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TNBS-COLITIS. CHARACTERISTICS, TREATMENT UND MECHANISM
Jabborov Sherbek Otabek o’g’li
Asian International University, Bukhara, Uzbekistan.
https://doi.org/10.5281/zenodo.15227519
Abstract
. Disease states, such as the occurrence of gastrointestinal inflammation
(Crohn’s disease and ulcerative colitis), can be secondary to a host of determinants that act in
conjunction to bring about pathologic change. The underlying factors that mediate the
development of such mucosal inflammation has recently been brought to the forefront with the
advent of animal models. The examination of these animal models have given researchers a
better understanding of the mechanisms involved in the pathogenesis of inflammatory bowel
disease. This review discusses one such model, TNBS-colitis, and the insights that it provides into
the occurrence of IBD and its future treatment.
Keywords:
Inflammatory bowel disease; Experimental colitis; Interleukin-1.
TNBS-КОЛИТ. ХАРАКТЕРИСТИКИ, ЛЕЧЕНИЕ И МЕХАНИЗМ
Аннотация.
Болезненные состояния, такие как возникновение желудочно-
кишечного воспаления (болезнь Крона и язвенный колит), могут быть вторичными по
отношению к множеству детерминант, которые действуют совместно, вызывая
патологические изменения. Основные факторы, которые опосредуют развитие такого
воспаления слизистой оболочки, недавно были выдвинуты на первый план с появлением
животных моделей. Изучение этих животных моделей дало исследователям лучшее
понимание механизмов, вовлеченных в патогенез воспалительного заболевания кишечника.
В этом обзоре обсуждается одна из таких моделей, TNBS-колит, и понимание, которое
она дает относительно возникновения ВЗК и его будущего лечения.
Ключевые слова:
Воспалительное заболевание кишечника; Экспериментальный
колит; Интерлейкин-1.
INTRODUCTION
In recent years, a number of murine models of chronic colitis have been developed
which are remarkably similar to one or another form of human inflammatory bowel disease. As
such, these models provide an excellent opportunity to study the immunopathogenesis and
possible treatment of these idiopathic diseases. One such model is TNBS-colitis, a chronic colitis
in mice induced by the intra-rectal administration of trinitrobenzene sulfonic acid (TNBS). In the
following section we shall discuss our recent studies of this model and show how these studies
have led to new insights into the immunologic mechanism underlying Crohn’s disease.
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CHARACTERISTICS OF TNBS -COLITIS
Characteristics of TNBS colitis TNBS is a classical skin contactant (a chemical
compound that induces delayed hypersensitivity reactions when applied to the skin), because it
haptenates proteins with TNP groups and renders such self-proteins immunogenic. It is induced
in SJL/J mice and a few other mouse strains, by the intrarectal instillation of an ethanolic
solution of TNBS, and is characterized by severe colonic inflammation, which increases over 2
weeks and culminates either in the death of the animal or in partial recovery with long-term low-
grade inflammation.
Clinical characteristics of this induced disease include diarrhea, wasting, rectal prolapse,
a scruffy coat, and a hunched over habitus. As shown, this is accompanied on the
histopathological level by a dense transmural mononuclear cell infiltration, loss of normal crypt
architecture, and occasional granuloma formation; in short, a pattern not dissimilar to that of
Crohn’s disease. One important difference between skin contact hypersensitivity and TNBS-
induced colitis is that in the skin the reaction is self-limited, whereas in the colon the reaction is
persistent. This is likely due to the fact that the effector immune cells called forth by TNBS
cross-react with ubiquitous mucosal antigens and thus continue to be stimulated even after the
TNP-haptenated proteins have disappeared. There are several pieces of evidence in support of
this view. First, as previously mentioned, if lamina propria T cells in a mouse with TNBS colitis
are transferred to a naïve mouse, they cause definite colitis in the recipients. Since antigen is not
transferred with such T cells, this reaction is probably due to a cross-reactivity with anti gens
encountered in the mucosal environment of the new host. Second, IL-2 deficient mice, which
have been shown to develop spontaneous colitis under certain circumstances, can be induced to
develop colitis within days by the systemic injection of trinitrophenyl keyhole limpet
hemocyanin (TNP KLH). This suggests that T cells stimulated by TNP can traffic to the gut,
where they encounter cross-reactive antigens and induce colitis. Third, it has recently been
shown that T cells from mice with TNBS colitis proliferate in response to exposure from their
own flora whereas normal mice do not. This finding implies that in the normal situation a mouse
is “tolerant” to its own flora while such tolerance is broken in TNBS colitis.
TREATMENT OF TNBS-COLITIS
One of the predictions of this proposed sequence of events underlying TNBS-colitis is
that the latter should be treatable by the systemic administration of antibodies (or other agents)
that interfere with the sequence at any one of several stages: in particular, it should be treatable
by the systemic administration of anti-IL-12. To formally test this possibility we administered
anti-IL-12 to mice either at the same time as TNBS was administered per rectum or after two to
three weeks following such administration.
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As shown in, these treatment regimens were remarkably effective in that they either
completely prevented the development of TNBS-colitis (when given at the time of induction of
the disease) or led to dramatic resolution of the TNBS- colitis (when given when the lesion was
fully developed). These studies, in showing that a murine model resembling Crohn’s disease is
treatablewith anti-IL-12, imply that Crohn’s disease itself is also treatable in this fashion.
On the basis of this possibility, we are currently planning to test “humanized” anti-IL-12
in clinical trials of patients with crohn’s disease (see further discussion below). While the
blocking of IL-12 activity with anti-IL-12 may be an efficient way of interrupting the Thl T cell
activation pathway necessary for TNBScolitis, it is certainly not the only way the latter can be
accomplished.
As indicated above, the critical APC-T cell inter- actions leading to Thl T cell
differentiation requires T cell expression of CD4OL on activated T cells and signaling of APC
via CD40 for production of IL-12. Thus, it is theoretically possible to interfere with Thl T cell
differentiation by blocking the CD40LXD40 interaction. To test this possibility, we administered
anti-CD40L antidiv to mice at the time of TNBS-colitis induction with intra-rectal TNBS
administration. Such treatment did indeed prevent colitis induction as well as the increased IFN--
y production in the lamina propria associated with colitis and thus is a second avenue available
for the prevention of TNBS-colitis. Whether anti-CD40L can also be used to treat ongoing
TNBS-colitis as can anti-IL-12 awaits further study. Another way the Thl pathway can be
experimentally thwarted in the context of the TNBScolitis model would be to inhibit more distal
inflammatory cytokine effects, either by the administration of anti- IFN-y or anti-TNF-a. In
studies relevant to this possibility we found that anti-IFN-7 also inhibited the development of
colitis, although such inhibition was not as effective as that achieved with anti-IL-12. Thus,
while prevention of TNBS-colitis was inhibitable with a single injection of anti-IL-12,
prevention of colitis with anti-IFN-7 required multiple injections and was, in general, not as
complete. In addition, wherein mice cured of colitis with anti-IL-12 were not subject to re-
induction of colitis with sub-colitis-inducing doses of TNBS, mice cured of colitis with anti-IFN-
y were subject to such colitis-induction. This suggests that anti-12-14-treated mice no longer
have cells reactive with colitis whereas anti-IFN treated mice have such cells. Important
confirmation of this possibility has recently come from the observation that mice with TNBS-
colitis treated with anti-IL-12 dis- play large numbers of apoptotic cells in the inflamed colons
whereas the same mice treated with display only modest numbers of apoptotic cells at this site.
Overall, then, these studies strongly suggest.
THE MECHANISM OF TNBS-COLITIS
So far in our discussion we have discussed the “how” of TNBS-colitis but not the “why”.
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In our approach to this question, we were aware of the fact that mucosal responses are
normally under the strict control counter-regulatory responses known collectively as ”oral
tolerance”. By such responses, encounters between the mucosal immune system and mucosal
antigens normally result in tolerance rather than immunity and thus the mucosal immune system
is spared of responses that could lead to autoimmunity and/or inflammation. Thus, it seemed
possible that TNBS colitis arises because the administration of TNBS per rectum bypasses or
subverts the oral tolerance mechanism. In our studies of the role of oral tolerance (or lack
thereof) in TNBS-colitis, we took note of the fact that oral tolerance is now known to be due to
two independent but interacting processes, the induction of suppressor T cells producing TGF-P
(and perhaps other suppressive cytokines) and the induction of clonal deletion and/or anergy. In
first of these, the induction of suppressor T cells, is the dominant mechanism of tolerance at low
antigen doses and appears to be dependent on the processing and presentation of antigen to T
cells in the Peyer’s patches. In contrast, the second of these processes, the induction of clonal
deletion or anergy, is the dominant mechanism of tolerance at higher antigen doses and is
dependent on the occurrence of “processed” antigen which induces deletion and or anergy not
only in mucosal tissues but also in other tissues as well. Emerging evidence shows that this
deletional tolerance is independent of suppressor T cell development and the presence of
suppressor cytokines. Finally, we also noted that with respect to oral tolerance mediated by
suppressor T cells, Th2 T cell cytokines (IL-4) appear to favor suppressor T cell development
whereas Thl T cell responses (IFN-y) appears to inhibit the latter.
CONCLUSION
Taken together, these studies suggest that a ying/yang relation between Th1 responses on
the one hand and TGF-/3 T cell responses on the other governs whether or not inflammation
develops in the gastrointestinal tract. Thus, in normal individuals, the mucosal response set point
is shifted towards tolerance and non-responsive- ness so that inflammation does not develop in
relation to ordinarily harmless exposure to mucosal antigens. In contrast, in individuals with
inflammatory bowel diseases, Crohn’s disease, the mucosal response set point is shifted toward
responsiveness and we have the development of inflammation. Evidence in favor of this view is
inherent in the recent finding that in Crohn’s disease, just as in TNBS- colitis, there is heightened
reactivity to one’s own bacterial microflora and thus a loss of tolerance to these mucosal
constituents. Future study will be focused on defining the precise mechanisms that determine the
all-important mucosal response set point, the genetically-determined factors that determine
whether or not tolerogenic responses or immunogenic response in the mucosa will be dominant.
Such studies will help to define the fundamental factors which determine why some
individuals develop Crohn’s disease and others do not.
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Meanwhile, work must go forward directed at attempts to treat Crohn’s disease by
addressing the outcome of these funda- mental abnormalities, the Thl T cell final common
pathway.
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