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The Discovery of Regulatory T Cells and Colon Cancer – Enhances Prospects for Future Immunotherapy

The Discovery of Regulatory T Cells and Colon Cancer – Enhances Prospects for Future Immunotherapy

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The materialization of a tumour is a consequence of trouble with the control of cell growth and failure of the immune response. It is believed that Regulatory T Cells have a vital role in preventing the Immune System from eradicating cancerous tumour cells and this suppression of the immune response can be avoided using different treatments.
The materialization of a tumour is a consequence of trouble with the control of cell growth and failure of the immune response. It is believed that Regulatory T Cells have a vital role in preventing the Immune System from eradicating cancerous tumour cells and this suppression of the immune response can be avoided using different treatments.

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Published by: Undergraduate Awards on Sep 01, 2012
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05/13/2014

 
The Discovery of Regulatory T Cells and Colon Cancer
 –
 Enhances Prospects for Future ImmunotherapyIntroduction
“Colorectal cancer is the fourth most commonly diagnosed malignant disease with an
estimated 1 million new cases and over 500,000 deaths each year worldwide and involvescancerous growths in the colon, rectum and appendix (Clarke
et al.,
2006). Thematerialization of a tumour is a consequence of trouble with the control of cell growth andfailure of the immune response to launch an adequate assault on the cancerous cells (Wolf 
et al,
2003).T cells develop in the thymus and are lymphocytes employed by the Immune System tocombat infection. T Cells that are self-reactive are destroyed by a process known as
negative selection
. Some T Cells evade this process but are suppressed by Regulatory TCells in the periphery. Tregs thus take
care of this “balance betwee
n immunity and
tolerance”, and
have an essential role to play in autoimmune diseases such as Colon Cancer(Pfoertner
et al.,
2006).It is believed that Regulatory T Cells have a vital role in preventing the Immune System fromeradicating cancerous tumour cells and this suppression of the immune response can beavoided using different treatments discussed below (Loddenkemper
et al.,
2006). Onemethod Tregs use to suppress the immune system is by secreting tumour growth factor(TGF)-
β
, a cytokine that can repress the immune response aiding in the progression of thecancer (Woo
et al.,
2001). Other Tregs can exert their immunosuppression of other T cells bycell-to-cell contact (Sasada
et al.,
2003). Tregs can also produce Interleukin-10 (IL-10) whichhas been shown to have the ability to prevent the stimulation and proliferation of the
Immune System’s T cells
(Asseman
et al.,
1999). Robert North demonstrated that there is amassive expansion of CD4+ Tregs when tumour cells are planted in normal mice which thenenhanced tumour expansion by inhibiting T Cells from suppressing the cancerous cells(Awwad
et al 
, 1988).Tregs have been shown to suppress anti-tumour immune responses in murine models. Theexistence of CD4+CD25+ Tregs can obstruct the production of T cells (Ni Choileain
et al.,
2005) and a reduction of CD4+CD25+ Tregs has inhibited the growth of the tumour in mice(Ling
et al.,
2007).
The verification that the removal of Tregs increases a patient’s immunityto a tumour implies that these cells do have an essential role to play in the body’s tolerance
to cancerous cells (Sasada
et al.,
2003).
 
Discussion:Precursors that give rise to Tregs & how T cells can be converted to Tregs
Naturally occurring Regulatory T Cells compose 2-3% of CD4+ T cells and are formed in thethymus. CD4+ T cells can be transformed into Tregs depending on the cytokines present, bythe potency of signals supplied by antigen presenting cells (APCs) and the affinity of thereceptors on the T cells to antigens (Ni Choileain
et al.,
2005).One group of Tregs, that express FOXP3 require major histocompatibility class II (MHCII),interleukin 2 and CD28 for their correct formation. FOXP3-negative CD4+ T cells might alsobe converted to FOXP3 expressing Tregs by tum
our growth factor β
(TGF-
β) and
prostaglandin E2 (Sharma
et al,
2005). FOXP3 is a significant T cell transcription factor andalso has the ability to convert naive T cells into CD4+CD25+ Tregs (Sasada
et al.,
2003).Naive CD4+CD25- or CD8+CD25- T cells can be transformed into Tregs when they arepresented with IL-10 and TGF-
β by immature dendritic
cells (Pfoertner
et al.,
2006). T-helper-1 (Th1) and T-helper-2 (Th2) cells can be converted to T-regulatory-2 cells whenpresented with IL-2 and TGF-
β
. Naive T cells can be transformed into T-regulatory-1 cellswhen stimulated by Vitamin D3 and dexamethasone
in vitro
(Ni Choileain
et al.,
2005).
Subgroups and the different types of Regulatory T cells
 There are numerous types of Regulatory T Cells. Those that occur naturally express CD25 (aninterleukin-2 receptor) and FOXP3 (Forkhead box P3) (Ni Choileain
et al.,
2005). Tregs thatexpress the CD25 receptor are highly suppressive
in vivo
and
in vitro
(Sasada
et al.,
2003).Tregs derived from naive CD4+ T cells can be further subdivided into T-regulatory-1 (Tr1), T-regulatory-2 (Tr2), T-helper-1 (Th1) and T-helper-2 (Th2) cells depending on the cytokinesthey produce. Tr1 and Tr2 cells mainly produce IL-10 and TGF-
β
. Due to the similaritiesbetween Tr-1 and Th-3, in the suppressive cytokines they produce and in their similarphenotypes it is likely they develop from the same population (Ni Choileain
et al.,
2005).A common feature of subgroups of Tregs is their capacity to suppress an immune responseboth
in vivo
and
in vitro
. Tr1 cells are capable of suppressing other T cells within
in vivo
and
in vitro
testing (Ni Choileain
et al.,
2005).CD4+CD25+ Tregs are the best studied of all the subgroups of Tregs (Ling
et al.,
2007) andrepresent less than 5% of CD4+ T-cells in humans (Ni Choileain
et al.,
2005). CD8+ Tregs alsoexist (Pfoertner
et al.,
2006).
 
Are the Suppressive effects of Regulatory T Cells antigen-specific or in response tocytokines?
 During
in vitro
studies, it has been shown that Tregs are not antigen-specific and theirsuppressive functions can be invalidated by the use of IL-2.
In Vitro
Tregs are not influencedby the disabling of TGF-
β, IL
-4 or IL-10 proving that the suppressive function of Tregs isdependent on cytokines (Ni Choileain
et al.,
2005).
Tests have been performed on ‘tumour
-
bearing’ murine models and it has been shown that
dendritic cells cause Tregs to increase in numbers. The same results were obtained in
‘tumour
-
free’ models when th
ey were incubated with the supernatants of tumour cells.Also, this proliferation was shown to be prevented using anti-TGF-
β
antibodies. The results,that the Tregs react to the presence of tumour antigen and that they react to the presenceof TFG-
β,
show that Tregs are both antigen-specific and act in response to the presence of cytokines
in vivo
(Clarke
et al.,
2006).

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