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 #
2P01CA023766-34
Application #
8435564
Study Section
Special Emphasis Panel (ZCA1-RPRB-B (O1))
Project Start
1998-09-01
Project End
2018-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
34
Fiscal Year
2013
Total Cost
$411,187
Indirect Cost
$178,615
Name
Sloan-Kettering Institute for Cancer Research
Department
Type
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10065
Boudreau, Jeanette E; Hsu, Katharine C (2018) Natural Killer Cell Education and the Response to Infection and Cancer Therapy: Stay Tuned. Trends Immunol 39:222-239
Lin, Richard J; Ho, Caleb; Hilden, Patrick D et al. (2018) Allogeneic haematopoietic cell transplantation impacts on outcomes of mantle cell lymphoma with TP53 alterations. Br J Haematol :
Malard, Florent; Labopin, Myriam; Cho, Christina et al. (2018) Ex vivo and in vivo T cell-depleted allogeneic stem cell transplantation in patients with acute myeloid leukemia in first complete remission resulted in similar overall survival: on behalf of the ALWP of the EBMT and the MSKCC. J Hematol Oncol 11:127
Luduec, Jean-BenoƮt Le; Kudva, Anupa; Boudreau, Jeanette E et al. (2018) Novel multiplex PCR-SSP method for centromeric KIR allele discrimination. Sci Rep 8:14853
Shah, Gunjan L; Moskowitz, Craig H (2018) Transplant strategies in relapsed/refractory Hodgkin lymphoma. Blood 131:1689-1697
Avanzi, Mauro P; Yeku, Oladapo; Li, Xinghuo et al. (2018) Engineered Tumor-Targeted T Cells Mediate Enhanced Anti-Tumor Efficacy Both Directly and through Activation of the Endogenous Immune System. Cell Rep 23:2130-2141
Staffas, Anna; Burgos da Silva, Marina; Slingerland, Ann E et al. (2018) Nutritional Support from the Intestinal Microbiota Improves Hematopoietic Reconstitution after Bone Marrow Transplantation in Mice. Cell Host Microbe 23:447-457.e4
Velardi, Enrico; Tsai, Jennifer J; Radtke, Stefan et al. (2018) Suppression of luteinizing hormone enhances HSC recovery after hematopoietic injury. Nat Med 24:239-246
Moskowitz, Craig H (2018) Should all patients with HL who relapse after ASCT be considered for allogeneic SCT? A consult, yes; a transplant, not necessarily. Blood Adv 2:821-824
Kim, Seong Jin; Huang, Yao-Ting; Foldi, Julia et al. (2018) Cytomegalovirus resistance in CD34+ -selected hematopoietic cell transplant recipients. Transpl Infect Dis 20:e12881

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