Graft Versus Host Disease Role of Nk Cells

Clancy, John

Abstract

Potentially lethal graft versus host disease (GVHD) is a frequent occurrence after human bone marrow transplantation (BMT) for treatment of leukemia, aplastic anemia, and immunodeficiency diseases. There is significant cell destruction within lymphoid and other tissues is human GVHD as a consequence of BMT and in rodent GVHD model systems. Alterations have also been reported in the levels of cells able to naturally kill (NK) various myeloblastoid, lymphoma, and sarcoma cell lines in vitro in patients receiving BMTs and in rodent GVHD model systems. The present proposal seeks to investigate the nature, temporal pattern, identity, and role of NK cells in rats with GVHD during the initiation and maintenance of acute lethal GVHD. GVHD will be induced in (DAxLEW)F1 rats of various ages by the intravenous injection of parental lymphoid LEW cells. Controls will receive the same dose of F1 cells. At various times after semiallogeneic or syngeneic cell injection, the peripheral blood, spleen lymph nodes, thymus, and when possible bone marrow and thoracic duct lymph will be fractionated on Percoll discontinuous gradients and the large granular lymphocyte (LGL) as well as other fractions examined for their concentration, ontogeny, and phenotype as well as lytic efficiency against various NK targets. The levels obtained at various stages of acute GVHD will be compared to NK cell levels developing in neonatally thymectomized (NTx) (DAxLEW)F1 as well as BN rats of various ages. Also, the ability of various Percoll fractions from GVHD animals to adoptively transfer GVHD to virgin animals will be compared with fractions obtained from various organs of controls and NTx. In addition, the development and level of NK suppressor cells in GVHD, and NTx rats as compared to controls will be examined in high and low density fractions of Percoll gradients. In an effort to understand the role of NK cells during acute GVHD in humans the long term objectives of this proposal are to clarify the level and role of NK cells and LGLs in the pathogenesis of acute GVHD in the rat. Because of the recently reported increase in NK cells within lymph nodes of patients with acquired immunodeficiency syndrome (AIDS), the proposed studies may shed some light on the etiology of AIDS.