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Improvements of immune responses against colorectal cancers and enterotoxins

Ulf Yrlid

Contact Information  |  List of Publications


The epithelial cells lining the intestine are constantly exposed to microbes and subjected to mechanical stress. Therefore, epithelial cells need to be constantly renewed, which increases the risk of accumulation of mutations and subsequent tumor formation. Immune cells persistently survey the intestine to ensure intestinal homeostasis by initiating appropriate immune responses.
 


Dendritic cells are vital for generation of T cells that counteract tumors and microbial pathogens. We have previously shown that subsets of lymph borne dendritic cells have distinct roles in activating T cells in rodent models. We are now applying multicolor histology and flow cytometry for analysis of dendritic cells and T cells in human primary colorectal cancer tissues and liver metastases. We also evaluate the anti-tumor capacity of tumor infiltrating T cells in vitro and with a patient-derived xenograft model in mice.

 

Multicolor staining of colorectal tumor tissue identifying dendritic cells, T cells and macrophages

 

Moreover, T cells activated in secondary lymphoid organs have to make the crucial decision on whether to stay and aid B cells, or re-enter circulation and home to the intestine. With murine transgenic models, we are determining the cellular interactions that regulate these processes, which are critical for intestinal anti-tumor responses and also following oral vaccination.

 
Cholera toxin greatly enhances oral immune responses but also intoxicates intestinal epithelial cells to cause the symptoms of Cholera disease. We have recently demonstrated that Cholera toxin can use a novel set of receptors. This finding could help uncoupling the toxicity of Cholera toxin from the immune activating potential and thereby aid the development of novel antidotes plus strong, yet safe, oral vaccines. In collaboration with Dr. Jen Kohler, UTS Southwestern, Dallas and Prof. Nicole Sampson, Stony Brook, New York, USA, we are now using murine models and primary human epithelial cells to determine the functional role of novel (non-GM1 related) receptors for Cholera toxin.
 


GM1 has long been considered the only receptor for cholera toxin (CT) but when mice lacking expression of GM1 and GM1-like gangliosides (KO) were fed CT this resulted in fluid accumulation in the small intestines and this even occurred at lower doses of CT in KO mice.(Cervin J, et al. (2018) GM1 ganglioside-independent intoxication by Cholera toxin. PLoS Pathog 14(2): e1006862)
 


The research is greatly facilitated by clinical collaborations at Sahlgrenska Hospital and supported by funding from LUA, Vetenskapsrådet, Cancerfonden and subawards from NIH and Familjen Erling-Perssons stiftelse.

We are looking for master students that would like to join the Cholera toxin project.
 

Press-release:
https://sahlgrenska.gu.se/english/research/news-events/news-article//fast-acting-antidote-in-sight-for-cholera-epidemics.cid1556128
 

Group members

Ulf Yrlid, Group leader, Senior Lecturer, Docent
Jakob Cervin, PhD student
Azar Sadat Rezapour Javareshk, PhD student
Frank Liang, Post doc

Sidansvarig: Dan Baeckström|Sidan uppdaterades: 2018-06-29
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