autologous blood and marrow transplantation - Blog Science ...

602 Chapter 11: Minitransplants
to be administered in the ambulatory care setting and may allow inclusion of older
patients currently not eligible for treatment with stem cell allografting.
INTRODUCTION
To have a successful hematopoietic stem cell (HSC) allograft, two immunologic
barriers must be crossed: the first consists of host-vs.-graft (HVG) and the second
is made up of graft-vs.-host (GVH) reactions. The high-dose conditioning regimens
whose primary goal has been to eradicate the patient's underlying disease—for
example, leukemia—also function to eliminate the HVG reaction by eradication of
the host's immune response. The patients experience pancytopenia from which
they are rescued by subsequent HSC allografts. The grafts also function to
eliminate any residual leukemia via GVH reactions. Conditioning regimens have
now been intensified to the point where organ toxicities are common, resulting in
morbidity and mortality. Because of potentially severe complications, the use of
transplantation has been restricted to relatively young patients at most transplant
centers. Additionally, the optimal postgrafting immunosuppression necessary for
control of GVHD often cannot be given to patients with organ toxicities such as
those of the liver or kidney. 1
To design effective conditioning regimens without excessive toxicity, four
factors were taken into consideration. First, observations by Burchenal et al., 2
who
found that murine leukemia could only be eradicated by several thousand
centigrays of TBI, indicated that some hematologic malignancies were incurable
with even the most intense conditioning regimens alone. Second, HSC allografts
not only rescue the patient from pancytopenia, but also provide a GVL effect which
is in part responsible for many of the observed cures, as predicted from the murine
studies of Barnes et al. 3
Weiden et al. published in 1979 4
and 1981 5
the landmark
papers describing GVH/GVL effects in human allograft recipients. This led to the
testing of donor buffy coat infusions to augment the GVL effect in marrow
allografts 6
and to the use of donor lymphocyte infusions as therapy for patients who
had relapsed after marrow allografting. 7
" 13
The third observation was that mixed
hematopoietic chimerism sufficed in some cases to "cure" inherited disorders such
as thalassemia major and sickle cell disease after conventional high-dose
conditioning. 1415
Last, HVG and GVH reactions are both mediated by T cells in the
MHC-identical setting. Therefore, we have investigated the hypothesis that
immunosuppression, primarily designed to prevent GVHD, can additionally be
used to suppress HVG, thereby facilitating allogeneic engraftment.
We have done studies in a canine model to test the hypothesis that the currently
used intensive cytoreductive conditioning therapy can be replaced by
nonmyelotoxic immunosuppression. Immunosuppression is directed first at host
cells before HSC transplant, and next at both donor and host cells after transplant.