Allogeneic stem cell transplantation is a highly effective therapy for mantle cell lymphoma. Much of the benefit is related to the graft-vs-lymphoma (GVL) effect in which donor T-cells eradicate the lymphoma. The major obstacle is the development of graft-vs-host disease (GVHD), a reaction of donor immune T-cells against recipient tissues. Depletion of T-cells from the transplant prevents GVHD. T-cells are required, however, to enhance engraftment and mediate GVL. T-cell depleted transplants are associated with an increased risk of graft rejection and lymphoma relapse. In this project we evaluate a novel strategy to combine stem cells with donor T-cells stimulated against a third party (an unrelated HLA mismatched individual). These anti 3rd party T-lymphocytes do not react against the recipient and do not cause GVHD, but they do facilitate engraftment and directly mediate GVL effects. These anti-third party CTL are also cytolytic against B-cell malignancies, including mantle cell lymphoma. During the last year supported by this grant, we have characterized the veto cell mechanism to facilitate engraftment which requires fas-fas ligand interactions. We have also determined that the anti-lymphoma effects occur through cell adhesion and do not involve the T-cell receptor. We have also developed a GMP process to perform large scale production of antithird party lymphocytes for a human clinical trial in mantle cell lymphoma patients. The major goal of this project is to develop a safer, more effective system for allotransplantation utilizing a nontoxic regimen to achieve engraftment and mediate antilymphoma effects without GVHD. Development of a means to achieve engraftment of an allogeneic hematopoietic transplant without GVHD has a broad range of potential applications in addition to its potential use for treatment for mantle cell lymphoma.