
immunoreactive TAP in pancreatic juice, before and
after activation by enterokinase. Gel filtration was
performed on a Sephadex G-50 column (0.9x60 cm).
Immunoreactive TAP was measured in each fraction
using radioimmunoassay based on the 9801 antibody.
Figure 5. Elution profile (after gel filtration) of
immunoreactive TAP from the urine of a patient with
acute pancreatitis, as measured by radioimmunoassay
with 9801 antibodies before and after boiling. Gel
filtration was performed on a Sephadex G-50 column
(0.9x60 cm). Arrows indicate the elution volume of
trypsinogen (Tg) and the elution volume of the
octapeptide APFD4K (TAP)
Table 1. Urine concentrations of trypsinogen activation
peptide (TAP; nmol/L) in patients with acute
pancreatitis using our radioimmunoassay (irTAP)
compared to the Biotrin assay.
Patient No. irTAP
Biotrin kit
(Unboiled)
irTAP
9801 assay
(Unboiled)
irTAP
9801 assay
(Boiled)
1
28
1.3
1.9
2
214
3.0
1.9
3
38
1.8
1.8
4
34
24
19
5
13
0.8
0
6
10
0.5
0
7
24
0.6
0
8
9
0.2
0
9
18
1.0
0
10
4.0
0
0
11
10
2.0
0
12
3.0
0
0
13
68
1.9
0
14
4.0
1.0
0
Mean±SD 34.1±54.7
2.7±6.2
1.8±5.0
Biotrin vs. unboiled irTAP 9801 assay: P=0.001a
Biotrin vs. boiled irTAP 9801 assay: P=0.001 a
irTAP 9801 assay unboiled vs. boiled: P=0.009 a
Wilcoxon matched-pairs test

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smaller peak was also detected, with the
elution volume corresponding to the size of
trypsinogen (with peak in fraction 30). This
peak was completely abolished when the
urine sample was boiled before gel filtration
while the peak corresponding to the activation
peptide was unchanged (Figure 5, boiled).
Biotrin Assay
The elution profile after gel filtration of the
TAP-like immunoreactivity in urine from
patient 2, using the assay from Biotrin, is
shown in Figure 6. All immunoreactivity was
eluted in a similar or perhaps slightly larger
volume (with peak in fraction 60) than the
activation peptide seen in Figure 5, indicating
that this immunoreactivity corresponded to
the same size of molecule. Testing these
fractions with our assay did not allow
detection of immunoreactivity in any fraction.
Stability of Synthetic APFD4K in Serum,
Plasma and Urine
The synthetic octapeptide loses its
immunoreactivity in serum within hours, as
shown in Figure 7. However, the
immunoreactivity appears to be more stable in
urine. The loss of immunoreactivity in serum
can be prevented by boiling the sample or by
adding EDTA, which chelates divalent
cations. This experiment was not performed
with the Biotrin assay.
DISCUSSION
This paper describes our efforts to develop a
radioimmunoassay for the trypsinogen
activation peptide TAP. We followed the
instructions of Hurley et al. [12] and
immunized rabbits with the N-terminally
conjugated synthetic octapeptide APFD4K.
However, we did not purify our antibody by
affinity chromatography on an immobilized
YD4K peptide, as suggested by these authors
[12]. In this study, we have compared the
results obtained with our assay with the
results obtained using the commercially
available Biotrin TAP ELISA assay.
Our antibody may show some cross-reaction
with the proenzyme trypsinogen, which may
be an explanation for the minor peak of “high
molecular weight” immunoreactivity seen
after gel chromatography of unboiled urine
(Figure 5). Boiling takes care of this problem,
which is also evident from the low amounts of
immunoreactivity found in boiled pancreatic
juice (Figure 3).
It is clear that the antisera appear to recognize
different parts of the activation peptide. The
Biotrin antibody reacts in a similar way with
both the octapeptide APFD4K (which was
Figure 6. Elution profile (after gel filtration) of
immunoreactive TAP from the urine of a patient with
acute pancreatitis, as measured by the Biotrin TAP kit
assay.
Figure 7. Stability of TAP in serum plasma and urine.
Synthetic APFD4K was incubated in fresh serum,
urine, EDTA plasma, boiled serum or Tris-HCl buffer,
pH 7.4, containing CaClfor up to 48 hours. Samples
were withdrawn at regular intervals, boiled and later
analyzed for irTAP using the 9801 antibody-based
radioimmunoassay.

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used as the standard in our assay) and the
pentapeptide D4K (which is used as the
standard in the Biotrin assay). In contrast, our
assay showed a much lower reactivity against
the pentapeptide. In our assay, the
immunoreactivity of this peptide was only 2-
4% of the immunoreactivity of the
octapeptide (Figure 1). Our conclusion is that
our antibody recognizes the middle or N-
terminal part of the activation peptide and that
the Biotrin antibody recognizes antigenic
determinants which are mainly located in the
C-terminal part of the octapeptide.
The real aim for the immunization procedure
described by Hurley et al. was to obtain an
antiserum specific for the C-terminal end of
the activation peptide using the N-terminally
conjugated pentapeptide and the procedure
they used was very successful. We used the
N-terminally conjugated octapeptide instead
of the pentapeptide and, unfortunately our
antibody mainly recognizes the N-terminal
part of the activation peptide. This also
explains the cross-reaction of our antibody
between the activation peptide and the
proenzyme.
The differences in immunoreactivity between
our polyclonal rabbit antibody (9801) and the
Biotrin polyclonal antibody can be used to
study the molecular structure of the activation
peptide in urine from patients with acute
pancreatitis. Most urine samples from patients
with acute pancreatitis do not possess any
immunoreactivity in our assay, and this must
mean that they do not contain the octapeptide
at higher concentrations than 1 nmol/L. Only
one sample showed increased immuno-
reactivity. According to gel chromatography,
the protein species responsible for this
immunoreactivity had the same molecular
size as the intact activation peptide (Figure 5).
In contrast to the results of our assay, the
Biotrin assay showed substantial TAP-like
immunoreactivity in several urine samples
and, in one sample, a concentration exceeding
200 nmol/L was measured. This discrepancy
can be explained by the assumption that urine
from patients with acute pancreatitis contains
the pentapeptide but not the octapeptide. If
this were the case, an obvious explanation
would be that the octapeptide is, to a large
extent, degraded by N-terminal proteolysis in
the circulation before, during or after
excretion into the urine.
A characterization of the TAP-like
immunoreactivity measured by the Biotrin
assay has never been published. The results of
this study show that it is composed of
material of a molecular size compatible with
that of the pentapeptide or the octapeptide
(Figure 6). Gel chromatography on a G-50
column is far from the optimal method for
showing differences in sizes between the
octapeptide and the pentapeptide. This
column was chosen to differentiate
trypsinogen (molecular weight 23 kDa) from
the octapeptide (molecular weight 0.9 kDa).
Further studies are required to show the
precise nature of the TAP-like immuno-
reactivity measured in the Biotrin assay.
It appears that the octapeptide is not very
stable after the activation of pancreatic juice,
as can be seen from Figure 3. Most of the
immunoreactivity is destroyed within hours.
The results shown in Figure 3 are in
accordance with the idea of rapid N-terminal
degradation of the octapeptide to the more
stable pentapeptide-like molecule, since the
reduction in immunoreactivity measured with
the Biotrin assay is substantially slower. The
octapeptide is probably very unstable in the
circulation, since it is rapidly destroyed in the
in vitro serum. This degradation can be
inhibited by boiling or by chelating agents
such as EDTA. Thus, a metalloprotease is
probably involved in this degradation.
We have developed an assay with high
specificity for the intact activation peptide
from human trypsinogen (APFD4K) but our
conclusion is that it has very little cross-
reaction with the pentapeptide D4K, which
represents a secondary and major degradation
product of the native activation peptide. Using
our radioimmunoassay together with the
Biotin assay, we found that urine from
patients with acute pancreatitis most often
contains small amounts of the octapeptide, but
substantial amounts of the pentapeptide. One
interpretation is that the octapeptide is rapidly
degraded in active pancreatic juice and in

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serum to the more stable pentapeptide
molecule. Due to this rapid degradation,
antibodies recognizing only the N-terminal
part of the activation peptide from
trypsinogen are not suitable for monitoring
trypsinogen activation in urine in cases of
human acute pancreatitis. The pentapeptide
D4K is more stable in urine after sampling,
but substantial amounts may be degraded
before sampling in the circulation during
passage to the kidneys.
Despite these drawbacks, our assay can be
used for molecular studies of the trypsinogen
activation process in in vitro studies where
boiling immediately after sampling can stop
the reaction and degradation.
Received, February 13
th
, 2006 - Accepted
February 28
th
, 2006
Keywords Biological Markers; Pancreatitis,
Acute Necrotizing; Trypsinogen; trypsinogen
activation peptide
Abbreviations TAP: trypsinogen activation
peptide
Acknowledgments This study was supported
by grants from the Swedish Medical Research
Council projects no 17-X-8305-09A, the
Foundations for Research at the University
Hospital in Malmö and the Einar and Inga
Nilsson Foundation for Surgical Research at
the Department of Surgery in Malmö. The
funding sources had no role in the study
design, in the collection, analysis, and
interpretation of data, in the writing of the
report, or in the decision to submit the paper
for publication.
Correspondence
Anders Borgström
Department of Surgery
Malmö University Hospital
Lund University
Södra Förstadsgatan 101
205 02 Malmö
Sweden
 
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