ELITE NETZWERK BAYERN

English  Sprachen Icon  |  Gebärdensprache  |  Leichte Sprache  |  Kontakt


Forschungsarbeit

Regulatory T cell infiltration in ulcerative colitis is mediated by

specific chemokines

By Dominik Lisowski (13.01.2015)

Millions of leucocytes are produced every single day in the human body and released into the blood. Their main function is to defend the body against infectious disease and foreign materials. An important requirement for proper functioning of leucocytes is the discrimination between self and non-self tissue. The ability of leucocytes to recognize self tissue and not to be activated by it is called immunologic tolerance.

There is substantial evidence that naturally arising CD25+CD4+ regulatory T (Treg) cells, most of which are produced by the normal thymus as a functionally mature T-cell subpopulation, are essential for maintaining immunologic self-tolerance in the periphery [1]. They are powerful inhibitors of T-cell activation both in vivo and in vitro [2-4]. On the one hand regulatory T cells, hence, play a key role in preventing autoimmune diseases and limiting chronic inflammatory diseases. On the other hand they are responsible for tumor immunity by suppressing the development of effective T cell mediated anti-tumor responses. Thus downregulation of these cells might be beneficial for the enhancement of immunologic responses against tumors and a promising cancer immunotherapeutic approach of vaccines that are specific for tumor antigens.

In order to suppress effective T cell responses in a tissue effectively, regulatory T cells have to infiltrate the tissue and accumulate. For this purpose they are reliant on chemokine-driven mechanisms.

Concentrating on chronic inflammatory diseases, firstly, we induced ulcerative colitis in mice by administering dextran sodium sulfate orally. With a set of experiments our main goal was to find out (a) whether regulatory T cells infiltrate the large intestines in the state of chronic inflammation and (b) which chemokines recruit them.

For that we tagged Tregs with a special FoxP3 antibody and analyzed the paraffin embedded colons of treated and untreated mice. Moreover, we measured various chemokine concentrations in the large intestines by Enzyme-linked Immunosorbent Assay (ELISA). Previous research results and publications suggested that the high levels of the chemokines CCL5, CCL17, CCL22 and CCL28 might play a crucial role in the chemotaxis of Tregs [5-10].

Therefore in vitro migration essays with regulatory T cells were conducted in order to determine the chemotaxis of regulatory T cells in respect to different chemokine concentrations.

Our study found that in the intestinal mucosa in treated mice, FoxP3 was highly expressed, suggesting that Treg may be actively recruited to the intestinal mucosa in order to suppress proinflammatory immune responses. Moreover, our results suggested that CCL1, CCL22 and CCL27 are potential candidates for recruitment of regulatory T cells in ulcerative colitis. Especially CCL22 seem to play a crucial role in Treg infiltration as described in other papers previously [9-12].

Future experiments with the murine anti-CCR4 monoclonal antibody might confirm our results and support our hypothesis. Upregulation of chemokines might mediate a stronger infiltration of Tregs in inflammatory tissues and may, hence, have therapeutic efficacy in ulcerative colitis and Crohn’s disease.


References

1. Sakaguchi, S., Naturally arising CD4+ regulatory t cells for immunologic self-tolerance and negative control of immune responses. Annu Rev Immunol, 2004. 22: p. 531-62.

2. Wood, K.J. and S. Sakaguchi, Regulatory T cells in transplantation tolerance. Nat Rev Immunol, 2003. 3(3): p. 199-210.

3. Yamaguchi, T. and S. Sakaguchi, Regulatory T cells in immune surveillance and treatment of cancer. Semin Cancer Biol, 2006. 16(2): p. 115-23.

4. von Boehmer, H., Mechanisms of suppression by suppressor T cells. Nat Immunol, 2005. 6(4): p. 338-44.

5. Facciabene, A., et al., Tumour hypoxia promotes tolerance and angiogenesis via CCL28 and T(reg) cells. Nature, 2011. 475(7355): p. 226-30.

6. Tan, M.C., et al., Disruption of CCR5-dependent homing of regulatory T cells inhibits tumor growth in a murine model of pancreatic cancer. J Immunol, 2009. 182(3): p. 1746-55.

7. Scrivener, S., et al., Abnormal T-cell function in B-cell chronic lymphocytic leukaemia. Leuk Lymphoma, 2003. 44(3): p. 383-9.

8. Ishida, T., et al., Clinical significance of CCR4 expression in adult T-cell leukemia/lymphoma: its close association with skin involvement and unfavorable outcome. Clin Cancer Res, 2003. 9(10 Pt 1): p. 3625-34.

9. Curiel, T.J., et al., Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med, 2004. 10(9): p. 942-9.

10. Ishida, T., et al., The CC chemokine receptor 4 as a novel specific molecular target for immunotherapy in adult T-Cell leukemia/lymphoma. Clin Cancer Res, 2004. 10(22): p. 7529-39.

11. Montane, J., et al., Prevention of murine autoimmune diabetes by CCL22-mediated Treg recruitment to the pancreatic islets. J Clin Invest, 2011. 121(8): p. 3024-8.

12. Menetrier-Caux, C., et al., Innate immune recognition of breast tumor cells mediates CCL22 secretion favoring Treg recruitment within tumor environment. Oncoimmunology, 2012. 1(5): p. 759-761.


Wissenschaftlicher Werdegang
  • seit 2013
  • Doktorand in der Klinischen Pharmakologie, LMU München
  • seit 2012
  • Studium der Humanmedizin an der Technischen Universität München
  • 2010-2012
  • Studium der Humanmedizin an der Ludwig-Maximilians Universität München

Auszeichnungen und Stipendien
  • * Stipendium im Rahmen des Graduiertenkollegs 1202 der Deutschen Forschungsgemeinschaft (seit 2013)
  • * Stipendium des Max Weber-Programms (seit 2010)
  • * Stipendium der Konrad-Adenauer-Stiftung (seit 2010)
  • * DMV-Abiturpreis 2010 für herausragende Abiturleistungen (2010)