Anti-CD40L monoclonal antibodies can replace anti-CD4 monoclonal antibodies for the nonmyeloablative induction of mixed xenogeneic chimerism.
BACKGROUND
We have previously demonstrated that xenogeneic bone marrow engraftment and donor-specific tolerance can be induced in mice receiving anti-CD4, -CD8, -Thy-1.2, and -NK1.1 monoclonal antibodies (mAbs) on Days -6 and -1, 3 Gy total body irradiation (TBI), and 7 Gy thymic irradiation on Day 0, followed by injection of T-cell depleted (TCD) rat bone marrow cells. We have recently demonstrated that anti-CD40L mAb treatment is sufficient to completely overcome CD4 cell-mediated resistance to allogeneic marrow engraftment and rapidly induce CD4 cell tolerance in an allogeneic combination.


METHODS
We investigated the ability of anti-CD40L mAb to promote mixed xenogeneic chimerism and donor-specific tolerance in B6 mice receiving anti-CD8, -Thy1.2 and -NK1.1 mAbs and 3 Gy TBI followed by TCD bone marrow transplantation (BMT) from F344 rats.


RESULTS
Administration of anti-CD4 mAb in this model could be completely replaced by one injection of anti-CD40L mAb. Evidence for deletional tolerance was obtained in mixed chimeras prepared with this anti-CD40L-based regimen. However, anti-NK1.1 and anti-Thy1.2 mAb could not be replaced by anti-CD40L mAb.


CONCLUSIONS
These results demonstrate that anti-CD40L in combination with xenogeneic BMT can tolerize preexisting peripheral and intrathymic CD4 cells to xenoantigens. However, anti-CD40L does not prevent NK cell and/or gammaDelta cell-mediated rejection of xenogeneic bone marrow.
Ito
Hiroshi
H
Bone Marrow Transplantation Section, Transplantation Biology Research Center, Massachusetts General Hospital/Harvard Medical School, Boston, 02129, USA.
Takeuchi
Yasuo
Y
Shaffer
Juanita
J
Sykes
Megan
M
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D016026:Bone Marrow Transplantation / Q000276:immunology*; D015704:CD4 Antigens / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D023201:CD40 Ligand / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D005260:Female; D005434:Flow Cytometry; D051379:Mice; D008810:Mice, Inbred C57BL; D051381:Rats; D011916:Rats, Inbred F344; D016038:Skin Transplantation / Q000276:immunology*; D018183:Transplantation Chimera / Q000276:immunology*; D014183:Transplantation, Heterologous / Q000276:immunology*; D014916:Whole-Body Irradiation
D000911:Antibodies, Monoclonal; D015704:CD4 Antigens; D023201:CD40 Ligand