Facilitation of engraftment of DLA-nonidentical marrow by treatment of recipients with monoclonal antibody directed against marrow cells surviving radiation.
Past studies in dogs have suggested that marrow graft rejection was mediated by major histocompatibility complex (MHC) class II antigen-positive non-T cells that survived standard doses of total-body irradiation (TBI). We have now raised 4 monoclonal antibodies (mAbs) against marrow cells harvested 6 days after TBI. The mAbs are highly reactive (greater than 70%) with marrow cells surviving radiation and also bind strongly (greater than 50%) to normal marrow cells, lymphocytes, monocytes, and granulocytes. One of the mAbs (34-S3) reacted strongly with NK-like cells. In vitro treatment of marrow with mAb and rabbit complement (C') did not affect erythroid colony-forming unit (CFU-E) growth, whereas 2 of the 4 mAbs inhibited granulocyte-macrophage colony-forming unit (CFU-GM) growth, and all 3 mAbs tested suppressed autologous marrow engraftment. One of the mAbs, 69-S5 (IgG1), bound to a 95,000 dalton antigen. It crossreacted with human cells, but not with cells from Rhesus monkeys, baboons, and cats. We administered this mAb intravenously at 0.2 mg/kg/day on days -5 to 0 to dogs given 9.2 Gy TBI on day 0 followed by marrow grafts (less than or equal to 4 x 10(8) cells/kg) from DLA-nonidentical unrelated donors. Three of five dogs had sustained grafts. Increasing the dose of mAb ten-fold (2 mg/kg/day) resulted in graft failure (2 of 2 dogs). Treatment with a dose of 0.2 mg/kg/day from day -7 to -2 showed sustained engraftment in 7 of 10 dogs. This result is in contrast to sustained grafts in 3 of 36 dogs not given mAb, and in 1 of 7 dogs treated with an irrelevant mAb (P = 0.0002 and 0.04, respectively). We conclude that treatment of recipients with a mAb raised against marrow cells surviving radiation and not directed at major histocompatibility complex (MHC) class II antigens and NK-like cells can also facilitate engraftment of DLA-nonidentical canine marrow. These results may be relevant for the transplantation of HLA-incompatible marrow in man, particularly after in vivo T cell depletion, where graft failure is frequent.
Schuening
F
F
Division of Oncology, Fred Hutchinson Cancer Research Center, Seattle, Washington 98104.
Storb
R
R
Goehle
S
S
Meyer
J
J
Graham
T C
TC
Deeg
H J
HJ
Appelbaum
F R
FR
Sale
G E
GE
Graf
L
L
Loughran
T P
TP
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000627:therapeutic use*; D001853:Bone Marrow / Q000276:immunology / Q000528:radiation effects; D016026:Bone Marrow Transplantation; D003429:Cross Reactions; D004285:Dogs; D004306:Dose-Response Relationship, Immunologic; D004912:Erythrocytes; D006098:Granulocytes; D006412:Hematopoietic Stem Cells; D006649:Histocompatibility Antigens / Q000276:immunology*; D015395:Histocompatibility Antigens Class I; D007694:Killer Cells, Natural / Q000276:immunology; D008264:Macrophages; D014916:Whole-Body Irradiation
D000911:Antibodies, Monoclonal; D006649:Histocompatibility Antigens; D015395:Histocompatibility Antigens Class I; C039692:histocompatibility antigen DLA