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Striking augmentation of hematopoietic cell chimerism in noncytoablated allogeneic bone marrow recipients by flt3 ligand and tacrolimus

Iyengar, AR and Bonham, CA and Antonysamy, MA and Subbotin, VM and Khanna, A and Murase, N and Rao, AS and Starzl, TE and Thomson, AW (1997) Striking augmentation of hematopoietic cell chimerism in noncytoablated allogeneic bone marrow recipients by flt3 ligand and tacrolimus. Transplantation, 63 (9). 1193 - 1199. ISSN 0041-1337

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Abstract

The influence of granulocyte-macrophage colony-stimulating factor (GM- CSF) and the recently identified hematopoietic stem-progenitor cell mobilizing factor flt3 ligand (FL) on donor leukocyte microchimerism in noncytodepleted recipients of allogeneic bone marrow (BM) was compared. B10 mice (H2 b ) given 50 x 10 6 allogeneic (B10.BR [H2(k)]) BM cells also received either GM-CSF (4 μg/day s.c.), FL (10 μg/day i.p.), or no cytokine, with or without concomitant tacrolimus (formerly FK506; 2 mg/kg) from day 0. Chimerism was quantitated in the spleen 7 days after transplantation by both polymerase chain reaction (donor DNA [major histocompatibility complex class II; I-E(k)] ) and immunohistochemical (donor [I-E(k+)] cell) analyses. Whereas GM-CSF alone significantly augmented (fivefold) the level of donor DNA in recipients' spleens, FL alone caused a significant (60%) reduction. Donor DNA was increased 10-fold by tacrolimus alone, whereas coadministration of GM-CSF and tacrolimus resulted in a greater than additive effect (28-fold increase). A much more striking effect was observed with FL + tacrolimus ( > 125-fold increase in donor DNA compared with BM alone). These findings were reflected in the relative numbers of donor major histocompatibility complex class II + cells (many resembling dendritic cells) detected in spleens, although quantitative differences among the groups were less pronounced. Evaluation of cytotoxic T lymphocyte generation by BM recipients' spleen cells revealed that FL alone augmented antidonor immunity and that this was reversed by tacrolimus. Thus, although FL may potentiate antidonor reactivity in nonimmunosuppressed, allogeneic BM recipients, it exhibits potent chimerism-enhancing activity when coadministered with recipient immunosuppressive therapy. This property of FL may offer considerable potential for the augmentation of microchimerism, with therapeutic implications for organ allograft survival and tolerance induction.


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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Iyengar, AR
Bonham, CA
Antonysamy, MA
Subbotin, VM
Khanna, A
Murase, N
Rao, AS
Starzl, TEtes11@pitt.eduTES11
Thomson, AW
Centers: Other Centers, Institutes, or Units > Thomas E. Starzl Transplantation Institute
Date: 15 May 1997
Date Type: Publication
Journal or Publication Title: Transplantation
Volume: 63
Number: 9
Page Range: 1193 - 1199
DOI or Unique Handle: 10.1097/00007890-199705150-00001
Institution: University of Pittsburgh
Refereed: Yes
ISSN: 0041-1337
Other ID: uls-drl:31735062134253, Starzl CV No. 1968
Date Deposited: 08 Apr 2010 17:33
Last Modified: 13 Oct 2017 17:55
URI: http://d-scholarship.pitt.edu/id/eprint/5354

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