Implication of Galectin-3 to regulate Graft vs. Host Disease (GvHD) and Graft vs. Tumor (GVT) Responses - Project Summary: 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.
