Acute Graft-versus-host disease (aGVHD) is a frequent and lethal complication of allogeneic hematopoietic stem cell transplantation in which donor T cells destroy HLA mismatched host tissues. Despite recent advances, aGVHD still remains a major clinical problem, underscoring the need to elucidate further its mechanisms to then develop novel therapeutic strategies. Complementary to this, establishing a blood aGVHD biomarker for diagnosis and prognosis will be relevant to stratify patients to more aggressive initial treatments. Recently plasma protein biomarkers for diagnosis and prognosis of aGVHD have been discovered and validated. While these discoveries represent an important step towards improving aGVHD diagnosis and prognosis assessment, there are some drawbacks such as the need for high affinity quality antibodies with the required affinity and specificity fo the target. Our group recently discovered that miR-155 plays a critical regulatory role in aGVHD. Remarkably, we found that miR-155 expression is up-regulated as well in the serum of mice and patients with aGVHD. Based on this fact, we hypothesized that miR-155 serum levels could be a marker for aGVHD diagnosis and it could predict the occurrence and severity of aGVHD. Furthermore, since our initial studies identified several miRNAs upregulated in donor T cells from organs with aGVHD, we reasoned that is likely that other miRNAs could be expressed in the serum of patients with aGVHD that could potentially provide diagnostic and prognostic information. Thus, the overall objective of this project is to expand the search for aGVHD miRNAs biomarkers, to validate candidate miRNAs and establish their prognostic significance. Therefore, here we propose to address these research questions by investigating whether human serum miR-155 expression levels increase before the onset of clinical aGVHD and whether correlate with aGVHD clinical diagnosis, severity and prognosis in allogeneic stem cell transplants recipients by measuring serum miR-155 expression levels in two independent cohort of patients (discovery and validation cohorts). Next we will intent to identify and validate other microRNAs that are associated with aGVHD clinical diagnosis and severity by performing serum global microRNA analysis in allogeneic recipients at the time of clinical suspicion of aGVHD. To achieve these goals we are proposing to use serum samples from allogeneic HSCT patients obtained from bone marrow transplant clinical trial network (BMT CTN) Protocol 0101 study, which are currently stored in the NHLBI Biologic Specimen Repository (NHLBI Biorepository). These results will then been confirmed in validation cohort of allogeneic HSCT patients obtained from OSU.
If aims achieved, the proposed study will improve our current scientific knowledge about the role of serum miRNAs in this disease and provide with a novel biomarker.
Acute graft-versus-host-disease (GVHD) and its associated significant morbidity and mortality have remained the major barrier against the wider and safer application of bone marrow transplant as a curative modality. Lack of significant improvement in the current results calls attention to the need for development of novel therapeutic strategies. However, in order to do that, the mechanisms responsible for aGVHD need to be further elucidated. We have discovered that a tiny RNA (miR-155) regulates strongly GVHD. The overall goal of this proposal is to identify whether the expression levels of miR-155 and other miRNAs in the serum of patients receiving bone marrow transplants could predict the development and the severity of this complications. Overall, these studies have the potential to improve our understanding of the role of this tiny RNAs in the regulation of GVHD and provide also an excellent opportunity to develop novel markers to predict this complication.
|Zitzer, Nina C; Snyder, Katiri; Meng, Xiamoei et al. (2018) MicroRNA-155 Modulates Acute Graft-versus-Host Disease by Impacting T Cell Expansion, Migration, and Effector Function. J Immunol 200:4170-4179|
|Ranganathan, Parvathi; Ngankeu, Apollinaire; Zitzer, Nina C et al. (2017) Serum miR-29a Is Upregulated in Acute Graft-versus-Host Disease and Activates Dendritic Cells through TLR Binding. J Immunol 198:2500-2512|