Bone marrow transplantation (BMT) is a curative approach for treating hematological malignancies and other life-threatening disorders. Military servicemen are under risk to develop such lethal conditions as a result of exposure to carcinogens ? like agent orange ? during their active service. The success of BMT is limited by graft versus host disease (GVHD), a lethal inflammatory complication of BMT. GVHD is driven by donor leukocyte subsets, such as donor T lymphocytes that are important for both bone marrow engraftment and the prevention of tumor recurrence. Novel treatment strategies are needed to keep donor T lymphocytes in the graft in order to maintain donor T lymphocyte-mediated anti-tumor (graft versus tumor; GVT) immunity while suppressing the GVHD. One novel approach to this is therapeutic stimulation of the function of regulatory T cells (Tregs). Our experiments show that augmentation of intestinal immune regulation induces Tregs in vivo, resulting in the suppression of GVHD and the preservation of anti-tumor immunity. We induce intestinal immune regulation, or ?conditioning,? using a completely novel approach: self-limited colonization of the gut with helminths, to stimulate T helper 2 (Th2) immune pathways. In this application, we propose to test the central hypothesis that the Th2 pathways are critical in intestinal immune conditioning, and that they lead to the generation of Tregs in vivo. We will use the murine nematode, Heligmosomoides polygyrus bakeri (Hpb) to infect mice. We will induce acute GVHD in uninfected and helminth- infected BMT recipients of MHC I/II major mismatch donors. To assess the roles of Th2 and Th2-associated pathways in regulating GVHD and the in vivo induction of Tregs, we will employ complementary genetic and pharmacological approaches. We will determine the mechanisms through which intestinal immune conditioning increases the regulatory activity of Tregs, and establish the extent to which helminth infection affects GVT immunity in mouse tumor models. Furthermore, we will deliver immune regulatory and Th2-associated cytokine, interleukin 10 microparticles into the gut of uninfected mice by oral gavage, to mimic helminth-induced intestinal immune conditioning. The findings from these studies are expected to help us achieve our long-term goals, which are to: identify the cellular and molecular immune regulatory pathways that are key to helminthic immune conditioning in preclinical models; and to apply this knowledge to veterans and other patient populations that undergo BMT. No significant side effects have been associated with helminth infection in immune suppressed patient groups, like individuals with inflammatory bowel disease or multiple sclerosis. Thus, the targeting of helminth-modulated signaling pathways ? using small molecules, helminth products or possibly even intact helminths ? may be a safe and potent treatment for GVHD that leaves the beneficial GVT immunity intact.

Public Health Relevance

According to U.S. Department of Defense Resources and National Marrow Donor Program, more than 12,000 people are diagnosed each year with blood cancers or other severe and lethal disorders that require hematopoietic stem cell transplantation (HSCT) or bone marrow transplantation (BMT). The veterans constitute an important group in these 12,000 patients, because during their active military service, veterans are exposed to carcinogens ? like agent orange ? or infected by viruses that can lead to the development of blood cancers or lethal conditions treated with HSCT/BMT. The success of BMT/HSCT is limited by the lethal inflammatory condition, called graft versus host disease (GVHD), for which no potent and safe treatment exists. We expect our studies, that are based on helminth-induced intestinal immune regulation, help better characterize the role of intestinal immune system in controlling GVHD and lead to identification of novel and less toxic therapeutic approaches to treat the severe and devastating GVHD and improve the health of U.S. veterans.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
5I01BX002906-02
Application #
9397958
Study Section
Immunology A (IMMA)
Project Start
2017-01-01
Project End
2020-12-31
Budget Start
2018-01-01
Budget End
2018-12-31
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Iowa City VA Medical Center
Department
Type
DUNS #
028084333
City
Iowa City
State
IA
Country
United States
Zip Code
52246