Understanding Diseases to Optimize Transfusion Practice
Dr. Branch’s research aims to understand the pathogenesis and functioning of cells in various diseases that require blood transfusion products and related biologics. In particular, Dr. Branch studies mononuclear phagocytes to understand and inhibit the phagocytosis function of these cells in autoimmune diseases and, using animal models of autoimmune diseases, the mechanism of amelioration by intravenous immunoglobulin (IVIg) therapies.
Understanding the cellular and molecular mechanisms associated with autoimmune diseases and mechanism of IVIg therapy should provide new treatment strategies.
Dr. Branch’s laboratory studies IVIg’s use as a therapy for immune thrombocytopenia (ITP) and other autoimmune/inflammatory diseases. Using mouse models, the group is studying the mechanisms of action of IVIg in ITP, in rheumatoid arthritis, Alzheimer’s disease and multiple sclerosis. Most recently, his group studied the relevance of various mouse models of ITP by studying their response to IVIg treatment and has reported on a novel mechanism of action for IVIg - the induction of a signaling molecule called interleukin (IL)-11. This discovery has led to his proposing a unifying theory of IVIg-induced IL-11 to explain all clinical effects of IVIg treatment. The group is also developing small molecule inhibitors of phagocytosis as well as examining recombinant hexamer Fc proteins as alternatives to IVIg which should provide hope for a new class of drugs for the treatment of ITP.
Purohit MK, Chakka SK, Scovell I, Neschadim A, Bello AM, Salum N, Katsman Y, Bareau MC, Branch DR, Kotra LP: Structure-activity relationships of pyrazole derivatives as potential therapeutics for immune thrombcytopenias. Bioorg Med Chem 2014; 22:2739-2752.
Figueiredo CA, Drohomyrecky P, Ma X-Z, Leontyev, D, BranchDR, Dunn SE: Optimal attenuation of experimental autoimmune encephalomyelitis by intravenous immunoglobulin requires interleukin-11 signaling. PLoS One 2014; 9:e101947.
Campbell IK, Miescher S, Branch DR, Mott PJ, Lazarus AH, Han D, Maraskovsky E, Zuercher AW, Neschadim A, Leontyev D, McKenzie BS, Kaesermann F: Theapreutic effect of IVIG on inflammatory arthritis in mice is dependent on the Fc portion and independent of silaylation or basophils. J Immunol 2014; 192:5031-5038.
von Gunten S, Shoenfeld Y, Blank M, Branch DR, Vassilev T, Kaesermann F, Babyry J, Kaveri S, Simon HU: IVIG pluripotency and the concept of Fc-sialylation: challenges to the scientist. Nat Rev Immunol 2014; 14:349.
Neschadim A, Branch DR: Mouse models of autoimmune diseases: immune thrombocytopenia. Curr Pharm Des 2015; 21:2487-2497.
Signaling in HIV/AIDS Pathogenesis and Disease Resistance and Investigation of Novel Therapies
Dr. Branch is applying his expertise in cell signaling to the study of HIV and has identified new targets for HIV/ Acquired Immune Deficiency Syndrome (AIDS) therapy. Why is this important? Understanding the signaling pathways used by HIV and identifying novel ways to interfere with viral signaling could lead to better treatment options for patients with HIV/AIDS and other viral diseases.
Dr. Branch’s team is investigating the potential efficacy of animal and/or human studies to determine if these new targets can be successfully used for treatment modalities. The team has described a new approach to vaccine development that could eventually result in the provision of necessary immunity to the vast population of people exposed to HIV. The team has also identified a neuroendocrine receptor family, known as VPAC, which has one member, VPAC1, which binds to HIV and signals to facilitate the infection and another, VPAC2, which can be externally activated to send an inhibitory signal to stop HIV infection. The team is working to further understand the role of signaling through this VPAC family of neuroendocrine receptors on HIV/AIDS infection and resistance to infection. Other interests include the function of protein tyrosine kinases in HIV infection and drug discovery for small molecular weight molecules that block HIV fusion. Dr. Branch is also interested in repurposing approved drugs for the treatment of both HIV/AIDS and Ebola virus disease and has contributed much to this intense area of research.
Veljkovic V, Glisic S, Muller CP, Scotch M,Branch DR, Perovic VR, Sencanski M, Veljkovic N, Colombatti A: In silico analysis suggests interaction between Ebola virus and the extracellular matrix. Front Microbiol 2015; 6:13.
Veljkovic V, Loiseau PM, Figadere B, Glisic S, Veljkovic N, Perovic VR, Cavanaugh DP, Branch DR: Virtual screening for repurposing approved and experimental drugs for candidate inhibitors of EBOLA virus infection. F1000Res 2015; 4:34.
Signal Transduction and Signaling Abnormalities in Malignancies
Understanding abnormal cell signaling in cancers and proliferative diseases helps to shed light on how these diseases develop and progress. This research aims to develop new strategies to treat cancers and proliferative diseases. Better treatment options for cancer patients could reduce the transfusion needs of these patients. In addition, work done on the role of c-Src in B-cell proliferation could be used to increase the production of monoclonal antibodies used in transfusion services for blood antigen testing.
Dr. Branch’s work focuses on the role of the Src family of protein tyrosine kinases and the SHP-1 protein tyrosine phosphatase in disease signaling. Dr. Branch’s team was the first to identify c-Src protein expression in primary human T- and B cells following activation to a proliferative state and has shown that c-Src expression correlates directly with this proliferation and may be required for these cells to multiply. The lab has shown that SHP-1 acts as a tumour suppressor protein in hematopoietic cells and that abnormal forms of this protein produced through alternative-splicing may be involved in breast and other epithelial cancers.
Wang Q, Rajshankar D, Branch DR, Abreu MTH, Downey GP, McCulloch CA: Protein tyrosine phosphatase-a and Src functionally link focal adhesions to the endoplasmic reticulum to mediate IL-1 signaling. J. Biol. Chem. 2009; 284:20763-20772.
Cayer M-P, Proulx M, Ma X-Z, Sakac D, Giguere J-F, Drouin M, Neron S, Branch DR, Jung D: c-Src tyrosine kinase co-associates with and phosphorylates STAT5b which mediates the proliferation of normal human B lymphocytes. Clin Exp Immunol 2009; 156:419-427.