Allogeneic mixed chimerism induced by non-myeloablative regimen consisting of co-stimulatory blockade-based minimum intensity conditioning and BMT achieved curative functional reconstitution in X-CGD mouse model

Ref ID: 18594

Author:

Y. Takeuchi (1), M. Otsu (1), E. Takeuchi (2), M. Higashihara
(2), M. Abe (3), H. Nakauchi (1)

Author address:

(1)University of Tokyo (Minato-Ku, JP); (2)Kitasato University
School of Medicine (Sagamihara, JP); (3)Kitasato University
(Sagamihara, JP)

Full conference title:

Annual Meeting of the EBMT, 36th

Abstract:

Background: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is useful for treatment of life-threatening,
non-malignant disease. The procedures, however, inevitably involve substantial risks including, 1) conditioning toxicity, 2) graft rejection, 3) graft-versus-host disease (GvHD).
To develop a safe and effective strategy, we have designed
non-myeloablative regimen consisting of anti-CD40Ligand
monoclonal antibody (aCD40LmAb)-based minimum conditioning with allogeneic bone marrow transplantation (alloBMT). X-linked chronic granulomatous disease (X-CGD) is a
primary immunodefi ciency characterized by functional defects
in phagocytes: affected cells are unable to kill microorganisms due to defective NADPH oxidase. Although allo-HSCT is
considered a promising therapy for X-CGD, curative long-term
reconstitution of granulocytes has not been established. Thus,
we attempted our regimen as a promising treatment option for
X-CGD mouse model.
Methods: X-CGD F1 (H-2
b + d
) mice were received 20 x 10
6
of
BCF1 (H-2
b + k
) bone marrow cells. 3 Gy TBI on day -1 and
aCD40LmAb (2 mg) on day 0 to BMT was given. The degree of
donor chimerism and functional reconstitution of granulocytes
with production of specifi c reactive oxygen species (sROS)
using APF fl uorescence staining in peripheral blood was followed by fl owcytometric analysis. Therapeutic effect was investigated using enhanced cutaneous infl ammatory reactions to
subcutaneous injection of Aspergillus Fumigatus (AF) hyphae.
Results: This strategy allowed induction of long-term (> 6 months),
multi-lineage mixed chimerism (donor B cell; 62.9 ± 19.1% at
24 wks) in 18 of 20 X-CGD mice. No clinical signs of GVHD were
shown. Granulocytes with production of sROS were reconstituted in chimeric X-CGD mice (APF
positive granulocytes
; 65.3 ± 20.7%
at 24 wks). Subcutaneous accumulation of granulocytes,
appearing granulomatous formation to AF hyphae was apparent
in non-chimeric X-CGD mice, while it was improved in chimeric
X-CGD mice.
Conclusion: aCD40LmAb-based minimum conditioning with
allo-BMT is a promising treatment option for X-CGD without
GVHD. This strategy may be applicable for other intractable
disorders.

Abstract Number: P894

Conference Year: 2010

Link to conference website: NULL

New link: NULL

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