Modulation of Pathogenic B Cells through Inhibition of Phosphatidylinositol 3-Kinases
Abstract
This proposal addresses the FY12 PRMRP topic area on lupus. Lupus is a life threatening disease that primarily affects women. Lupus patients develop antibodies that recognize proteins made by the body. This leads to tissue damage and complexes of the antibodies bound to the proteins can lodge in the kidneys resulting in damage to the filtering capacity of the kidney. The disease is most often managed using drugs that nonspecifically reduce inflammation and suppress the immune system. However that leaves the patient susceptible to other types of infections. Lupus treatment could be improved by specifically targeting the B cells involved in making the self antibodies. This proposal outlines one possible approach that could help solve this problem. B cells express an important signaling molecule called PI3 kinase (PI3K). Activation of this enzyme leads to induction of survival pathways and is needed to promote development of antibodies. Therefore inhibition of PI3 kinase is expected to be beneficial for lupus by impairing survival of the pathogenic B cells and inhibiting their ability to produce antibodies. B cells express a specific form of PI3 kinase called delta. Small molecule inhibitors of the delta isoform have been shown to specifically kill B cell malignancies but leave other cells unaffected. Based on the success of the delta inhibitor in cancer research, it is anticipated that this approach will be particularly useful in lupus. Mice that are genetically predisposed to developing lupus will be treated with the PI3K delta inhibitor to determine if this ameliorates disease. If this works, it will provide an unprecedented level of control to target B cells and affect them by two mechanismssurvival and antibody production.
Document Details
- Document Type
- Technical Report
- Publication Date
- Mar 01, 2016
- Accession Number
- AD1011387
Entities
People
- Paul L. Stein
Organizations
- SRI International