Blood, Vol. 96 No. 3 (August 1), 2000:
pp. 1166-1172
A novel application of cyclosporine A in
nonmyeloablative pretransplant host conditioning for allogeneic BMT
Boris Nikolic,
Guiling Zhao,
Kirsten Swenson, and
Megan Sykes
From the Bone Marrow Transplantation Section, Transplantation
Biology Research Center, Surgical Service, Massachusetts General
Hospital/Harvard Medical School, Boston, MA.
The treatment of mice with anti-CD4 and anti-CD8 monoclonal
antibodies (mAbs) on day 
5, plus 3 Gy whole body irradiation (WBI)
and 7 Gy thymic irradiation (TI) on day 0, allows fully major-histocompatibility-complex-mismatched allogeneic bone marrow engraftment and the induction of immunologic tolerance. TI is required
in this model to overcome alloreactivity and possibly to make
"space" in the recipient thymus so that lasting central tolerance
can be achieved. In addition to suppressing mature T cells in the
periphery, Cyclosporine A (CYA) and glucocorticoids have a
powerful influence on the thymus. In this study, we evaluated whether
the administration of CYA to recipient mice for 12 days prior to bone
marrow transplant (BMT), of glucocorticosteroids on the day of BMT, or
a combination of both, could create space and overcome alloresistance
in the thymus by specifically depleting immature and mature thymocytes
prior to BMT. High levels of multilineage donor hematopoietic
repopulation and specific transplantation tolerance were achieved in
mice treated from days 15 to 3 with CYA (20 mg/kg/d
subcutaneously), anti-CD4/CD8 mAbs on day 5, followed by 3 Gy WBI
and 15 × 106 allogeneic bone marrow cells
on day 0. V
analysis suggested a central deletional tolerance
mechanism. The same treatment without CYA pretreatment allowed only
transient chimerism, without tolerance. Corticosteroid treatment
abolished the engraftment-promoting and tolerance-inducing effects of
CYA. These results demonstrate a novel pretransplantation-only
application of CYA, which facilitates allogeneic marrow engraftment
with minimal conditioning, by creating thymic space and/or overcoming
intrathymic alloresistance.
