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Title: Enhancement of bone marrow allografts from nude mice into mismatched recipients by T cells void of graft-versus-host activity

Abstract

Transplantation of 8 x 10(6) C57BL/6-Nu+/Nu+ (nude) bone marrow cells into C3H/HeJ recipients after conditioning with 8 Gy of total body irradiation has resulted in a markedly higher rate of graft rejection or graft failure compared to that found in recipients of normal C57BL/6 or C57BL/6-Bg+/Bg+ (beige) T-cell-depleted bone marrow. Mixing experiments using different numbers of nude bone marrow cells with or without mature thymocytes (unagglutinated by peanut agglutinin) revealed that engraftment of allogeneic T-cell-depleted bone marrow is T-cell dependent. To ensure engraftment, a large inoculum of nude bone marrow must be supplemented with a trace number of donor T cells, whereas a small bone marrow dose from nude donors requires a much larger number of T cells for engraftment. Marked enhancement of donor type chimerism was also found when F1 thymocytes were added to nude bone marrow cells, indicating that the enhancement of bone marrow engraftment by T cells is not only mediated by alloreactivity against residual host cells but may rather be generated by growth factors, the release of which may require specific interactions between T cells and stem cells or between T cells and bone marrow stroma cells.

Authors:
; ; ; ; ;  [1]
  1. (Weizmann Institute of Science, Rehovot (Israel))
Publication Date:
OSTI Identifier:
6703946
Resource Type:
Journal Article
Resource Relation:
Journal Name: Proceedings of the National Academy of Sciences of the United States of America; (USA); Journal Volume: 87:12
Country of Publication:
United States
Language:
English
Subject:
63 RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTANT EFFECTS ON LIVING ORGS. AND BIOL. MAT.; BONE MARROW CELLS; TRANSPLANTS; LYMPHOCYTES; BIOLOGICAL FUNCTIONS; GRAFT-HOST REACTION; LECTINS; MICE; RADIATION CHIMERAS; STEM CELLS; SURVIVAL TIME; THYMOCYTES; WHOLE-BODY IRRADIATION; ANIMAL CELLS; ANIMALS; BIOLOGICAL MATERIALS; BLOOD; BLOOD CELLS; BODY FLUIDS; CHIMERAS; CONNECTIVE TISSUE CELLS; EXTERNAL IRRADIATION; FUNCTIONS; IRRADIATION; LEUKOCYTES; MAMMALS; MATERIALS; MOSAICISM; RODENTS; SOMATIC CELLS; VERTEBRATES 560152* -- Radiation Effects on Animals-- Animals

Citation Formats

Lapidot, T., Lubin, I., Terenzi, A., Faktorowich, Y., Erlich, P., and Reisner, Y.. Enhancement of bone marrow allografts from nude mice into mismatched recipients by T cells void of graft-versus-host activity. United States: N. p., 1990. Web. doi:10.1073/pnas.87.12.4595.
Lapidot, T., Lubin, I., Terenzi, A., Faktorowich, Y., Erlich, P., & Reisner, Y.. Enhancement of bone marrow allografts from nude mice into mismatched recipients by T cells void of graft-versus-host activity. United States. doi:10.1073/pnas.87.12.4595.
Lapidot, T., Lubin, I., Terenzi, A., Faktorowich, Y., Erlich, P., and Reisner, Y.. 1990. "Enhancement of bone marrow allografts from nude mice into mismatched recipients by T cells void of graft-versus-host activity". United States. doi:10.1073/pnas.87.12.4595.
@article{osti_6703946,
title = {Enhancement of bone marrow allografts from nude mice into mismatched recipients by T cells void of graft-versus-host activity},
author = {Lapidot, T. and Lubin, I. and Terenzi, A. and Faktorowich, Y. and Erlich, P. and Reisner, Y.},
abstractNote = {Transplantation of 8 x 10(6) C57BL/6-Nu+/Nu+ (nude) bone marrow cells into C3H/HeJ recipients after conditioning with 8 Gy of total body irradiation has resulted in a markedly higher rate of graft rejection or graft failure compared to that found in recipients of normal C57BL/6 or C57BL/6-Bg+/Bg+ (beige) T-cell-depleted bone marrow. Mixing experiments using different numbers of nude bone marrow cells with or without mature thymocytes (unagglutinated by peanut agglutinin) revealed that engraftment of allogeneic T-cell-depleted bone marrow is T-cell dependent. To ensure engraftment, a large inoculum of nude bone marrow must be supplemented with a trace number of donor T cells, whereas a small bone marrow dose from nude donors requires a much larger number of T cells for engraftment. Marked enhancement of donor type chimerism was also found when F1 thymocytes were added to nude bone marrow cells, indicating that the enhancement of bone marrow engraftment by T cells is not only mediated by alloreactivity against residual host cells but may rather be generated by growth factors, the release of which may require specific interactions between T cells and stem cells or between T cells and bone marrow stroma cells.},
doi = {10.1073/pnas.87.12.4595},
journal = {Proceedings of the National Academy of Sciences of the United States of America; (USA)},
number = ,
volume = 87:12,
place = {United States},
year = 1990,
month = 6
}
  • Studies were performed to determine whether pre-T cells develop normally in the bone marrow of mice displaying thymic dysplasia and T cell immunodeficiency as a consequence of a graft-versus-host (GVH) reaction. GVH reactions were induced in CBAxAF1 mice by the injection of A strain lymphoid cells. To test for the presence of pre-T cells in GVH-reactive mice, bone marrow from GVH-reactive mice (GVHBM) was injected into irradiated syngeneic F1 mice and 30-40 days later thymic morphology and function were studied. Morphology studies showed nearly normal thymic architectural restoration; moreover, such glands contained normal numbers of Thy-1-positive cells. Functional pre-T cellsmore » were evaluated by transferring thymocytes from the irradiated GVHBM-reconstituted mice into T-cell-deprived mice. These thymocytes reconstituted allograft reactivity, T helper cell function and Con A and PHA mitogen responses of T-cell-deprived mice. These results suggest that the pre-T cell population in the bone marrow is not affected by the GVH reaction. Therefore, the T cell immunodeficiency associated with the GVH reaction is not due to a deficiency of pre-T cells in the bone marrow but is more likely associated with GVH-induced thymic dysplasia.« less
  • Heat-killed BCG in paraffin exerted a lethal effect on C57BL/6 mice irradiated lethally and transferred with syngeneic bone marrow cells. Such an effect was not detectable when mice were subjected to adult thymectomy and used as the hosts. Lymphoid cells from such nonthymectomized mice exhibited cytotoxicity to syngeneic tumor cells but not to allogeneic tumor cells in an in vivo cytotoxicity test and induced splenomegaly in sublethally irradiated syngeneic recipients after systemic transfer. The cytotoxicity of such lymphoid cells was abolished by a treatment with anti-theta serum and complement. In the bone marrow of mice irradiated and transferred with bonemore » marrow cells, the number of nucleated cells, the ratio of mycloid to erythroid cell series, and the percentage of lymphocytes were increased by BCG injection. These results suggest the possibility that self-tolerance may be broken by BCG injection. These results suggest the possibility that self-tolerance may be broken by BCG stimulation in the process of reconstitution of lymphoid cells in the irradiated mice.« less
  • The report describes a subacute syndrome consisting of anorexia, mouth ulcers, abdominal pain, and diarrhea which occurred in three allogenic transplant recipients which appears to be distinct from the usual patterns of acute or chronic graft-versus-host disease (GVHD). The patient with myelomonocytic leukemia was treated with cyclophosphamide (60 mg/kg) i.v. 4 and 3 days before and total body X irradiation to 800 rad 1 day before transplantation. The radiation was administered from a 6-Mev source at least 3.5 m from the patient via opposing lateral fields. The patients were maintained in the protected environment until their absolute neutrophil counts (ANC)more » became greater than 1000/mm/sup 3/. All blood products were irradiated (1500 rad) prior to transfusion. Methotrexate was administered weekly for 100 days to prevent GVHD. (JMT)« less
  • The graft-versus-host (GVH) reaction induces thymic dysplasia and an arrest in T cell differentiation. Studies were performed to test the effect of irradiation and reconstitution with bone marrow on GVH-induced thymic dysplasia and T cell differentiation. GVH reactions were induced in CBAxAF1 adult mice by the injection of A strain lymphoid cells. All GVH-reactive mice were immunosuppressed by day 7 after GVH induction and thymic dysplasia was evident by day 24. Forty days after the induction of the GVH reaction the mice were irradiated (850 rads) and repopulated with 10-15 X 10(6) syngeneic or parental bone marrow cells. Thirty daysmore » after irradiation and bone marrow reconstitution, GVH-reactive mice were used for histological and functional studies. These mice displayed near-normal thymus morphology with scattered epithelial cells in the medulla, and normal numbers of Thy-1-positive cells. Donor cells had totally repopulated thymuses of irradiated bone marrow reconstituted mice by day 19 after irradiation. T helper cell function did not recover in the reconstituted mice. These results suggest that (1) the process responsible for GVH-induced thymic dysplasia is radiosensitive, and (2) the thymus has the potential to regenerate a normal structure, but fails to regain normal function.« less
  • The proliferative capacity of bone marrow cells from thymusdeprived nude mice was investigated in lethally irradiated recipients. Although the colony- forming capacity of these cells was found to be similar to that of normal littermates, a reduction in the number of nucleated cells was observed in the bone marrow of nude mice. Moreover when the radioprotective effect of such cells was studied, 5 x 10/sup 5/ or 2 x 10/sup 6/ bone marrow cells from nude mice were less effective in restoring hemopoiesis and establishing permanent chimerism than similar amounts of bone marrow cells of normal controls. In addition, irradiatedmore » animals surviving after injection of bone marrow cells from nude mice were found to have lower immune responses to SRBC than normal chimeras. The possibility that mortality of irradiated recipients injected with bone marrow of nude mice is due to the presence of a latent infective agent or of some inhibitory factor of hematopoiesis in the bone marrow of such nude mice is shown to be improbable. Alternatively it is suggested that nude mice suffer from an intrinsic defect in the proliferatlve capacity of their bone marrow colony-forming cells (CFUs). (auth)« less