Alpha Omega Alpha Honor Medical Society

2014 Research Abstract

Role for the Alternatively Spliced BAFF Isoform in Patients Without Chronic Graft Versus Host Disease (cGVHD)

Investigator: Sharmistha Rudra

Mentor: Stefanie Sarantopoulos, MD, PhD

Background: Graft versus host disease is a leading cause of morbidity and mortality after hematopoietic stem cell transplant (HCT). GVHD can be acute or chronic. Historically the pathogenesis focus was on T cells, but recently the importance of B cells in chronic GVHD has been highlighted.1,2 One specific factor, BAFF (B cell activating factor) is known to be increased in autoimmune diseases like Sjogren’s, lupus, and recently cGVHD. 3-5 The purpose of the study is to regulate BAFF in two ways—1) therapeutic blockade and 2) blockade with a dominant negative isoform of BAFF (delta 3)—to define BAFF-driven mechanisms of cGVHD.

Methods & Results: For therapeutic blockade of BAFF signaling, the effects of imatinib on phosphorylation of specific signaling molecules were quantitated by flow cytometry. We found that imatinib inhibited the phosphorylation of Bruton’s tyrosine kinase (BTK) and Spleen tyrosine kinase (Syk) in B cells from healthy donors. We anticipated this decrease in B cells of patient samples from phase I-II imatinib clinical trial, but phosphorylation was comparable between pre- and post- imatinib in vivo treatment.

For direct blockade of BAFF, we focused on the delta 3 isoform, named for the spliced out exon 3. We first compared levels in different clinical manifestations and found decreased levels of isoform in cGVHD patients compared to HCT patients who did not develop disease. Then, we attempted to create a tool to study the splice variants caused by four tagged single nucleotide polymorphisms that coincidentally flank exon 3. While three segments were successfully inserted into the plasmid, the last three segments need to be inserted before studying splice variants.

Conclusions: My research shows that while the role of BAFF is complex it remains an important avenue for further research. Understanding how to appropriately target BAFF may provide insights into the pathophysiology of cGVHD.

Last updated: 10/28/2014

Updated on October 28, 2014.

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