Tbi Dose Deescalation In The Dlaidentical Dog Model

In the preclinical canine dog leukocyte antigen (DLA)-identical transplant model, a dose-response relationship with respect to TBI and allogeneic marrow engraftment has been demonstrated (Table 96.2). A

aMixed or full chimerism.

bGranulocyte colony-stimulating factor mobilized peripheral blood mononuclear cells.

single TBI dose of 9.2 Gy was sufficiently immunosuppressive to allow engraftment of DLA-identical littermate marrow in 95% of dogs not given postgrafting immunosuppression.28 When the dose was decreased to 4.5 Gy, only 41% of dogs had stable engraftment.29 When dogs were given 4.5 Gy TBI and posttransplant prednisone, none engrafted.29 However, the addition of postgrafting CSP for 5 weeks led to engraftment in all animals studied.29 When the TBI dose was further decreased to 2 Gy, postgrafting immunosuppression, either with CSP alone or with a combination of CSP and methotrexate (MTX), resulted in graft rejection with autologous recovery in the majority of the dogs.30 On the other hand, a postgrafting immunosuppressive regimen combining CSP and MMF lead to the development of stable mixed chimerism in 11 of 12 dogs studied.30 However, when the TBI dose was further decreased to 1 Gy, stable long-term engraftment did not occur, demonstrating a delicate balance between host and donor cells.30 More recently, the combination of rapamycin (sirolimus) and CSP was found to be as effective as MMF/CSP in dogs given DLA-identical marrow followed by 2 Gy TBI (Figure 96.1).31 However, here again, stable long-term engraftment did not occur when the TBI dose was further decreased to 1 Gy.31

There is some evidence that the rejections observed after 1 Gy TBI are due to immune-mediated host antigraft reactions. First, stable mixed chimerism could be achieved after only 1 Gy TBI by reducing the intensity of host immune responsiveness before HCT with the help of the fusion peptide, CTLA4-Ig, which blocks T-cell costim-ulation through the B7-CD28 signal pathway.33 Second, o

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