High dose bone marrow transplantation induces deletion of antigen-specific T cells in a Fas-independent manner.

Abstract:

BACKGROUND:Monoclonal antibody induced tolerance to high doses of multiple lymphocyte stimulating (MLS)+minor mismatched bone marrow has recently been associated with clonal deletion, as reported in fully allogeneic models of bone marrow transplantation. FasL-induced apoptosis has been shown to mediate antigen-specific T cell deletion after antigenic stimulation in wild-type and T cell receptor transgenic mice. Therefore, we investigate a role for the Fas pathway in deletional tolerance to high dose bone marrow. METHODS:Fas mutant and control mice (H-2k, MLS-1b) were tolerized under the cover of monoclonal antibodies to high dose (5 x 10(7) cells) AKR (H-2k, MLS-1a) bone marrow. Tolerance was confirmed by AKR skin grafting after antibody clearance. Antigen-reactive cell deletion was monitored by Vbeta6+ T cell elimination, measured by flow cytometry of peripheral blood throughout the experiment. Donor T cell (Thy1.1+) chimerism was assessed in a similar manner. RESULTS:Fas mutant mice infused with high dose AKR bone marrow under the cover of antibody were tolerant, as demonstrated by indefinite survival of AKR skin grafts. When high levels of donor cell chimerism were established in Fas mutant mice, peripheral deletion of antigen-reactive cells was observed to be independent of signaling through Fas. CONCLUSIONS:Apoptosis mediated by Fas receptor signaling is not the mechanism of clonal deletion of antigen-reactive cells after antibody facilitated high dose marrow transplantation. However, the Fas mutation does impair the development of adequate donor chimerism.

journal_name

Transplantation

journal_title

Transplantation

authors

Honey K,Bemelman F,Cobbold SP,Waldmann H

doi

10.1097/00007890-200004270-00025

subject

Has Abstract

pub_date

2000-04-27 00:00:00

pages

1676-82

issue

8

eissn

0041-1337

issn

1534-6080

journal_volume

69

pub_type

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