Abstracts (complete list) - Wissenschaft Online

Marion Nonn, Shamsul A. Khan, Eva Distler, Ralf G. Meyer, Leonard D. Shultz, Rupert
Handgretinger, Christoph Huber, Wolfgang Herr, Udo F. Hartwig
Establishment of a NOD/SCID/IL2Rγc null hematopoietic stem
cell transplantation model to study graft-vs-host and graft-vsleukemia
immune responses of ex vivo modified human T
lymphocyte grafts.
Donor lymphocyte graft engineering to abrogate graft-vs-host (GVH) reactivity while
improving graft-vs-leukemia (GVL) immunity is of key interest in allogeneic
hematopoietic stem cell transplantation (HSCT). We established a HSCT model using
NOD/SCID/IL2R common γ-chain null (γc null ) mice to evaluate GVH and GVL immunity of
human leukemia-reactive T cell lines in vivo. These T cells were generated by in vitro
stimulation of donor lymphocytes against primary acute myeloid leukemia (AML) blasts
followed by CD137-mediated immunodepletion of alloreactivity using allogeneic
fibroblasts (FB).>sup>1>/sup>
Firstly, GVH responses of T cell lines were tested by subcutaneously implanting skin
substitutes composed of primary dermal or bone marrow stromal FB embedded in a
collagen matrix into NOD/SCID/γc>sup>null mice. Following adoptive transfer of
undepleted human haploidentical CD3 + T cells, up to 23% of alloreactive T cells
specifically migrated into viable and vascularized substitutes explanted 21d post
adoptive transfer. In addition, selected T cell subsets elicited xenoreactivity induced by
residual murine antigen-presenting cells. In contrast, no allo- and xenoreactivity was
observed upon transfer of donor T cells enriched for leukemia reactivity.
Secondly, to study GVL immunity, we examined protection to engraftment of human
primary AML blasts in NOD/SCID/γc null mice by AML-reactive cytotoxic T cells (CTL)
expanded from CD8 + donor lymphocytes in short term cultures. After 24h coculture of
anti-leukemia CTL with AML blasts in vitro, both T cells and leukemia were transferred
into NOD/SCID/γc null recipients. In contrast to controls, AML-reactive CTL were capable
of completely preventing AML engraftment in these mice.
We conclude that the NOD/SCID/γc null HSCT model may be a valuable tool for
evaluating GVH and GVL immunity in vivo following donor T lymphocyte graft
modifications in vitro.
1 Wehler T and Nonn M, et al. Blood 2007;109:365-373