Influence of alloreactive T cells on initial hematopoietic reconstitution after marrow transplantation.
One possible mechanism by which donor T cells might facilitate allogeneic marrow engraftment is through the production of lymphokines or cytokines that promote proliferation and differentiation of hematopoietic stem cells. To address this hypothesis, we have tested whether alloactivated donor T cells can accelerate initial engraftment in mice when limiting numbers of marrow cells were given to recipients in parent-->F1 strain combinations where rejection is not a limiting factor. Lethally irradiated (11 Gy) F1 recipients were transplanted with grafts composed of 1 x 10(6) T cell-depleted parental marrow cells with no T cells added or with 1 to 2 x 10(6) purified CD3+ parental or F1 lymph node cells added. Parental T cells capable of causing graft-vs.-host disease (GVHD) slowed the rate of initial engraftment, as measured by the number of nucleated cells in the marrow between 7- and 14-days posttransplantation, while F1 T cells had no effect compared to controls transplanted without T cells in the graft. Both F1 and parental T cells caused an increase in peripheral blood leukocyte counts first apparent at 2 weeks posttransplantation. Splenic erythropoiesis as measured by 59Fe incorporation was not affected by either parental or F1 T cells during the first 2 weeks posttransplantation. The slower marrow reconstitution in recipients transplanted with parental T cells may have several explanations that are not mutually exclusive. Elaboration of tumor necrosis factor (TNF), interferon-gamma (INF-gamma), or transforming growth factor-beta (TGF-beta) by activated T cells may directly inhibit hematopoiesis or may interfere with the production of another cytokine necessary for hematopoiesis. Inflammatory mediators elaborated during the initiation of GVHD may also promote early mobilization of cells from the marrow into the blood. Finally, GVHD could cause damage to the hematopoietic microenvironment.
Martin
P J
PJ
Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA 98104.
D000818:Animals; D016026:Bone Marrow Transplantation / Q000276:immunology / Q000502:physiology*; D005260:Female; D006410:Hematopoiesis / Q000276:immunology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D013601:T-Lymphocytes / Q000502:physiology*