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.

National Institute of Health (NIH)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZCA1)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
New York
United States
Zip Code
Tarek, N; Gallagher, M M; Chou, J F et al. (2015) KIR and HLA genotypes have no identifiable role in single-unit dominance following double-unit umbilical cord blood transplantation. Bone Marrow Transplant 50:150-2
Hubbard-Lucey, Vanessa M; Shono, Yusuke; Maurer, Katie et al. (2014) Autophagy gene Atg16L1 prevents lethal T cell alloreactivity mediated by dendritic cells. Immunity 41:579-91
Dubrovsky, Leonid; Pankov, Dmitry; Brea, Elliott Joseph et al. (2014) A TCR-mimic antibody to WT1 bypasses tyrosine kinase inhibitor resistance in human BCR-ABL+ leukemias. Blood 123:3296-304
Maguire, William F; McDevitt, Michael R; Smith-Jones, Peter M et al. (2014) Efficient 1-step radiolabeling of monoclonal antibodies to high specific activity with 225Ac for ?-particle radioimmunotherapy of cancer. J Nucl Med 55:1492-8
Olson, Amanda L; Dahi, Parastoo B; Zheng, Junting et al. (2014) Frequent human herpesvirus-6 viremia but low incidence of encephalitis in double-unit cord blood recipients transplanted without antithymocyte globulin. Biol Blood Marrow Transplant 20:787-93
Curran, Shane A; Romano, Emanuela; Kennedy, Michael G et al. (2014) Phenotypic and functional activation of hyporesponsive KIRnegNKG2Aneg human NK-cell precursors requires IL12p70 provided by Poly(I:C)-matured monocyte-derived dendritic cells. Cancer Immunol Res 2:1000-10
Dahi, P B; Ponce, D M; Devlin, S et al. (2014) Donor-recipient allele-level HLA matching of unrelated cord blood units reveals high degrees of mismatch and alters graft selection. Bone Marrow Transplant 49:1184-6
Dahi, Parastoo B; Ponce, Doris M; Devlin, Sean et al. (2014) "No wash" albumin-dextran dilution for double-unit cord blood transplantation is safe with high rates of sustained donor engraftment. Biol Blood Marrow Transplant 20:490-4
Tyler, Eleanor M; Jungbluth, Achim A; Gnjatic, Sacha et al. (2014) Cancer-testis antigen 7 expression and immune responses following allogeneic stem cell transplantation for multiple myeloma. Cancer Immunol Res 2:547-58
Pai, Sung-Yun; Logan, Brent R; Griffith, Linda M et al. (2014) Transplantation outcomes for severe combined immunodeficiency, 2000-2009. N Engl J Med 371:434-46

Showing the most recent 10 out of 304 publications