Dog leukocyte antigen-haploidentical stem cell allografts after anti-CD44 therapy and nonmyeloablative conditioning in a preclinical canine model.
BACKGROUND
We previously described a reduced-intensity hematopoietic cell transplantation (HCT) regimen in dog leukocyte antigen (DLA)-haploidentical littermate recipients consisting of 450 cGy total body irradiation (TBI) and anti-CD44 monoclonal antibody (mAb) S5 before and mycophenolate mofetil (MMF)/cyclosporine (CSP) after HCT.


METHODS
We tested a nonmyeloablative regimen of mAb S5 and 200 cGy TBI with postgrafting MMF/CSP in 44 DLA-haploidentical recipients using eight different regimens. Ten dogs also received escalating doses of donor lymphocyte infusion (DLI) alone or with pentostatin to convert to complete donor chimerism.


RESULTS
All dogs achieved initial engraftment between one to two weeks after HCT with peripheral blood mononuclear cell (PBMC) donor chimerism ranging from 2% to 98% (median 37%) on day +35. Twenty-five (57%) dogs rejected their donor grafts at a median of seven (range; 1-19) weeks after HCT. Low levels of PBMC donor chimerism at three weeks predicted graft rejection. DLI neither facilitated conversion to full donor chimerism after HCT nor prevented rejection. Higher total nucleated cells, CD4+, CD8+, and CD14+ cell subset numbers in the PBMC graft were associated with stable full donor engraftment. Dogs given higher cell subset doses of infused PBMC achieved longer duration of mixed chimerism.


CONCLUSIONS
Nonmyeloablative conditioning with 200 cGy TBI and anti-CD44 mAb was sufficient for initial uniform engraftment across DLA haplotype-mismatched barriers. However, sustained donor engraftment was seen in only 43% of recipients. Graft composition and donor-dominant chimerism early after HCT may be the most important factors for sustained donor engraftment.
Fukuda
Takahiro
T
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
Kerbauy
Fabio R
FR
Gooley
Theodore
T
Santos
Erlinda B
EB
Storb
Rainer
R
Sandmaier
Brenda M
BM
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology* / Q000627:therapeutic use*; D002452:Cell Count; D002678:Chimera / Q000276:immunology; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D006084:Graft Rejection / Q000276:immunology / Q000517:prevention & control; D006086:Graft vs Host Disease / Q000276:immunology; D006238:Haploidy; D018380:Hematopoietic Stem Cell Transplantation; D018960:Hyaluronan Receptors / Q000276:immunology*; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007167:Immunotherapy; D007962:Leukocytes / Q000276:immunology* / Q000528:radiation effects; D023421:Models, Animal; D022423:Myeloid Cells / Q000166:cytology / Q000528:radiation effects; D013234:Stem Cells / Q000187:drug effects / Q000276:immunology*; D013997:Time Factors; D019172:Transplantation Conditioning; D014184:Transplantation, Homologous / Q000276:immunology
D000911:Antibodies, Monoclonal; D018960:Hyaluronan Receptors; D007166:Immunosuppressive Agents