GRAFT-VS-LEUKEMIA EFFECT in a MOUSE MODEL of CHRONIC MYELOID LEUKEMIA.

Abstract 4500

Graft-vs-Host Disease (GVHD) is a frequent and severe complication of allogeneic hematopoietic stem cell transplants (allo-HSCT), mediated by donor's T cells reacting against host antigens. However, donor's T lymphocytes also generate the beneficial Graft-vs-Leukemia effect (GVL) by recognizing tumor antigens as non-self, thus contributing to the eradication of residual leukemic cells. With the purpose of studying factors that could affect the GVHD/GVL effects, we generated a chronic myeloid leukemia (CML) mouse model by the transplantation of lin^- bone marrow (BM) cells transduced with a retroviral vector carrying the BCR/ABL and tNGFR marker genes (p210-tNGFR RV) into syngeneic, lethally irradiated, B6D2F1 (H2^b/d) mice. Transplanted mice developed chronic myeloid leukemia (CML), characterized by hemorrhagic lungs, hepatomegaly, splenomegaly and granulocytosis. Additionally, NGFR⁺ leukemic cells were detected in the peripheral blood and bone marrow. All mice died on days +18-20 after infusion of the transduced cells. The co-transplantation of B6D2F1 mice with syngeneic p210-tNGFR transduced lin^- BM cells together with allogeneic BM cells from C57Bl/6 mice (H2^b/b), determined a slower progression of the disease. In this case, transplanted mice died of leukemia on days +28-72 after the co-infusion.

To investigate in this CML mouse model the GVHD/GVL effect mediated by donor allogeneic T-lymphocytes, splenocytes from allogeneic C57Bl/6 mice were additionally infused together with the allogeneic BM cells and the symgeneic p210-tNGFR transduced lin^- cells. No CML signs developed, and no NGFR⁺ cells were detected in mice receiving the allogeneic T cells. In this experimental group, however, all the animals died from acute GVHD on days +13-36 after the co-transplantation, similar to the GVHD control group that received allogeneic bone marrow cells and T-lymphocytes but not the p210-tNGFR transduced lin^- cells.

In previous works, we demonstrated that the infusion of adipose tissue-derived mesenchymal stromal cells (Ad-MSCs) prevented GVHD in a haploidentical hematopoietic progenitor cells transplantation mouse model (Yañez et al, Stem Cells 2006). With the present GVHD/GVL mouse model we are now investigating the impact of the infusion of the immunosuppressive adipose tissue-derived mesenchymal stromal cells on the GVHD/GVL effect mediated by allogeneic T cells.