Allogeneic hematopoietic cell transplantation (allo-HCT) is an effective form of immunotherapy that is potentially curative for malignant (e.g. leukemia, lymphoma) and non-malignant conditions (e.g. anemia, immunodeficiencies). However, graft?versus?host disease (GvHD) remains a major deleterious side-effect for many patients. While studying GvHD in murine allo-HCT models, we surprisingly discovered an important role for Galectin-3 (Gal-3) in mitigating GvHD. Gal-3 is expressed by hematopoietic and non-hematopoietic cells and is known to influence innate and adaptive immunity. Interestingly, its contribution to GvHD is unknown. In murine allo-HCT experiments, recipient mice were reconstituted with T cell depleted bone marrow (TCD-BM) and T cells from wild type (WT) or Gal-3 deficient mice. I discovered that Gal-3 deficiency in donor T-cells significantly exacerbated the severity and mortality of GvHD and that Gal-3 is important for protecting recipient tissues from GvHD. Based on my preliminary data, the goal of this study is to explore a new paradigm regarding the role of Gal-3 in GvHD after allo-HCT. I hypothesize that Gal-3 is the key regulator of GvHD that modulates both donor and recipient hematopoietic and non-hematopoietic cell functions and decreases GvHD severity and mortality. Therefore, I will study murine models and human HCT patients to pursue three aims.
Aim 1 will explore the cellular mechanism(s) by which Gal-3 signaling impacts GvHD. I will use Gal-3 deficient mice as donors to determine how Gal-3 signaling affects the functions of major T cell subsets known to dictate the onset and severity of GVHD, including CD4+, CD8+ and CD4+Foxp3+ regulatory T cells.
Aim 2 will evaluate the therapeutic potential of manipulating Gal-3 signaling to modulate GvHD and the graft versus tumor (GvT) effect. To increase the translatability of this work, I established a xenotransplantation system using humanized NSG-HLA-A2 mice as HCT recipients to examine GvHD severity induced by human immune cells.
Aim 3 will analyze the clinical association of Gal-3 with GvHD severity after allo-HCT. I will measure Gal-3 plasma levels in 200 de-identified allogeneic HCT patients and analyze the relationship between Gal-3 levels and clinical outcomes including GvHD incidence and severity, engraftment, and infection. In summary, this project will not only improve our understanding of the biology of allo-HCT, but my results may identify a new biomarker which will help identify patients at risk for developing severe GvHD after HCT. Moreover, this research may lead to a novel therapeutic rationale for modulating Gal-3 signaling to control GvHD. This project will be carried out under the supervision of the candidate's primary mentor Dr. Elizabeth Repasky, co-mentor Dr. Philip McCarthy, and advisory committee including Drs. Bruce Blazer, Pawel Kalinski, Theresa Hahn and Jonathan Bramson. By completing the training outlined in this application (K99), I will obtain the knowledge and skills required to take the initial steps toward scientific autonomy in the subsequent phase (R00), and successfully complete the transition from a postdoctoral trainee to an independent researcher.
Graft-versus-host disease (GvHD) is a serious, and unfortunately common, complication of allogeneic hematopoietic cell transplantation (allo-HCT). Although allo-HCT can potentially be curative for a variety of malignant (e.g. leukemia, lymphoma) and non-malignant (e.g. anemia, immunodeficiencies) diseases, continued research is critical for the development of novel methods of mitigating the debilitating consequences of GvHD. This proposal builds on the discovery I made using mouse models that Galectin-3 from donor and host cells protects normal tissues from GvHD resulting in decreased severity and mortality and may determine the therapeutic potential and cellular mechanisms by which Galectin-3 inhibits GvHD following allo-HCT.
