NK, T and NK T-cells in ageing, coeliac disease and IBD Randall Grose i NK, T and NK T-cells in ageing, coeliac disease and inflammatory bowel disease BY RANDALL HILTON GROSE B.Biotech (Hons) A thesis submitted to the University of Adelaide as the requirement for the degree of Doctor of Philosophy The Department of Medicine, the University of Adelaide; The Basil Hetzel Institute for Medical Research and the Department of Gastroenterology and Hepatology, The Queen Elizabeth Hospital March 2008
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NK, T and NK T -cells in ageing, coeliac disease and ......NK cells in untreated and treated coeliac subjects was 3.6±0.5 x10 5 and 5.5±0.6 x10 5 cells per ml, respectively Figure
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NK, T and NK T-cells in ageing, coeliac disease and IBD Randall Grose
i
NK, T and NK T-cells in ageing,
coeliac disease and inflammatory
bowel disease
BY
RANDALL HILTON GROSE B.Biotech (Hons)
A thesis submitted to the University of Adelaide as the requirement for the
degree of Doctor of Philosophy
The Department of Medicine, the University of Adelaide;
The Basil Hetzel Institute for Medical Research and the Department of
Gastroenterology and Hepatology, The Queen Elizabeth Hospital
March 2008
Chapter 5: NK, T and NK T cells in coeliac disease Randall Grose
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5 CHAPTER 5 NK, T and NK T-CELLS IN COELIAC
DISEASE
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5.1 INTRODUCTION Coeliac disease is mediated by an inappropriate reaction of intestinal T-cells to
dietary wheat derived-gluten causing intestinal damage in genetically
susceptible individuals. Gliadin peptides are deamidated by intestinal tTG
enzyme and are presented by DQ2 (or DQ8) dendritic cells to mucosal T-cells.
This inappropriate T-cell activity has been attributed to lack of immunological
oral tolerance (Mowat et al., 1987), but there is limited evidence of loss of
immunological suppression in coeliac disease. NK T-cells are recognized as
important immunoregulatory cells that are deficient in several autoimmune
diseases.
Previous studies have shown a relative deficiency in the number of intestinal
and peripheral NK cells in coeliac disease (Hadziselimovic et al., 1992). Di
Sabatino et al. (1998b) briefly investigated and showed a deficiency of CD16+
NK T-like cells in coeliac subjects. Nevertheless, these studies did not
investigate the number or function of Vα24+ T-cells or iNK T-cells in subjects
with coeliac disease. A report by van der Vliet et al. (2001) investigated a
variety of diseases characterised by autoreactive tissue damage, including
coeliac disease, and showed that Vα24+ Vβ11+ T-cells were not deficient in
ten coeliac subjects.
5.2 AIMS AND HYPOTHESIS The aim of this Chapter was to investigate the number of circulating NK cells,
T-cells, NK T-like and iNK T-cells in coeliac disease. Cytokine production by
Vα24+ T-cells and iNK T-cells after in vitro anti-CD3 stimulation were
examined and compared to cytokine production by CD3+ T-cells after in vitro
anti-CD3 and gluten fraction 3 stimulation in normal subjects and in subjects
with coeliac disease.
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The hypothesis of this Chapter was that NK cells, immunoregulatory Vα24+ T-
cells, NK T-like cells and/or iNK T-cells are deficient in subjects with coeliac
disease.
5.3 MATERIALS AND METHODS
5.3.1 Subjects Coeliac subjects were recruited from patients attending the Department of
Gastroenterology and Hepatology at The Queen Elizabeth Hospital. Additional
volunteers were recruited through the Coeliac Society of South Australia who
responded to a notice in their newsletter. All coeliac subjects had been
diagnosed by intestinal biopsy and clinical response to a GFD. Coeliac subjects
were generally reviewed at 12 monthly intervals as part of this study. They
were strongly encouraged to adhere to a GFD and had repeat serology tests to
ascertain this. Upon sample collection, details regarding adherence to and
duration of diet were recorded. Control subjects were recruited from those
attending for endoscopy for non-ulcer dyspepsia or iron deficiency in the
Department of Gastroenterology and Hepatology at The Queen Elizabeth
Hospital, in whom no major pathology was identified. The Human Ethics
Committee of The Queen Elizabeth Hospital approved this study.
5.3.2 Flow cytometry Peripheral blood lymphocytes were collected and stained using antibodies
directed against CD56, CD57, CD94 or CD161 NK markers, CD3, CD4,
Vα24, Vβ11 or Vβ13 T-cell, Vα24 6B11 and Vα24 α-GalCer/CD1d tetramer
iNK T-cell markers as previously described in Chapter 2.
5.3.3 In vitro anti-CD3 stimulation of peripheral blood T-cells Peripheral blood lymphocytes were stimulated in vitro for 4 h and 24 h with
anti-CD3 antibody as previously described in Chapter 2.
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5.3.4 Depletion of Vα24+ NK T-cells by magnetic beads
Vα24+ cells were depleted from blood of normal healthy control subjects using
magnetic beads as previously described in Chapter 2.
5.3.5 In vitro gluten fraction 3 stimulation of peripheral blood T-
cells Blood was collected in lithium heparin tubes and mononuclear cells isolated on
a density gradient. Cells were washed and resuspended in RPMI 1640 (Gibco,
Life Technologies, Melbourne, Australia) supplemented with 10% foetal calf
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Figure 5.16 Intracellular (A) IL-4 and (B) IFN-γ cytokine production CD3+ T-cells after 4 h in vitro anti-CD3 (♦) or gluten fraction 3 (◊) stimulation in normal and coeliac subjects. Data are given as the change in number (graphed) and percentage (Table) of cytokine producing CD3+ T-cells unstimulated (-) or stimulated (+) for 4 h (n=number of subjects).
Figure 5.17 Intracellular IL-4 and IFN-γ cytokine production CD3+ T-cells after 24 h in vitro anti-CD3 (♦) or gluten fraction 3 (◊) stimulation in normal and coeliac subjects. Data are given as the change in number (graphed) and percentage (Table) of cytokine producing CD3+ T-cells unstimulated (-) or stimulated (+) for 24 h (n=number of subjects).
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Thus, short term (4 h) incubation with anti-CD3 increased IL-4+ T-cells only in
normal control subjects, but not in coeliac subjects. However, after longer
incubations (24 h) both normal and coeliac subjects had increased IL-4+
production by T-cells. Gluten fraction 3 antigen stimulation only increased
IFNγ+ T-cells in coeliac subjects.
To investigate whether low numbers of circulating Vα24 cells are sufficient to
prime an appropriate cytokine response, Vα24+ cells were depleted using
magnetic beads from blood of normal healthy control subjects. IL-4 and IFN-γ
production by CD3+ T-cells was investigated from normal subjects with
depleted levels of Vα24+ T-cells. There was no significant change in IL-4 or
IFN-γ producing CD3+ T-cells for normal subjects with depleted levels of
Vα24+ cells after 4 h in vitro anti-CD3 stimulation (Figure 5.18). After 24 h
anti-CD3 stimulation there was as increase in the number of IL-4 producing
CD3+ T-cells for normal subjects with depleted levels of Vα24+ T-cells, but no
significant change in those CD3+ T-cells producing IFN-γ. The number of IL-4
producing CD3+ T-cells increased by 1.2±0.3 x104 (Figure 5.19). There was no
significant change in IL-4 or IFN-γ intracellular production by CD3+ T-cells of
normal subjects with depleted levels of Vα24+ T-cells after 4 or 24 h in vitro
gluten fraction 3 stimulation (Figure 5.18 and Figure 5.19).
The increase in IL-4 producing CD3+ T-cells as shown in Figure 5.16 was not
observed in normal control subjects with depleted levels of Vα24+ T-cells
(Figure 5.18). This suggests that Vα24+ T-cells were the main source of IL-4,
during the initial stimulation of CD3+ T-cells.
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Figure 5.18 Intracellular IL-4 and IFN-γ cytokine production by blood CD3+ T-cells after 4 h in vitro anti-CD3 (♦) or gluten fraction 3 (◊) stimulation in
normal subjects that have been depleted of Vα24+ cells. Data are given as the change in number (graphed) and percentage (Table) of cytokine producing CD3+ T-cells unstimulated (-) or stimulated (+) for 4 h (n=number of subjects).
Figure 5.19 Intracellular IL-4 and IFN-γ cytokine production by blood CD3+ T-cells after 24 h in vitro anti-CD3 (♦) or gluten fraction 3 (◊) stimulation in
normal subjects that have been depleted of Vα24+ cells. Data are given as the change in number (graphed) and percentage (Table) of cytokine producing CD3+ T-cells unstimulated (-) or stimulated (+) for 24 h (n=number of subjects).
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5.4.10 Comparison of Vα24+ T-cells cytokine production in coeliac
disease
In view of previous studies showing impaired IL-4 production by Vα24+ T-
cells in type 1 diabetes (Wilson et al., 1998), production of IL-4, IL-10, IL-13
and IFN-γ by Vα24+ T-cells was investigated for subjects with coeliac disease.
As shown in Chapter 3, intracellular IL-4 and IL-10 increased for Vα24+ T-
cells, while variable changes in IL-13 and IFN-γ cytokine production after 4 h
in vitro anti-CD3 stimulation for normal subjects. No significant change in the
number of IL-4, IL-10, IL-13 or IFN-γ producing Vα24+ T-cells for coeliac
subjects was observed (Figure 5.20). Vα24+ T-cells were not only deficient in
number but had a functional deficiency of IL-4 and IL-10 production in coeliac
disease.
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Figure 5.20 Intracellular IL-4, IL-10, IL-13 and IFN-γ cytokine production by
circulating Vα24+ T-cells after 4 h in vitro anti-CD3 stimulation in normal
subjects and in subjects with coeliac disease. Data are given as the mean±SEM
change in cytokine producing Vα24+ T-cells after 4 h incubation without (-) or
with (+) anti-CD3 stimulation. Also shown (Table below) are the percentages
of total Vα24+ T-cells that produced cytokines before and after stimulation for
normal subjects and subjects with coeliac disease. Data are given as the change
of cytokine producing Vα24+ T-cells x103 cells/ml and percentage (n=number
of subjects).
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5.4.11 Comparison of iNK T-cells cytokine production in coeliac
disease.
Intracellular IL-4, IL-10, IL-13 and IFN-γ cytokine production by 6B11+ and
Vα24+ α-GalCer/CD1d tetramer+ iNK T-cells was examined after 4 h in vitro
anti-CD3 stimulation for normal subjects and subjects with coeliac disease.
As shown in Chapter 3, intracellular IL-4, IL-10 and IL-13, but not IFN-γ
cytokine production increased for 6B11+ iNK T-cells after in vitro anti-CD3
stimulation for normal subjects. Like circulating Vα24+ T-cells, there was no
significant change in the number of IL-4, IL-10, IL-13 or IFN-γ cytokine
producing 6B11+ iNK T-cells for coeliac subjects after 4 h in vitro anti CD3-
stimulation (Figure 5.21).
Cytokine production by Vα24+ α-GalCer/CD1d tetramer+ iNK T-cells was
detectable even in normal control subjects with low numbers of circulating
Vα24+ α-GalCer/CD1d tetramer+ iNK T-cells (Figure 5.22). There was a
significant increase in the mean number of IL-4 and IL-10 producing Vα24+
α-GalCer/CD1d tetramer+ iNK T-cells of normal subjects after 4 h in vitro
anti-CD3 stimulation as shown in Chapter 3. There was no significant change
in the production of IL-4 or IL-10 by Vα24+ α-GalCer/CD1d tetramer+ iNK
T-cells in subjects with coeliac disease after 4 h in vitro anti-CD3 stimulation.
There was no significant change in IL-13 or IFN-γ production by Vα24+ α-
GalCer/CD1d tetramer+ iNK T-cells in both normal subjects and subjects with
coeliac disease (Figure 5.23).
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Figure 5.21 Intracellular IL-4, IL-10, IL-13 and IFN-γ cytokine production by
circulating 6B11+ iNK T-cells after 4 h in vitro anti-CD3 stimulation in normal
subjects and in subjects with coeliac disease. Data are given as the mean±SEM
change in cytokine producing 6B11+ iNK T-cells after 4 h in vitro incubation
without (-) or with (+) anti-CD3. Also shown (boxed below) are the
percentages of total 6B11+ iNK T-cells that produced cytokines before and
after 4 h in vitro stimulation for normal subjects and subjects with coeliac
disease. Data are given as the change of cytokine producing 6B11+ iNK T-cells
x103 cells/ml and percentage (n=number of subjects).
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Figure 5.22 Comparison of circulating Vα24+ IL-4+ cells that were α-
GalCer/CD1d tetramer+/- for a normal subject with low number of circulating
Vα24 cells and a subject with coeliac disease after 4 h in vitro anti CD3
stimulation.
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Figure 5.23 Intracellular IL-4, IL-10, IL-13 and IFN-γ cytokine production by circulating Vα24+ α-GalCer/CD1d tetramer+ iNK T-cells after 4 h in vitro anti-CD3 stimulation in normal subjects and in subjects with coeliac disease. Data are given as the mean±SEM change in cytokine producing Vα24+ α-GalCer/CD1d tetramer+ iNK T-cells after 4 h in vitro incubation without (-) or with (+) anti-CD3. Also shown (boxed below) are the percentages of total Vα24+ α-GalCer/CD1d tetramer+ iNK T-cells producing cytokines before and after stimulation. Data are given as the change of cytokine producing Vα24+ α-GalCer/CD1d tetramer+ iNK T-cells x103 cells/ml and percentage (n=number of subjects).
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Principal findings of this Chapter
• Coeliac subjects have reduced numbers of circulating:
o CD161+ NK cells (total, bona fide and NK T-like).
o Vα24+ T-cells.
o Vβ11+ T-cells.
o Vα24+ CD4+ T-cells.
o Vα24+ Vβ11+ T-cells.
o Vα24+ CD161+ NK T-cells.
o Vα24+ 6B11+ and Vα24+ Vβ11+ α-GalCer/CD1d tetramer+
iNK T-cells.
• The number of circulating CD94+ NK cells was dependant upon
disease state, as untreated coeliac subjects had lower numbers of
circulating CD94+ NK cells compared to treated coeliac subjects and
normal healthy control subjects.
• Intestinal Vα24+ T-cells were deficient in coeliac disease.
• Coeliac subjects had impaired IL-4 production and increased IFN-γ
production by CD3+ T-cells after 4 h in vitro anti-CD3 stimulation.
• Coeliac subjects had increased in IFN-γ production by CD3+ T-cells
after 24 h in vitro gluten fraction 3 stimulation.
• Coeliac subjects had impaired IL-4, IL-10 and IL-13 production by
Vα24+ T-cells, 6B11+ and Vα24+ α-GalCer/CD1d tetramer+ iNK T-
cells after 4 h in vitro anti-CD3 stimulation.
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5.5 DISCUSSION This Chapter has shown that circulating CD161 NK cells were deficient in
coeliac disease, reduced to approximately 75% of the levels from blood of
normal healthy subjects. Coeliac subjects at diagnosis have reduced numbers of
circulating CD94+ NK cells compared to normal subjects and coeliac subjects
on a GFD. The number of circulating CD94+ NK cells in untreated coeliac
subjects was reduced to 65% of the numbers present in coeliac subjects on a
GFD, yet the number of circulating CD56, CD57 and CD161 NK cells was
independent of diet. The decreased number of circulating CD94+ NK cells in
untreated coeliac subjects can be explained by their localization to the mucosa
as described by Jabri et al. (2000).
Circulating CD56+ NK T-like cells were increased in subjects with coeliac
disease by approximately 60% the levels of normal control subjects. The entire
CD161+ NK lineage (i.e.; total, bona fide and NK T-like) was affected in
coeliac disease. The number of circulating bona fide CD161+ and CD161+ NK
T-like cells were reduced to approximately 80% and 68%, respectively, of the
levels of normal control subjects. Unlike CD94, the deficiency of CD161 was
independent of diet. Chen et al. (1997) have shown that NK1.1 expression is
lost on Vα14+ T-cells after prolonged in vitro stimulation. The work of this
Chapter was unable exclude a similar process for coeliac disease although; re-
suppression in treated coeliac subjects who still had NK T-cell deficiency
would be expected. The functional significance of other NK T-like cells,
especially CD161+ NK T-like cells remains unknown, although this Chapter
has shown they were deficient in coeliac disease. The decrease of circulating
CD161+ NK cells, bona fide CD161+ and CD161+ NK T-like cells may be in
keeping with the increased prevalence of malignancy in coeliac disease (Di
Sabatino et al., 1998a)
Although there was no deficiency in the number of circulating CD3+, CD4+ or
Vβ13+ T-cells there was a selective deficiency of circulating Vα24+ and
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Vβ11+ T-cells in coeliac disease. The mean number of circulating Vα24+ T-
cells was reduced in blood of coeliac subjects to approximately 27% of the
number present in normal subjects. The deficiency of Vα24+ T-cells was
independent of diet, duration of the GFD and was present at all ages. Thus the
deficiency was unlikely to be due to inflammation alone in coeliac disease. In
contrast, Vα24+ T-cells declined with age in control subjects (Chapter 4). The
deficiency of Vα24+ T-cell was not confined to the circulating lymphocytes,
but was present in the small intestine mucosa as shown by decreased Vα24
mRNA expression and immunofluorescence staining.
The number of the SP subset was reduced to 30% of the numbers present in
normal subjects. The co-expression of Vα24 and Vβ11 was also reduced in
coeliac disease. Vα24+ Vβ11+ T-cells were markedly deficient in coeliac
subjects, reduced to 15% of the numbers present in normal subjects. These
results contrast with that of Van der Vliet et al. (2001), who investigated
Vα24+ Vβ11+ T-cells in blood from 10 coeliac subjects and concluded these
cells were not deficient. Their data were distributed in the lower end of their
range for normal subjects. They did not have α-GalCer/CD1d tetramers
available, which are regarded as the gold standard for identifying iNK T-cells,
nor did they investigate the cytokine production by these cells. The work
presented within this Chapter further defined iNK T-cells by the co-expression
of Vα24 and 6B11 as well as Vα24, Vβ11 and α-GalCer/CD1d tetramer+
markers. Invariant NK T-cells were reduced in coeliac subjects to
approximately 9-30% of the numbers present in normal subjects. The loss of
these immunoregulatory iNK T-cells could partly explain the inappropriate
activation of gluten response T-cells that result in intestinal damage in coeliac
disease. The deficiency of Vα24+ T-cells and iNK T-cells in coeliac disease
was independent of age, diet or duration of gluten free diet. I acknowledge that
it is difficult to assess compliance with a gluten-free diet and to ensure full
exclusion of gluten.
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Previous studies have investigated cytokine profiles of both circulating and
intestinal lymphocytes after polyclonal stimulation. While Kerttula et al.
(1999) and Lahat et al. (1999) were able to detect cytokine changes within the
intestinal lymphocytes they found it difficult to determine cytokine profiles in
coeliac subjects (both treated and untreated coeliac subjects). In vitro activation
of peripheral blood was investigated and this demonstrated that circulating
CD3+ T-cells of coeliac subjects produced detectable levels of IL-4 and IFN-γ
cytokines after in vitro anti-CD3 stimulation. This work has shown that
classical CD3+ T-cells from coeliac subjects, although depleted in Vα24+ T-
cells and iNK T-cells, were still able to produce cytokines IL-4 and IFN-γ at
levels, which were lower yet comparable to the levels of normal subjects.
As well as being deficient in coeliac disease, the work of this Chapter has
shown that Vα24+ T-cells, Vα24+ 6B11+ and Vα24+ α-GalCer/CD1d
tetramer+ iNK T-cells were functionally defective after in vitro anti-CD3
stimulation, unlike equivalent cells from normal subjects. A negligible cytokine
response was observed in Vα24+ T-cells, 6B11+ and Vα24+ α-GalCer/CD1d
tetramer+ iNKT-cells from coeliac subjects, although some IL-4, IL-10, IL-13
and IFN-γ intracellular staining was evident prior to stimulation for both
normal and coeliac subjects. Multiple differences in gene expression of IL-4-
null Vα24+ T-cell clone from a human monozygotic twin affected with type I
diabetes has been identified compared to an IL-4 intact Vα24+ T-cell clone
from the other unaffected twin (Wilson et al., 2000). The same may be present
in Vα24+ T-cells and iNK T-cells from coeliac subjects.
Vα24+ T-cells are believed to be immunoregulatory because they direct a Th2
immune response, rather then a Th1 outcome that is associated with coeliac
disease. The Th1 bias was seen in our studies of gluten-stimulation of
conventional CD3 T-cells from coeliac subjects, as production of IFN-γ (a Th1
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cytokine) increased, whereas IL-4 (a Th2 cytokine) increased in similar cells
from normal healthy subjects. The IL-4 produced by normal Vα24+ T-cells
presumably suppresses activation of gluten-stimulated CD3 T-cells in vivo. An
additional mechanism is that Vα24+ T-cells are cytotoxic to antigen-presenting
dendritic cells which otherwise would induce a Th1 response (Nicol et al.,
2000a). Thus, Vα24+ T-cells may be important in preventing development of
coeliac disease in those who are genetically predisposed. What remains
unexplained is how natural glycolipid antigenic stimulation of Vα24+ iNK T-
cells occurs. It is possible that damaged epithelial cells from a viral infection in
the gastrointestinal tract may provide such stimulation. Van der Vliet et al.
(2001) suggest that Vα24+ Vβ11+ immunoregulatory cells are unable to
differentiate and/or proliferate adequately in response to T-cell activation or
cytokine stimulation. This defect might result from either exhaustion or
replicative senescence due to overstimulation, exogenous factors such as viral
infections, since these have repeatedly been implicated in the pathogenesis of
coeliac disease (van der Vliet et al., 2001).
In summary, Vα24 T-cells are deficient in animal models and human
autoimmune disease. It has been shown that autoimmune disease increases
with the duration of coeliac disease from 5.1% at diagnosis of less than 2 years
to 34% at diagnosis at greater than 20 years (Ventura et al., 1999). Ventura et
al. (1999) found that the prevalence of autoimmune disease in all coeliac
subjects was 14% compared to 3% in normal control subjects. This raises the
possibility that both coeliac and autoimmune diseases share a common disease
pathway (i.e., genetic predisposition, Vα24+ T-cell deficiency) or that gluten
exposure in coeliac disease predisposes to autoimmune disease. In relation to
this present Chapter, a possibility might be that gluten exposure causes
progressive Vα24+ T-cell and iNK T-cell deficiency, however this was not
evident. Vα24+ T-cells and iNK T-cells did not decline with age in coeliac
subjects, though they did decrease in normal subjects. There was no significant
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difference in numbers of circulating Vα24 T-cells or iNK T-cells with respect
to diet. Vα24 T-cell and iNK T-cell deficiency was present at the time of
diagnosis and thus likely contributed to the pathogenesis rather than be caused
by coeliac disease. Vα24 T-cell and iNK T-cell deficiency was not confined to
the circulating lymphocytes but also observed at the site of the disorder, within
the small intestine of coeliac subjects. This work shows an association of
coeliac disease and autoimmune disease through a common deficiency of
Vα24+, Vα24+ Vβ11+ T-cells, Vα24+ 6B11+ and Vα24+ Vβ11+ α-
GalCer/CD1d tetramer+ iNK T-cells.
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6 Chapter 6 NK, T and NK T-cells in IBD
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6.1 INTRODUCTION The pathogenesis of ulcerative colitis and Crohn’s disease seems to be due
primarily due to a loss of immunoregulation resulting from a combination of
genetic and environmental factors. There is loss of immunoregulation to
luminal bacterial antigens in both Crohn’s disease and ulcerative colitis
(Duchmann et al., 1995b; Kraus et al., 2004a; Kraus et al., 2004b; MacDonald,
1995). The inflammation involved with Crohn’s disease is due to an
inappropriate T-cell response to endogenous bacterial antigens (Duchmann et
al., 1995a; Lodes et al., 2004; MacDonald, 1995; Targan et al., 2005). In
Crohn’s disease there is an exaggerated response to bacterial flagellin antigens
(Lodes et al., 2004), with an increased expression of Th1 cytokines by lamina
propria cells (Cobrin and Abreu, 2005) although recent data indicate that IL-17
may also be pro-inflammatory (Seiderer et al., 2007). Inflammation in
ulcerative colitis is more complex and involves both T-cell and neutrophil
mediated responses (Olives et al., 1997; Targan, 1998). The immune response
in ulcerative colitis is less well defined but includes an atypical Th2 response
from a non-invariant NK T-cell producing IL-13, possibly mixed with an
Arthus reaction with immune complex activation and neutrophil recruitment
(Fuss et al., 2004; Heller et al., 2005; Mayer, 2005). An unexplained feature of
both Crohn’s disease and ulcerative colitis is low or absent mucosal expression
of IL-4 (Karttunnen et al., 1994).
The basis of this work originated from the deficiency of Vα24 T-cells in
autoimmune diseases (Baxter et al., 1997; Maeda et al., 1999; Sumida et al.,
1995; Wilson et al., 1998). A preliminary study by van der Vliet et al (2001)
showed that Vα24+ Vβ11+ T-cells are deficient in Crohn’s disease and
ulcerative colitis. This deficiency of NK T-cells could contribute to the loss of
immunoregulation of the gut-associated immune response to commensal
bacteria. The deficiency of immunoregulatory NK T-cells could identify new
targets for IBD therapy.
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6.2 AIMS AND HYPOTHESIS The aim of this Chapter was to investigate the number of circulating NK cells,
T-cells, NK T-like and iNK T-cells in IBD. Cytokine production by Vα24+ T-
cells and iNK T-cells after in vitro anti-CD3 and PMA:ionomycin stimulation
were examined and compared to cytokine production by CD3+ T-cells after in
vitro anti-CD3 and PMA:ionomycin stimulation in normal subjects and
subjects with IBD.
The hypothesis of this Chapter is that a deficiency of NK cells,
immunoregulatory T-cells, NK T-like cells and/or iNK T-cells could explain
loss of immunoregulation in IBD.
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6.3 MATERIALS AND METHODS
6.3.1 Subjects Subjects with IBD were recruited from those attending the Department of
Gastroenterology and Hepatology, The North West Adelaide Health Service at
The Queen Elizabeth and Lyell McEwin Hospitals, as well as from those who
responded to an invitation in the newsletter of the Crohn’s and Colitis
Association of South Australia. Only those with a verified diagnosis of either
Crohn’s disease or ulcerative colitis were recruited. A total of 97 subjects with
Crohn’s disease, 68 subjects with ulcerative colitis and 156 subjects who were
healthy (apart from non-ulcer dyspepsia) were recruited. Crohn’s patients were
divided into those who only had disease of the small intestine and those who
had large intestinal disease (either alone or with small intestinal involvement).
Where known, disease activity was assessed by bowel frequency, pain, quality
of life and extra intestinal features or by erythrocyte sedimentation rate and C-
reactive protein levels. Blood was collected for flow cytometry and for a
complete blood examination. Members of the normal control group were also
used in previous Chapters. This study had ethical permission from the Human
Ethics’ Committee of the North West Adelaide Health Service.
6.3.2 Flow cytometry Peripheral blood lymphocytes were collected and stained using antibodies
directed against the CD56, CD57, CD94 and CD161 NK markers and CD3,
CD4, Vα24, Vβ11, Vβ13 T-cells or 6B11 iNK T-cell markers as previously
described in Chapter 2. α-GalCer/CD1d tetramer binding to ligand Vα24+
Vβ11+ was examined as previously described in Chapter 2.
autoimmune encephalomyelitis and IBD (Naumov et al., 2001; Saubermann et
al., 2000; Wang et al., 2001; Yang et al., 2003; Zeng et al., 2003). NK T-cells
exert a protective effect in the TNBS and DSS induced colitis model.
Stimulation of iNK T-cells by α-galactosylceramide has a protective effect and
the adoptive transfet of NK T-cells reduces inflammation in the DSS model of
colitis (Saubermann et al., 2000). Likewise, the adoptive transfer of ex vivo
colitis-extracted protein-pulsed NKT cells reduced inflammation in the TNBS-
induced model (Shibolet et al., 2004). The same may be possible in humans
with coeliac disease, Crohn’s disease, ulcerative colitis and autoimmune
disorders. Saubermann et al., (2000) also showed that CD1d knock out mice
did not benefit from α-galactosylceramide treatment nor did mice with
depleted levels of NK T-cells. Taken together, suggests that NK T-cells may be
a target for future therapies.
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204
The affect iNK T-cell manipulation has on human autoimmune disorders and
inflammatory diseases remains unknown. Further investigations are warranted
in these diseases such as repleating iNKT-cells from normal subjects in an in
vitro suppression cell assay using mixed lymphocyte culture. The manipulation
of iNK T-cells for the therapeutic intervention of coeliac disease, ulcerative
colitis, Crohn’s disease, type 1 diabetes, rheumatoid arthritis, as well as other
autoimmune and inflammatory disorders may be possible, however more
extensive work is required.
Appendix Randall Grose
205
8 APPENDIX
Appendix Randall Grose
206
8.1 APPENDIX 1: Publications arising from this thesis
8.1.1 R H. Grose, A G. Cummins, and F M. Thompson. Deficiency
of invariant NK T-cells in coeliac disease. Gut, 2007; 56:
790-795.
Appendix Randall Grose
207
A Grose, R.H., Cummins, A.G. & Thompson, F.M. (2007) Deficiency of invariant NK T-cells in coeliac disease. Gut, v. 56, pp. 790-795
A NOTE:
This publication is included on pages 207-209 in the print copy of the thesis held in the University of Adelaide Library.
A It is also available online to authorised users at:
A http://dx.doi.org/10.1136/gut.2006.095307
A
Appendix Randall Grose
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8.1.2 R H. Grose, F M. Thompson, A G. Baxter, D G. Pellicci and
A G. Cummins. Deficiency of invariant NK T-cells in
Crohn’s disease and ulcerative colitis. Dig Dis Sci, 2007; 52:
1415-1422.
Appendix Randall Grose
211
A Grose, R.H., Thompson, F.M., Baxter, A.G., Pellicci, D.G. & Cummins, A.G. (2007) Deficiency of invariant NK T-cells in Crohn’s disease and ulcerative colitis. Digestive Diseases and Sciences, v. 52 (6), pp. 1415-1422
A NOTE:
This publication is included on pages 211-214 in the print copy of the thesis held in the University of Adelaide Library.
A It is also available online to authorised users at:
A http://dx.doi.org/10.1007/s10620-006-9261-7
A
Appendix Randall Grose
215
8.1.3 R H. Grose, A G. Cummins, and F M. Thompson. Deficiency
of 6B11+ invariant NK T-cells in celiac disease (accepted for
publication in Digestive Diseases and Sciences, 2007).
Appendix Randall Grose
�
� ��6�
��
A Grose, R.H., Cummins, A.G. & Thompson, F.M. (2007) Deficiency of 6B11+ Invariant NK T-cells in celiac disease. Digestive Diseases and Sciences, v. 53 (7), pp. 1846-1851
A NOTE:
This publication is included on pages 216-218 in the print copy of the thesis held in the University of Adelaide Library.
A It is also available online to authorised users at:
A http://dx.doi.org/10.1007/s10620-007-0093-x
A
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