Assistant Professor of Internal Medicine and
Adjunct Assistant Professor of Pathology
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 an effective and curative therapy for many hematologic malignancies. It is the most utilized immunotherapeutic modality and relies on differences between recipient’s tumor and transplanted immune system to exert its therapeutic benefit. The same antigenic disparities, however, fuel an indiscriminate immune attack on many of the recipient’s normal organs and lead to acute and chronic graft versus host disease (GVHD). Despite improving prophylaxis, disease still occurs in the majority of patients and confers high morbidity and mortality. Global immunosuppression is used to mitigate GVHD injury. However, this intervention carries a high risk of infections, end organ damage, and substantially blunts the graft versus tumor (GVT) activity of the transplant. Chronic GVHD, particularly its fibrotic form, remains a poorly understood entity with consequent lack of effective therapeutic strategies leading to frequent late transplant failure. Thus, new approaches to prevent and treat GVHD are warranted.
Our research focuses on early adaptive and innate immune responses that define occurrence of GVHD along the posttransplant continuum:
- We have identified a critical role for Notch signaling in development of graft-versus-host disease (GVHD) and established blockade of Notch ligands Delta-like-1/4 as a therapeutic strategy for ameliorating murine GVHD, without diminishing graft-versus-leukemia efficacy. Delta-like-1/4 targeting, however, exerts therapeutic benefits in mouse models only if pursued within the narrow post-transplant window, emphasizing the critical importance of early events that shape pathogenic T cells causing GVHD. We use modified mouse models of GVHD that allow for separation of pathogenic from bulk T cell populations allowing for detailed probing of core molecular events driving GVHD under different therapeutic interventions. We have identified distinct genetic signature associated with Notch blockade and are pursuing validation in distinct models of acute and chronic GVHD with goal to isolate broadly relevant candidates for novel GVHD therapy.
- Fibrosis represents the final step of the chronic GVHD injury, but its origins are increasingly recognized in the early posttransplant immune disturbance. Csf2-dependent pathogenic donor macrophages and their precursors infiltrate target GVHD organs early, and their elimination ameliorates disease. The contribution of morphogen pathways, including Notch, to fibrotic responses is well described, however, the inter-cellular signaling cascades remain unknown. Our data suggests enhanced Notch activity in myeloid elements during fibrotic chronic GVHD. We now seek to characterize mechanistic role of Notch signaling in macrophages causing chronic GVHD and investigate its interaction with other polarizing signals that tip balance towards the fibrotic response. Goal is to further the understanding of immunologic basis of fibrosis and devise novel strategies for its control.
- 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.
- Durakovic N, Radojcic V, Skarica M, Bezak KB, Powell JD, Fuchs EJ, Luznik L (2007). Factors governing the activation of adoptively transferred donor T cells infused after allogeneic bone marrow transplantation in the mouse. Blood, 109(10), 4564-74.