Thymus repopulation after allogeneic reconstitution in hematological malignancies.
OBJECTIVE
Active vaccination in the allogeneically reconstituted tumor-bearing host essentially requires donor T-cell tolerance. To create a basis for vaccination in the allogeneically reconstituted, lymphoma-bearing host, we elaborate a reconstitution protocol that supports thymus repopulation and tolerance induction.


METHODS
Myeloreductively conditioned, lymphoma-bearing mice were vaccinated after reconstitution with hematopoietic progenitor cells. Readout systems included recovery of donor-derived T cells, graft vs host disease (GVHD), anti-host and anti-lymphoma cytotoxicity, as well as tumor growth rate and tumor rejection.


RESULTS
In tumor-free mice, myeloreductive conditioning, together with natural killer cell depletion of the host and transfer of T cell-depleted bone marrow cells, allows reconstitution without severe GVHD. However, in hematological malignancies, donor-derived T-progenitor cells hardly immigrated into the thymus. As a consequence, the frequency of severe GVHD was significantly increased, which prohibited active vaccination. Thymus repopulation became improved by strengthening myeloreductive conditioning; by supporting thymocyte expansion via interleukin-7; and, most strongly, by a small dose of donor-derived CD4(+)CD8(+) thymocytes, which preferentially homed into the thymus. Active vaccination, in combination with this reconstitution protocol, did not strengthen GVHD, but significantly improved survival time and survival rate of lymphoma-bearing mice.


CONCLUSIONS
The negative impact of hematological malignancies on thymus repopulation and central tolerance induction can, at least in part, be corrected by application of a small number of donor-derived T-progenitor cells.
Zöller
Margot
M
Department of Tumor Progression and Tumor Defense, German Cancer Research Center, Heidelberg, Germany. m.zoeller@dkfz.de
Rajasagi
Mohini
M
Vitacolonna
Mario
M
Luft
Thomas
T
D000818:Animals; D005434:Flow Cytometry; D019337:Hematologic Neoplasms / Q000473:pathology*; D007377:Interleukin-3 / Q000008:administration & dosage; D015851:Interleukin-7 / Q000008:administration & dosage; D051379:Mice; D008807:Mice, Inbred BALB C; D013950:Thymus Gland / Q000473:pathology*
D007377:Interleukin-3; D015851:Interleukin-7