Graft-versus-host disease (GVHD) is a major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). It occurs because immunocompetent donor T cells in the allograft recognize the genetically disparate host as foreign and attack the transplant recipient's tissues. While genetic incompatibility between the donor and the recipient is the primary factor that determines the extent of the alloimmune response, non-genetic factors can also influence the incidence and severity of GVHD. Recent advances in immunology establish that environmental factors, including dietary micronutrients, actively participate in modifying a variety of immune responses and influence the susceptibility of experimental animals and humans to autoimmune and inflammatory diseases. The role of dietary micronutrients in GVHD pathogenesis is poorly understood. We and others recently identified retinoic acid (RA), the active metabolite of vitamin A, as a key molecule in facilitating the development of intestinal GVHD. These studies reveal how the metabolite of a single common vitamin can profoundly influence GVHD risk after allogeneic HSCT. These findings prompted us to examine the potential role of other dietary micronutrients in modulating the alloimmune response. The objective of this grant is to define how vitamin D influences the development of GVHD. We will test the novel hypothesis that enhancing intestinal vitamin D receptor (VDR) signaling strengthens mucosal epithelial barrier to mitigate GVHD. This hypothesis is based on our exciting preliminary data demonstrating that selectively enhancing intestinal VDR signaling protects against GVHD in experimental mice. We will combine genetic, pharmacologic, and dietary approaches to examine this hypothesis. Studies in Aim 1 will define the role of intestinal epithelial VDR signaling in modulating alloimmunity after HSCT.
Aim 2 will determine how therapeutic targeting of vitamin D/VDR pathway mitigates GVHD risk. We expect that results from these studies will advance our understanding with respect to the role of vitamin D, as an environmental factor, in GVHD pathogenesis. Furthermore, these studies will provide preclinical data that support the use of vitamin D and its analogs as simple and cost-effective adjunct therapies with minimal side effects for GVHD prevention and/or treatment.

Public Health Relevance

The proposed research is relevant to public health because graft-versus-host disease (GVHD) is the major complication of allogeneic stem cell transplantation (HSCT). The elucidation of protective role of vitamin D receptor signaling in intestines offers the potential to mitigate GVHD and reduce overall mortality in allogeneic stem cell transplant patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI144424-02
Application #
10079464
Study Section
Cancer Immunopathology and Immunotherapy Study Section (CII)
Program Officer
Nabavi, Nasrin N
Project Start
2020-01-03
Project End
2021-12-31
Budget Start
2021-01-01
Budget End
2021-12-31
Support Year
2
Fiscal Year
2021
Total Cost
Indirect Cost
Name
Medical College of Wisconsin
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
937639060
City
Milwaukee
State
WI
Country
United States
Zip Code
53226