autologous blood and marrow transplantation - Blog Science ...

Sandmaier et al. 607
interactions of immune function, whereas DR is an MHC class II molecule
involved in alloantigen recognition, and mAbs against these molecules have proven
useful in marrow allografting. Table 5 summarizes data in MHC-nonidentical
unrelated recipients conditioned with 920 cGy TBI. Pretreatment with an irrelevant
mAb 6.4 was ineffective in promoting engraftment, whereas significant increases
in engraftment were seen with mAbs directed against CD44, DR, and CD 18,
although none of the mAbs was uniformly successful in achieving that goal.
Nevertheless, the fact that recipient treatment with relatively small doses of mAb
modified recipient immunity sufficiently for engraftment to occur in a majority of
dogs was encouraging. The exact mechanisms of action by which mAbs improve
engraftment have not yet been determined, although as far as mAb S5 (anti-CD44)
is concerned, in vitro studies have shown that it interfered with the function of
natural killer (NK) cells. 2728
In turn, NK cells are known to mediate rejection of
MHC-mismatched grafts in the canine model. 29
' 30
Not surprisingly, S5 failed to
enhance grafts from MHC-matched littermates after 4.5 Gy TBI, 31
the notion that T cells and not NK cells reject MHC-matched grafts. 32
consistent with
TOWARD NONMYELOABLATTVE REGIMENS FOR TRANSPLANTATION
OF MHC-MISMATCHED MARROW
In recipients of PBSC grafts from MHC-haploidentical littermates, rejection
uniformly occurred when the radiation dose was lowered from 920 to 450 cGy.
When the recipients were given postgrafting immunosuppression with MMF/CSP,
half of the dogs had sustained donor engraftment (unpublished data). When
antibody S5 directed at CD44 was used in addition to MMF/CSP, virtually all dogs
had sustained allogeneic engraftment (unpublished data).
MIXED CHIMERISM IN THE TREATMENT OF HEMATOLOGIC DISEASES:
SEVERE CANINE HEREDITARY HEMOLYTIC ANEMIA
Based on previous studies, it is known that severe canine hereditary hemolytic
anemia due to pyruvate kinase deficiency can be corrected by conventional HSC
transplants from healthy littermates following a conventional high-dose
conditioning regimen. 33,34
Furthermore, the severe hepatic iron overload that
existed before transplant regressed over time after transplant. The preclinical
findings in this model encouraged the application of HSC transplants to the
treatment of patients with beta-thalassemia [35].
Canine hereditary hemolytic anemia represents an ideal model to test the
hypothesis that mixed chimerism can correct phenotypic manifestations of the
genetic disease. Accordingly, a 5-year-old Basenji dog with pyruvate kinase
deficiency was given 200 cGy TBI before, and MMF/CSP after, a marrow