An immunoablative regimen of fludarabine and cyclophosphamide prevents fully MHC-mismatched murine marrow graft rejection independent of GVHD

• Published in: Biology of blood and marrow transplantation Vol. 6; no. 2; pp. 182 - 189
• Main Authors: Petrus, Matthew J., Williams, Jonathan F., Eckhaus, Michael A., Gress, Ronald E., Fowler, Daniel H.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-01-2000
• Subjects: Animals; Antineoplastic Agents - therapeutic use; Bone Marrow Transplantation - adverse effects; Bone Marrow Transplantation - immunology; CD4-Positive T-Lymphocytes - drug effects; CD4-Positive T-Lymphocytes - radiation effects; CD8-Positive T-Lymphocytes - drug effects; CD8-Positive T-Lymphocytes - radiation effects; Cell Lineage; Cyclophosphamide - pharmacology; Disease Models, Animal; Graft Rejection - drug therapy; Graft Rejection - prevention & control; Graft vs Host Disease; Hematopoietic Stem Cells - drug effects; Hematopoietic Stem Cells - radiation effects; Histocompatibility - drug effects; Immunosuppressive Agents - therapeutic use; Lymphocyte Depletion; Mice; Mice, Inbred C57BL; Transplantation Chimera; Transplantation, Homologous; Vidarabine - analogs & derivatives; Vidarabine - pharmacology; Whole-Body Irradiation
• ISSN: 1083-8791; 1523-6536
• DOI: 10.1016/S1083-8791(00)70041-3

The prevention of graft rejection in the setting of nonmyeloablative transplant approaches might be mediated by chemotherapy-induced host immunoablation and by the graft-promoting effects of graft-versus-host disease (GVHD). To evaluate whether host immunoablation alone might allow for alloengraftment, we developed an F1-into-parent murine marrow rejection model using host preparative regimens of lethal total body irradiation (TBI; 950 cGy), sublethal irradiation (600 cGy), or combinations of fludarabine (Flu) and cyclophosphamide (Cy). A preparative regimen selectivity index (SI) was calculated to determine whether host lymphocytes were preferentially depleted relative to myeloid cells (SI = number of host myeloid/number host T lymphoid cells remaining after preparative regimen administration). Saline-treated recipients were assigned an SI value of 1.0. Recipients of lethal TBI had reduced myeloid cells relative to T cells (SI = 0.6). In contrast, all Flu/Cy regimens preferentially depleted host T cells: recipients of Flu (100 mg/kg per day)/Cy (50 mg/kg per day) for 10 days (SI = 28.1); recipients of Flu (100 mg/kg per day)/Cy (100 mg/kg per day) for 10 days (SI = 64.1); and recipients of Flu (100 mg/kg per day)/Cy (50 mg/kg per day) for 19 or 27 days (SI = 74.6). The 10-day regimen of Flu/Cy (50 mg/kg per day) did not severely reduce host T cell numbers, nor did it prevent F1 marrow rejection (<1% chimerism, n = 14). In contrast, the 10-day regimen of Flu/Cy (100 mg/kg per day) reduced T-cell numbers below that of lethal TBI recipients and prevented F1 marrow rejection (11.4% chimerism, n = 15); donor chimerism was predominant in lymphoid cells and was stable through day 240 post-BMT. Additionally, the 19- or 27-day regimen of Flu/Cy, which most selectively depleted host T cells, also prevented F1 marrow rejection (6.3% chimerism, n = 15). These results therefore demonstrate that optimized Flu-containing, immunoablative preparative regimens can prevent fully MHC-disparate marrow rejection independent of GVHD.
Biol Blood Marrow Transplant 2000;6(2A):182-9.