Dog leukocyte antigen-haploidentical stem cell allografts after anti-CD44 therapy and reduced-intensity conditioning in a preclinical canine model.
OBJECTIVE
We previously described a nonmyeloablative hematopoietic stem cell transplantation regimen in dog leukocyte antigen (DLA)-identical littermate recipients consisting of low-dose total body irradiation (TBI) before and mycophenolate mofetil (MMF)/cyclosporine (CSP) given after transplant to control both graft-vs-host and residual host-vs-graft reactions. In this study, we sought to develop a reduced-intensity regimen to achieve engraftment across major histocompatibility complex barriers in DLA-haploidentical littermate recipients.


METHODS
We tested a regimen of 450-cGy TBI with or without postgrafting MMF/CSP for 28 and 35 days, respectively, and with the administration of monoclonal antibody (mAb) S5 (anti-CD44), at a dose of 0.2 mg/kg/day from days -7 through -2, prior to receiving TBI.


RESULTS
One of six dogs conditioned with 450-cGy TBI alone achieved engraftment of granulocyte colony-stimulating factor-mobilized peripheral blood stem cells. Three of six dogs achieved sustained donor cell engraftment using 450-cGy TBI and posttransplantation MMF/CSP. None of three dogs given mAb S5 followed by 450-cGy TBI showed signs of donor cell engraftment. However, when S5 mAb pretreatment was added to 450-cGy TBI and postgrafting MMF/CSP, 10 of 12 dogs achieved sustained engraftment (p = 0.008 or 0.007 vs 450-cGy alone or to S5 + 450-cGy TBI without MMF/CSP, respectively), with only three dogs developing severe graft-vs-host disease on this short regimen of immunosuppression.


CONCLUSIONS
These results show that engraftment across a DLA haplotype-mismatched barrier can be achieved after reduced-intensity conditioning when mAb S5 directed at CD44 is added to this regimen.
Sandmaier
Brenda M
BM
Clinical Research Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue N., D1-100, PO Box 19024, Seattle, WA 98109-1024, USA. bsandmai@fhcrc.org
Fukuda
Takahiro
T
Gooley
Theodore
T
Yu
Cong
C
Santos
Erlinda B
EB
Storb
Rainer
R
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D003131:Combined Modality Therapy; D016572:Cyclosporine / Q000008:administration & dosage; D004285:Dogs; D006085:Graft Survival / Q000187:drug effects / Q000528:radiation effects; D006680:HLA Antigens / Q000235:genetics / Q000276:immunology*; D006239:Haplotypes / Q000276:immunology; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D018960:Hyaluronan Receptors / Q000276:immunology*; D023421:Models, Animal; D009173:Mycophenolic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives; D019172:Transplantation Conditioning / Q000379:methods*; D014181:Transplantation Immunology / Q000187:drug effects / Q000528:radiation effects; D014184:Transplantation, Homologous / Q000276:immunology / Q000379:methods; D016896:Treatment Outcome; D014916:Whole-Body Irradiation
D000911:Antibodies, Monoclonal; D006680:HLA Antigens; D018960:Hyaluronan Receptors; D016572:Cyclosporine; D009173:Mycophenolic Acid