Hematopoietic cell transplantation (HCT) is an effective therapy for patients with a broad range of hematologic malignancies. The benefits of HCT are in large part derived from the immunological recognition of malignant cells resulting in their removal termed the graft vs. tumor (GVT) effect clearly demonstrating the impact of immune based control of malignancy. The success of HCT is limited by the risk of graft vs. host disease (GVHD) which results in tissue specific immune destruction. In this proposal we will focus on natural killer (NK) cells which have known anti-tumor capabilities yet do not cause GVHD. We will utilize a novel bioluminescent imaging (BLI) strategy to probe GVHD and GVT reactions. NK and T cell populations of interest will be isolated from a novel luciferase (luc) transgenic mouse and emit light. Trafficking and survival of luc+ cells can be followed in real time with high precision and sensitivity. BLI will be utilized to identify the major sites of GVHD induction and explore the impact of NK cells on GVHD induction building upon our extensive previous experience of T cell imaging. These studies will direct more probing analysis of the infiltrating tissues and cell populations. We have shown that GVHD develops through the spatial and temporal migration of lymphocytes to key anatomical sites whereby alloreactive cells proliferate and upregulate other cell surface molecules required for entry into GVHD target organs. We will evaluate the impact of NK cells on T cell trafficking and survival as well as explore NK cell trafficking to examine underlying mechanisms of why this cell population does not result in GVHD. Our hypothesis is that NK cells are capable of modulating the proliferation and survival of alloreactive T cells and can induce apoptosis of activated alloreactive T cells at lymphoid tissue sites. We further hypothesize that alloreactive T cells up-regulate NKG2D ligand expression which is recognized by NK cells via NKG2D resulting in apoptosis induction. We will further evaluate the specific populations of NK cells capable of proliferating and trafficking to tumor sites and explore phenotypic and functional immune reconstitution following transplantation in the presence and absence of NK cells. The goals of this Project are to gain greater biological insight into NK cell biology in the context of the clinically important yet complex GVHD and GVT reactions and to explore the role of NK cells in these reactions. We believe these studies will reveal basic biological insights into the pathophysiology of important immune reactions, the interplay between immune effector and regulatory lymphocytes and strategies which may be translated to the clinic.

Public Health Relevance

The goal of this proposal is to further our understanding of the immunobiology of hematopoietic cell transplantation through the study of natural killer cells which have the unique capabilities of improving anti-tumor effects without causing graft vs host disease. We hope to understand the mechanisms of improved graft vs. tumor effects without graft vs host disease using novel bioluminescent based imaging strategies to explore the temporal and spatial events in natural killer cell biology in models of these events.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Transplantation, Tolerance, and Tumor Immunology (TTT)
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Mccarthy, Susan A
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Stanford University
Internal Medicine/Medicine
Schools of Medicine
United States
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Gill, Saar; Vasey, Adrianne E; De Souza, Alysha et al. (2012) Rapid development of exhaustion and down-regulation of eomesodermin limit the antitumor activity of adoptively transferred murine natural killer cells. Blood 119:5758-68
Benjamin, Jonathan E; Gill, Saar; Negrin, Robert S (2010) Biology and clinical effects of natural killer cells in allogeneic transplantation. Curr Opin Oncol 22:130-7
Olson, Janelle A; Leveson-Gower, Dennis B; Gill, Saar et al. (2010) NK cells mediate reduction of GVHD by inhibiting activated, alloreactive T cells while retaining GVT effects. Blood 115:4293-301
Olson, Janelle A; Zeiser, Robert; Beilhack, Andreas et al. (2009) Tissue-specific homing and expansion of donor NK cells in allogeneic bone marrow transplantation. J Immunol 183:3219-28
Gill, Saar; Olson, Janelle A; Negrin, Robert S (2009) Natural killer cells in allogeneic transplantation: effect on engraftment, graft- versus-tumor, and graft-versus-host responses. Biol Blood Marrow Transplant 15:765-76