The Graft-vs-Leukemia effect (GVL) mediated by T cells that accompany allogeneic stem cell grafts and delayed leukocyte infusions (DLI), has revolutionized the treatment of leukemia and lymphoma. Chronic phase CML (CP-CML) is the prototypical GVL-sensitive neoplasm in which complete remissions are achieved in 80% of recipients of DLI. In spite of this success, alloimmune therapy has two principle weaknesses. First, many neoplasms including CML in blast crisis (BC-CML), are GVL-resistant. The basis for this differential susceptibility is unknown. Second, GVL has proven difficult to separate from Graft-vs.-Host Disease (GVHD), the attack by donor T cells on recipient tissues. We hypothesize that manipulation of alloimmune responses can render GVL-resistant tumors more sensitive and lessen GVHD while retaining GVL. We believe this is possible because some patients with GVL-resistant disease do benefit from alIoSCT and some patients have GVL without GVHD. A first step in developing such strategies is to understand alloimmunity against GVL-sensitive neoplasms and how this response differs from GVHD and from GVL against less sensitive neoplasms. These are the objectives of this proposal. A major obstacle in achieving these goals has been the absence of murine models for GVL-sensitive and resistant leukemias that share a common pathology and genetic etiology with their human counterparts and are inducible on different strains, including KO mice that will yield leukemias lacking critical molecules. Leukemia cell lines, the mainstay of murine GVL research, lack these features. We have adopted novel murine models of CP-CML (mCP-CML) and BC-CML (mBC-CML) that address these problems, mCP-CML is a myeloproliferative disorder induced via retroviral transduction of murine progenitors with the bcr-abl fusion cDNA, the defining genetic abnormality in human CP-CML. mBC-CML is induced via the retroviral introduction of both bcr-abl and the NUP98/HOXA9 fusion, a translocation found in BC-CML. The use of retrovirus allows the induction of both leukemias in any mouse, most notably gene-deficient mice. Using gene deficient recipients, donors, and leukemias, we will examine antigen presentation, T cell polarization, and T cell effector mechanisms in GVL and GVHD.
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