Assistant Professor of Internal Medicine and
Adjunct Assistant Professor of Microbiology and Immunology
M.D. University of Zagreb School of Medicine
Vedran Radojcic's Lab Page
Vedran Radojcic's PubMed Literature Search
Molecular Biology Program
Transplant immunology, Alloantigen specific T cell responses, Innate immunity and fibrosis
Allogeneic hematopoietic cell transplantation (allo-HCT) is a curative therapy for many hematologic malignancies. Its anti-cancer efficacy relies on the successful immune recognition of antigenic disparity by transplanted donor immune system. Because the antigenic difference is not limited to the cancer, majority of patients still develop immune injury to healthy organs during acute and chronic graft versus host disease (GVHD). Global immunosuppression used to control GVHD injury significantly dampens the anti-tumor properties of the transplant (graft versus tumor - GVT) and in addition carries a high risk of infections and end organ damage. Chronic fibrotic GVHD remains poorly understood and consequently lacks effective therapy.
Our research focuses on adaptive and innate immune responses that define acute and chronic GVHD and GVT responses:
- Notch is an essential regulator of pathogenic alloresponse in acute and chronic GVHD. Notch blockade can successfully prevent GVHD if administered during a very early post-transplant period. We use this finding to investigate mechanisms of Notch activity in T cells that cause GVHD and have identified distinct genetic signature associated with Notch blockade. We are probing these targets in mouse models and human samples to identify new candidates for GVHD prevention and treatment.
- Donor macrophages are major and early contributors to chronic GVHD and related fibrosis. During chronic GVHD development, macrophages show signs of enhanced Notch signaling. We seek to characterize the mechanistic role of Notch signaling in macrophages during chronic GVHD and investigate its interaction with other polarizing signals that promote fibrosis. The goal is to further the understanding of immunologic basis of fibrosis and devise novel strategies for its control.
- Cancer recurrence is the most common cause of allo-HCT failure. Recent advances in solid tumor immunotherapy field with use of checkpoint blockade (CPB) have not extended to allo-HCT arena due to the development of severe GVHD. However, pre-clinical and clinical use of post-transplant cyclophosphamide immunosuppression appears to be a promising strategy allowing for safe integration of CPB into allo-HCT. Using translational approaches, we are investigating molecular foundations behind this observation to enhance GVT immunotherapy potential after allo-HCT.
- Radojcic V, Paz K, Chung J, Du J, Perkey ET, Flynn R, Ivcevic S, Zaiken M, Friedman A, Yan M, Pletneva MA, Sarantopoulos S, Siebel CW, Blazar BR, Maillard I (2018). Notch signaling mediated by Delta-like1/4 ligands controls the pathogenesis of chronic graft-versus-host disease in mice. Blood.
- Chung J, Ebens CL, Perkey E, Radojcic V, Koch U, Scarpellino L, Tong A, Allen F, Wood S, Feng J, Friedman A, Granadier D, Tran IT, Chai Q, Onder L, Yan M, Reddy P, Blazar BR, Huang AY, Brennan TV, Bishop DK, Ludewig B, Siebel CW, Radtke F, Luther SA, Maillard I (2017). Fibroblastic niches prime T cell alloimmunity through Delta-like Notch ligands. J Clin Invest, 127(4), 1578-88.
- Wood S, Feng J, Chung J, Radojcic V, Sandy-Sloat AR, Friedman A, Shelton A, Yan M, Siebel CW, Bishop DK, Maillard I (2015). Transient blockade of delta-like Notch ligands prevents allograft rejection mediated by cellular and humoral mechanisms in a mouse model of heart transplantation. J Immunol, 194(6), 2899-908.
- Tran IT, Sandy AR, Carulli AJ, Ebens C, Chung J, Shan GT, Radojcic V, Friedman A, Gridley T, Shelton A, Reddy P, Samuelson LC, Yan M, Siebel CW, Maillard I (2013). Blockade of individual Notch ligands and receptors controls graft-versus-host disease. J Clin Invest, 123(4), 1590-604.
- Zhang Y, Sandy AR, Wang J, Radojcic V, Shan GT, Tran IT, Friedman A, Kato K, He S, Cui S, Hexner E, Frank DM, Emerson SG, Pear WS, Maillard I (2011). Notch signaling is a critical regulator of allogeneic CD4+ T-cell responses mediating graft-versus-host disease. Blood, 117(1), 299-308.
- Radojcic V, Pletneva MA, Yen HR, Ivcevic S, Panoskaltsis-Mortari A, Gilliam AC, Drake CG, Blazar BR, Luznik L (2010). STAT3 signaling in CD4+ T cells is critical for the pathogenesis of chronic sclerodermatous graft-versus-host disease in a murine model. J Immunol, 184(2), 764-74.
- Radojcic V, Bezak KB, Skarica M, Pletneva MA, Yoshimura K, Schulick RD, Luznik L (2010). Cyclophosphamide resets dendritic cell homeostasis and enhances antitumor immunity through effects that extend beyond regulatory T cell elimination. Cancer Immunol Immunother, 59(1), 137-48.