Normal donor bone marrow is superior to Flt3 ligand-mobilized bone marrow in prolonging heart allograft survival when combined with anti-CD40L (CD154).
Flt3 ligand (FL) administration markedly increases bone marrow (BM) stem cells and immature dendritic cells. We investigated the influence of CD40-CD40Ligand (CD154) pathway blockade on antidonor immunity, cytokine production, microchimerism and heart graft survival in BALB/c (H2d) recipients of fully allogeneic C57BL/10 (H2b) FL-mobilized BM (FL-BM) or normal BM. Anti-CD40L mAb strongly suppressed anti-donor T-cell proliferative responses in recipients of either normal or FL-BM, but was less efficient in inhibiting antidonor cytolytic T-cell (CTL) activity, especially in recipients of FL-BM. Interestingly, CD40L blockade was more effective in recipients of multiple compared with single donor BM infusions. Anti-donor cytokine responses revealed complete impairment of IFN-gamma, IL-4 and IL-10 production in recipients of normal BM and CD40L mAb. By contrast, and in agreement with the CTL data, mice given FL-BM retained ability to produce IFN-gamma CD40-CD40L blockade did not promote microchimerism, as evidenced by immunohistology and real time polymerase chain reaction. Nevertheless, anti-CD40L mAb enhanced heart allograft survival in recipients of FL-BM, but the effect was inferior to that achieved with normal BM. These data provide insight into the influence of growth factor-expanded donor BM and costimulation blockade on antidonor immune reactivity and transplant outcome. The comparatively poor outcome obtained using FL-BM plus anti-CD40L mAb in this model may be ascribed to the failure of effectively interdicting antidonor CTL activity.
Hackstein
Holger
H
Wang
Zhiliang
Z
Morelli
Adrian E
AE
Kaneko
Katsuhiko
K
Takayama
Takuya
T
Colvin
Bridget L
BL
Bein
Gregor
G
Thomson
Angus W
AW
D000818:Animals; D016026:Bone Marrow Transplantation / Q000276:immunology*; D023201:CD40 Ligand / Q000627:therapeutic use*; D005434:Flow Cytometry; D006085:Graft Survival / Q000187:drug effects / Q000276:immunology*; D016027:Heart Transplantation / Q000276:immunology*; D007165:Immunosuppression Therapy / Q000379:methods*; D008024:Ligands; D007959:Lymphocyte Culture Test, Mixed; D008565:Membrane Proteins / Q000627:therapeutic use*; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D016133:Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D013997:Time Factors; D014184:Transplantation, Homologous
D008024:Ligands; D008565:Membrane Proteins; C084881:flt3 ligand protein; D023201:CD40 Ligand