There is currently little understanding of how transplant recipients recover from tissue damage due to graft vs. host disease (GVHD) and pre-transplant conditioning. Furthermore, virtually all strategies available to reduce clinical GVHD do so by limiting the donor immune system at the expense of therapeutic graft vs. leukemia/lymphoma (GVL) responses. iL-22 is a recently characterized cytokine that has been shown to protect intestinal epithelium during experimental inflammatory bowel disease. IL-22 receptor expression is restricted to non-hematopoietic cells, thus providing specificity to recipient epithelium in the transplant setting. Manipulation ofthis cytokine could therefore protect epithelial tissues in transplant recipients without altering donor immunity or reducing GVL. Our preliminary data demonstrate that IL-22 is produced post-transplant by radioresistant host-derived innate lymphoid cells. These cells were eliminated during GVHD, and deficiency of host-derived IL-22 led to increased GVHD morbidity, mortality, and pathology. Our data also indicate that iL-22 may be critical during GVHD for maintaining the intestinal stem cells necessary for epithelial recovery from tissue damage. Finally, our data indicate that IL-22 is essential for protecting the function of thymic epithelium post-transplant, and that IL-22 administration can eliminate thymic damage due to GVHD. We propose to test the hypothesis that IL-22 promotes survival and healing of damaged epithelium during bone marrow transplantation. This project aims to study the regulation of IL-22 expression post- transplant, the function of IL-22 in reducing GVHD and conditioning-related epithelial damage, and the administration of IL-22 for reduction of post-transplant morbidity and mortality. Our ultimate goal is to develop a novel therapeutic strategy for prevention and treatment of GVHD. Potential therapeutic strategies will be tested in leukemia-bearing mice to ensure that GVL activity is preserved. These translational studies will lead to better understanding of immunobiology, intestinal stem cell physiology, and epithelial regeneration, and will also lead to novel strategies for reducing epithelial damage post-transplant.

Public Health Relevance

Bone marrow transplantation (BMT) is a potentially curative treatment for many blood diseases, but it is limited by complications of tissue damage and graft vs. host disease (GVHD). This grant aims to study how IL-22 protects transplant recipients from GVHD and tissue damage, and this grant aims to translate these findings into new treatments to improve the health and survival of BMT patients.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA023766-38
Application #
9277365
Study Section
Special Emphasis Panel (ZCA1-RPRB-B)
Project Start
Project End
Budget Start
2017-04-01
Budget End
2018-03-31
Support Year
38
Fiscal Year
2017
Total Cost
$378,651
Indirect Cost
$164,592
Name
Sloan-Kettering Institute for Cancer Research
Department
Type
Research Institutes
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10065
Ataie, Niloufar; Xiang, Jingyi; Cheng, Neal et al. (2016) Structure of a TCR-Mimic Antibody with Target Predicts Pharmacogenetics. J Mol Biol 428:194-205
Richardson, Paul G; Riches, Marcie L; Kernan, Nancy A et al. (2016) Phase 3 trial of defibrotide for the treatment of severe veno-occlusive disease and multi-organ failure. Blood 127:1656-65
Hasan, A N; Selvakumar, A; Shabrova, E et al. (2016) Soluble and membrane-bound interleukin (IL)-15 Rα/IL-15 complexes mediate proliferation of high-avidity central memory CD8(+) T cells for adoptive immunotherapy of cancer and infections. Clin Exp Immunol 186:249-265
Spitzer, Barbara; Perales, Miguel-Angel; Kernan, Nancy A et al. (2016) Second Allogeneic Stem Cell Transplantation for Acute Leukemia Using a Chemotherapy-Only Cytoreduction with Clofarabine, Melphalan, and Thiotepa. Biol Blood Marrow Transplant 22:1449-54
Park, Jae H; Geyer, Mark B; Brentjens, Renier J (2016) CD19-targeted CAR T-cell therapeutics for hematologic malignancies: interpreting clinical outcomes to date. Blood 127:3312-20
Xiong, Huizhong; Keith, James W; Samilo, Dane W et al. (2016) Innate Lymphocyte/Ly6C(hi) Monocyte Crosstalk Promotes Klebsiella Pneumoniae Clearance. Cell 165:679-89
Jiang, Yanwen; Ortega-Molina, Ana; Geng, Huimin et al. (2016) CREBBP Inactivation Promotes the Development of HDAC3 Dependent Lymphomas. Cancer Discov :
Shono, Yusuke; Docampo, Melissa D; Peled, Jonathan U et al. (2016) Increased GVHD-related mortality with broad-spectrum antibiotic use after allogeneic hematopoietic stem cell transplantation in human patients and mice. Sci Transl Med 8:339ra71
Hobbs, G S; Kaur, N; Hilden, P et al. (2016) A novel reduced intensity conditioning regimen for patients with high-risk hematological malignancies undergoing allogeneic stem cell transplantation. Bone Marrow Transplant 51:1010-2
Huang, Yao-Ting; Neofytos, Dionysios; Foldi, Julia et al. (2016) Cytomegalovirus Infection after CD34(+)-Selected Hematopoietic Cell Transplantation. Biol Blood Marrow Transplant 22:1480-6

Showing the most recent 10 out of 392 publications