CXCR5 is a chemokine G protein-coupled receptor (GPCR) that is found on the membrane of T follicular helper (TFH) cells, TFH lymphoma, and angioimmunoblastic T-cell lymphoma (AITL). Stromal cells in lymph nodes secrete the agonist for CXCR5, the chemokine CXCL13, leading to recruitment and retention of TFH in the lymph node. TFH lymphoma leads to a more aggressive lymphoma, AITL, both of which secrete CXCL13. The presence of CXCL13 and CXCR5 in the same anatomical compartment can lead to proliferation of THF lymphoma and AITL. The secretion of CXCL13 by follicular stromal cells can also lead to metastasis of these tumors. There has not been any study with CXCR5 antagonists in AITL, which has a 30% survival rate over a five-year period despite aggressive and cytotoxic therapy with no increase in survival for the last two decades.
The aims of this application is to (1) introduce a CXCR5 gene deletion in a mouse model of AITL, (2) develop a biotherapeutic CXCR5 antagonist for testing on the only mouse model of AITL, and (3) quantitate CXCL13 and CXCR5 in human AITL tissues. The CXCR5 gene deletion will be performed using the CRISPR/Cas9 technology, which has transformed in vivo genetic modification in that knockout mice can be produced within 6- 12 weeks at a total cost of less than $10,000. These three specific aims will result in genetic methods to identify the importance of CXCR5 in AITL and CXCL13-Fc antagonist for CXCR5 that can be used to study the effects in mice, and quantitate CXCL13 and CXCR5 to lay the foundation for clinical trials. There are also other biomedical science applications for these antagonists. For example, a number of autoimmune diseases have implicated CXCR5, which could also be tested by antagonists. The successful completion of this project will have significance in basic research and translational research.
CXCR5 is a chemokine G protein-coupled receptor that is found in the aggressive cancer, angioimmunoblastic T-cell lymphoma (AITL), a precursor of follicular T-cell lymphoma or follicular T-cells. These cells as well as stromal cells in follicles secrete the CXCR5 chemokine agonist, CXCL13, leading to possible autocrine proliferation and metastasis. We will investigate the importance of CXCR5 in AITL by knockout CXCR5 in a mouse model of AITL, developing a CXCR5 antagonist to treat the mouse model of AITL, and to quantitate CXCL13 and CXCR5 from sera and tissues of AITL patients.