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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Experimental Therapeutics Subcommittee 1 (ET)
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Howcroft, Thomas K
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Yale University
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Schools of Medicine
New Haven
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MacDonald, Kelli P; Shlomchik, Warren D; Reddy, Pavan (2013) Biology of graft-versus-host responses: recent insights. Biol Blood Marrow Transplant 19:S10-4
Li, Ning; Matte-Martone, Catherine; Zheng, Hong et al. (2011) Memory T cells from minor histocompatibility antigen-vaccinated and virus-immune donors improve GVL and immune reconstitution. Blood 118:5965-76
Matte-Martone, Catherine; Venkatesan, Srividhya; Tan, Hung Sheng et al. (2011) Graft-versus-leukemia (GVL) against mouse blast-crisis chronic myelogenous leukemia (BC-CML) and chronic-phase chronic myelogenous leukemia (CP-CML): shared mechanisms of T cell killing, but programmed death ligands render CP-CML and not BC-CML GVL resist J Immunol 187:1653-63
Matte-Martone, Catherine; Wang, Xiajian; Anderson, Britt et al. (2010) Recipient B cells are not required for graft-versus-host disease induction. Biol Blood Marrow Transplant 16:1222-30
Zheng, Hong; Matte-Martone, Catherine; Jain, Dhanpat et al. (2009) Central memory CD8+ T cells induce graft-versus-host disease and mediate graft-versus-leukemia. J Immunol 182:5938-48
Matte-Martone, Catherine; Liu, Jinli; Jain, Dhanpat et al. (2008) CD8+ but not CD4+ T cells require cognate interactions with target tissues to mediate GVHD across only minor H antigens, whereas both CD4+ and CD8+ T cells require direct leukemic contact to mediate GVL. Blood 111:3884-92
Zheng, Hong; Matte-Martone, Catherine; Li, Hongmei et al. (2008) Effector memory CD4+ T cells mediate graft-versus-leukemia without inducing graft-versus-host disease. Blood 111:2476-84
Shlomchik, Warren D (2007) Graft-versus-host disease. Nat Rev Immunol 7:340-52
Matte, Catherine C; Liu, Jinli; Cormier, James et al. (2004) Donor APCs are required for maximal GVHD but not for GVL. Nat Med 10:987-92
Matte, Catherine C; Cormier, James; Anderson, Britt E et al. (2004) Graft-versus-leukemia in a retrovirally induced murine CML model: mechanisms of T-cell killing. Blood 103:4353-61

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