It is the goal of this proposal to use the mouse as an experimental system to improve allogeneic bone marrow transplantation (BMT). Ultimately, we seek to develop long term chimerism in transplant recipients without graft-versus-host disease (GVHD), the most common clinical complication of transplant recipients. We will accomplish our goal by simultaneously investigating two very important aspects of BMT. 1) Conditioning of the recipient by various radiological regimens which will permit engraftment with minimal morbidity. We will evaluate various irradiation conditioning regimens including total lymphoid irradiation (single dose and fractionated) and total body irradiation (Fractionated, hyperfractionated and split-dose) with and without chemical conditioning. 2) Utilizing our new approach of depletion of GVHD-causing T cells from the donor graft. Our new approach involves the use of antibody linked to potent toxin, termed immunotoxin (IT). Our experimental and clinical data suggest that the use of IT to deplete marrow T cells will have a major impact on allogeneic BMT. Importantly, data from our laboratory as well as from other clinical centers indicate that in certain instances, transplants involving T cell depleted bone marrow sometimes result in engraftment failures. Because the use of T cell depletion in allogeneic BMT is gaining more momentum, it is urgent that the relationship between T cell depletion and recipient conditioning be determined. Therefore, we will investigate various conditioning regimens in animals that receive matched or mismatched bone marrow combined with T cell depletion using IT. The major challenge in the next grant period is to develop improved radiation conditioning regimens in animals that receive T-depleted bone marrow. If transplanted mice are to survive, it is important that their immune responses be intact. Therefore, in conditioning regimens which result in successful marrow engraftment, mice will be studied for immunocompetence employing in vivo and in vitro assays to measure immunological responses. Many responses will be measured, but we will concentrate on determining T cell function since T cells have been shown to contribute both to the development of GVHD and engraftment. We will also investigate the therapeutic use of thymic hormones or T cell growth factors that may accelerate engraftment and shorten the period of post transplant immunodeficiency. These studies will provide information which will be of great clinical value leading to the development of new protocols for the University of Minnesota BMT Program.
Showing the most recent 10 out of 69 publications
